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1. Genetically encoded tools for measuring and manipulating metabolism

Author

Choe, Mangyu and Titov, Denis V

Subjects
Biochemistry and Cell Biology, Biological Sciences, Substance Misuse, Nutrition, Animals, Humans, Ion Channels, Signal Transduction, Medicinal and Biomolecular Chemistry, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Over the past few years, we have seen an explosion of novel genetically encoded tools for measuring and manipulating metabolism in live cells and animals. Here, we will review the genetically encoded tools that are available, describe how these tools can be used and outline areas where future development is needed in this fast-paced field. We will focus on tools for direct measurement and manipulation of metabolites. Metabolites are master regulators of metabolism and physiology through their action on metabolic enzymes, signaling enzymes, ion channels and transcription factors, among others. We hope that this Perspective will encourage more people to use these novel reagents or even join this exciting new field to develop novel tools for measuring and manipulating metabolism.

Published
2022

2. Listeria monocytogenes requires cellular respiration for NAD+ regeneration and pathogenesis

Author

Rivera-Lugo, Rafael, Deng, David, Anaya-Sanchez, Andrea, Tejedor-Sanz, Sara, Tang, Eugene, Ruiz, Valeria M Reyes, Smith, Hans B, Titov, Denis V, Sauer, John-Demian, Skaar, Eric P, Ajo-Franklin, Caroline M, Portnoy, Daniel A, and Light, Samuel H

Subjects
Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Biodefense, Regenerative Medicine, Emerging Infectious Diseases, Infectious Diseases, Digestive Diseases, 2.1 Biological and endogenous factors, Animals, Cell Respiration, Disease Models, Animal, Immune Evasion, Listeria monocytogenes, Listeriosis, Mice, NAD, bacterial pathogenesis, cellular respiration, microbial metabolism, Other, biochemistry, chemical biology, infectious disease, microbiology, Biochemistry and Cell Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Cellular respiration is essential for multiple bacterial pathogens and a validated antibiotic target. In addition to driving oxidative phosphorylation, bacterial respiration has a variety of ancillary functions that obscure its contribution to pathogenesis. We find here that the intracellular pathogen Listeria monocytogenes encodes two respiratory pathways which are partially functionally redundant and indispensable for pathogenesis. Loss of respiration decreased NAD+ regeneration, but this could be specifically reversed by heterologous expression of a water-forming NADH oxidase (NOX). NOX expression fully rescued intracellular growth defects and increased L. monocytogenes loads >1000-fold in a mouse infection model. Consistent with NAD+ regeneration maintaining L. monocytogenes viability and enabling immune evasion, a respiration-deficient strain exhibited elevated bacteriolysis within the host cytosol and NOX expression rescued this phenotype. These studies show that NAD+ regeneration represents a major role of L. monocytogenes respiration and highlight the nuanced relationship between bacterial metabolism, physiology, and pathogenesis.

Published
2022

3. Physical bioenergetics: Energy fluxes, budgets, and constraints in cells

Author

Yang, Xingbo, Heinemann, Matthias, Howard, Jonathon, Huber, Greg, Iyer-Biswas, Srividya, Le Treut, Guillaume, Lynch, Michael, Montooth, Kristi L, Needleman, Daniel J, Pigolotti, Simone, Rodenfels, Jonathan, Ronceray, Pierre, Shankar, Sadasivan, Tavassoly, Iman, Thutupalli, Shashi, Titov, Denis V, Wang, Jin, and Foster, Peter J

Subjects
1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Affordable and Clean Energy, Cells, Energy Metabolism, Physical Phenomena, physical bioenergetics, energy fluxes, energetic costs, energetic constraints
Abstract

Cells are the basic units of all living matter which harness the flow of energy to drive the processes of life. While the biochemical networks involved in energy transduction are well-characterized, the energetic costs and constraints for specific cellular processes remain largely unknown. In particular, what are the energy budgets of cells? What are the constraints and limits energy flows impose on cellular processes? Do cells operate near these limits, and if so how do energetic constraints impact cellular functions? Physics has provided many tools to study nonequilibrium systems and to define physical limits, but applying these tools to cell biology remains a challenge. Physical bioenergetics, which resides at the interface of nonequilibrium physics, energy metabolism, and cell biology, seeks to understand how much energy cells are using, how they partition this energy between different cellular processes, and the associated energetic constraints. Here we review recent advances and discuss open questions and challenges in physical bioenergetics.

Published
2021

4. Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell.

Author

Mick, Eran, Titov, Denis V, Skinner, Owen S, Sharma, Rohit, Jourdain, Alexis A, and Mootha, Vamsi K

Subjects
ATF4, GCN2, genetics, genomics, human, human biology, integrated stress response, medicine, metabolism, mitochondria, mouse, p53, Biochemistry and Cell Biology
Abstract

Mitochondrial dysfunction is associated with activation of the integrated stress response (ISR) but the underlying triggers remain unclear. We systematically combined acute mitochondrial inhibitors with genetic tools for compartment-specific NADH oxidation to trace mechanisms linking different forms of mitochondrial dysfunction to the ISR in proliferating mouse myoblasts and in differentiated myotubes. In myoblasts, we find that impaired NADH oxidation upon electron transport chain (ETC) inhibition depletes asparagine, activating the ISR via the eIF2α kinase GCN2. In myotubes, however, impaired NADH oxidation following ETC inhibition neither depletes asparagine nor activates the ISR, reflecting an altered metabolic state. ATP synthase inhibition in myotubes triggers the ISR via a distinct mechanism related to mitochondrial inner-membrane hyperpolarization. Our work dispels the notion of a universal path linking mitochondrial dysfunction to the ISR, instead revealing multiple paths that depend both on the nature of the mitochondrial defect and on the metabolic state of the cell.

Published
2020

5. A genetically encoded tool for manipulation of NADP+/NADPH in living cells

Author

Cracan, Valentin, Titov, Denis V, Shen, Hongying, Grabarek, Zenon, and Mootha, Vamsi K

Subjects
Biochemistry and Cell Biology, Biological Sciences, HeLa Cells, Humans, NADH, NADPH Oxidoreductases, NADP, Oxidation-Reduction, Protein Engineering, Hela Cells, Medicinal and Biomolecular Chemistry, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

The redox coenzymes NADH and NADPH are broadly required for energy metabolism, biosynthesis and detoxification. Despite detailed knowledge of specific enzymes and pathways that utilize these coenzymes, a holistic understanding of the regulation and compartmentalization of NADH- and NADPH-dependent pathways is lacking, partly because of a lack of tools with which to investigate these processes in living cells. We have previously reported the use of the naturally occurring Lactobacillus brevis H2O-forming NADH oxidase (LbNOX) as a genetic tool for manipulation of the NAD+/NADH ratio in human cells. Here, we present triphosphopyridine nucleotide oxidase (TPNOX), a rationally designed and engineered mutant of LbNOX that is strictly specific to NADPH. We characterized the effects of TPNOX expression on cellular metabolism and used it in combination with LbNOX to show how the redox states of mitochondrial NADPH and NADH pools are connected.

Published
2017

7. Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio

Author

Titov, Denis V, Cracan, Valentin, Goodman, Russell P, Peng, Jun, Grabarek, Zenon, and Mootha, Vamsi K

Subjects
Catalysis, Cytosol, Electron Transport, Electron Transport Chain Complex Proteins, Genetic Complementation Test, Gluconeogenesis, HeLa Cells, Humans, Levilactobacillus brevis, Mitochondria, Mitochondrial Diseases, Multienzyme Complexes, NAD, NADH, NADPH Oxidoreductases, Oxidation-Reduction, Hela Cells, General Science & Technology
Abstract

A decline in electron transport chain (ETC) activity is associated with many human diseases. Although diminished mitochondrial adenosine triphosphate production is recognized as a source of pathology, the contribution of the associated reduction in the ratio of the amount of oxidized nicotinamide adenine dinucleotide (NAD(+)) to that of its reduced form (NADH) is less clear. We used a water-forming NADH oxidase from Lactobacillus brevis (LbNOX) as a genetic tool for inducing a compartment-specific increase of the NAD(+)/NADH ratio in human cells. We used LbNOX to demonstrate the dependence of key metabolic fluxes, gluconeogenesis, and signaling on the cytosolic or mitochondrial NAD(+)/NADH ratios. Expression of LbNOX in the cytosol or mitochondria ameliorated proliferative and metabolic defects caused by an impaired ETC. The results underscore the role of reductive stress in mitochondrial pathogenesis and demonstrate the utility of targeted LbNOX for direct, compartment-specific manipulation of redox state.

Published
2016

8. Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood.

Author

Lewis-Smith, David, Kamer, Kimberli J, Griffin, Helen, Childs, Anne-Marie, Pysden, Karen, Titov, Denis, Duff, Jennifer, Pyle, Angela, Taylor, Robert W, Yu-Wai-Man, Patrick, Ramesh, Venkateswaran, Horvath, Rita, Mootha, Vamsi K, and Chinnery, Patrick F

Subjects
Genetics, Neurosciences
Abstract

ObjectiveTo define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy.MethodsExome sequencing, long-range PCR, and Sanger sequencing to identify the pathogenic mutation. Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein.ResultsAnalysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion. No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele.ConclusionsMICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle. The fluctuating clinical course is likely mediated through the mitochondrial calcium uniporter, which is regulated by MICU1.

Published
2016

10. Covalent Modification of a Cysteine Residue in the XPB Subunit of the General Transcription Factor TFIIH Through Single Epoxide Cleavage of the Transcription Inhibitor Triptolide

Author

He, Qing‐Li, Titov, Denis V, Li, Jing, Tan, Minjia, Ye, Zhaohui, Zhao, Yingming, Romo, Daniel, and Liu, Jun O

Subjects
Genetics, Cysteine, Epoxy Compounds, Transcription Factor TFIIH, inhibitors, medicinal chemistry, natural products, target validation, transcription factors, Chemical Sciences, Organic Chemistry
Abstract

Triptolide is a key component of the traditional Chinese medicinal plant Thunder God Vine and has potent anticancer and immunosuppressive activities. It is an irreversible inhibitor of eukaryotic transcription through covalent modification of XPB, a subunit of the general transcription factor TFIIH. Cys342 of XPB was identified as the residue that undergoes covalent modification by the 12,13-epoxide group of triptolide. Mutation of Cys342 of XPB to threonine conferred resistance to triptolide on the mutant protein. Replacement of the endogenous wild-type XPB with the Cys342Thr mutant in a HEK293T cell line rendered it completely resistant to triptolide, thus validating XPB as the physiologically relevant target of triptolide. Together, these results deepen our understanding of the interaction between triptolide and XPB and have implications for the future development of new analogues of triptolide as leads for anticancer and immunosuppressive drugs.

Published
2015

11. Association of obesity with 3-month mortality in kidney failure patients with COVID-19

Author

Tantisattamo, Ekamol, Imhof, Celine, Jager, Kitty J., Hilbrands, Luuk B., Guidotti, Rebecca, Islam, Mahmud, Katicic, Dajana, Konings, Constantijn, Molenaar, Femke M., Nistor, Ionut, Noordzij, Marlies, Rodríguez Ferrero, Mariá Luisa, Verhoeven, Martine A. M., de Vries, Aiko P. J., Kalantar-Zadeh, Kamyar, Gansevoort, Ron T., Vart, Priya, van der Net, Jeroen B., Essig, Marie, du Buf-Vereijken, Peggy W. G., van Ginneken, Betty, Maas, Nanda, van Jaarsveld, Brigit C., Bemelman, Frederike J., Klingenberg-Salahova, Farah, Heenan-Vos, Frederiek, Vervloet, Marc G., Nurmohamed, Azam, Vogt, Liffert, Abramowicz, Daniel, Verhofstede, Sabine, Maoujoud, Omar, Malfait, Thomas, Fialova, Jana, Melilli, Edoardo, Favà, Alexandre, Cruzado, Josep M., Perez, Nuria Montero, Lips, Joy, Krepel, Harmen, Adilovic, Harun, Radulescu, Daniela, Hengst, Maaike, Rydzewski, Andrzej, Braconnier, Philippe, Weis, Daniel, Gellert, Ryszard, Oliveira, Joaõ, Alferes, Daniela G., Zakharova, Elena V., Ambuehl, Patrice Max, Walker, Andrea, Lepeytre, Fanny, Rabate, Clementine, Rostoker, Guy, Marques, Sofia, Azasevac, Tijana, Majstorovic, Gordana Strazmester, ten Dam, Marc, Krüger, Thilo, Brzosko, Szymon, Liakopoulos, Vassilios, Zanen, Adriaan L., Logtenberg, Susan J. J., Fricke, Lutz, Kuryata, Olexandr, Slebe, Jeroen J. P., Elhafeez, Samar Abd, Kemlin, Delphine, van de Wetering, Jacqueline, Reinders, Marlies E. J., Hesselink, Dennis A., Kal-van Gestel, J., Eiselt, Jaromir, Kielberger, Lukas, el-Wakil, Hala S., Logan, Ian, Canal, Cristina, Facundo, Carme, Ramos, Ana M., Debska-Slizien, Alicja, Veldhuizen, Nicoline M. H., Tigka, Eirini, Konsta, Maria Anna Polyzou, Panagoutsos, Stylianos, Mallamaci, Francesca, Postorino, Adele, Cambareri, Francesco, Matceac, Irina, Covic, Adrian, Groeneveld, J. H. M., Jousma, Jolanda, van Buren, Marjolijn, Diekmann, Fritz, Oppenheimer, Federico, Blasco, Miquel, Pereira, Tiago Assis, Santos, Augusto Cesar S., Arias-Cabrales, Carlos, Crespo, Marta, Llinàs-Mallol, Laura, Buxeda, Anna, Tàrrega, Carla Burballa, Redondo-Pachon, Dolores, Jimenez, Maria Dolores Arenas, Mendoza-Valderrey, Alberto, Martins, Ana Cristina, Mateus, Catarina, Alvila, Goncalo, Laranjinha, Ivo, Hofstra, Julia M., Siezenga, Machiel A., Franco, Antonio, Arroyo, David, Castellano, Sandra, Manzanos, Sagrario Balda, Haridian Sosa Barrios, R., Lemahieu, Wim, Bartelet, Karlijn, Dirim, Ahmet Burak, Demir, Erol, Sever, Mehmet Sukru, Turkmen, Aydin, Safak, Seda, Hollander, Daan A. M. J., Büttner, Stefan, Meziyerh, Soufian, van der Helm, Danny, Mallat, Marko, Bouwsma, Hanneke, Sridharan, Sivakumar, Petruliene, Kristina, Maloney, Sharon-Rose, Verberk, Iris, van der Sande, Frank M., Christiaans, Maarten H. L., Hemmelder, Marc H., Kumar, Mohan N., di Luca, Marina, Tuǧlular, Serhan Z., Ziekenhuis, Martini, Kramer, Andrea B., Beerenhout, Charles, Luik, Peter T., Kerschbaum, Julia, Tiefenthaler, Martin, Watschinger, Bruno, Adema, Aaltje Y., Stepanov, Vadim A., Zulkarnaev, Alexey B., Turkmen, Kultigin, Gandolfini, Ilaria, Maggiore, Umberto, Fliedner, Anselm, Åsberg, Anders, Mjoen, Geir, Miyasato, Hitoshi, de Fijter, Carola W. H., Mongera, Nicola, Pini, Stefano, de Biase, Consuelo, Kerckhoffs, Angele, Els van de Logt, Anne, Maas, Rutger, Duivenvoorden, Raphaël, Lebedeva, Olga, Lopez, Veronica, Reichert, Louis J. M., Verhave, Jacobien, Titov, Denis, Parshina, Ekaterina V., Zanoli, Luca, Marcantoni, Carmelita, van Kempen, Gijs, van Gils-Verrij, Liesbeth E. A., Harty, John C., Meurs, Marleen, Myslak, Marek, Battaglia, Yuri, Lentini, Paolo, den Deurwaarder, Edwin, Stendahl, Maria, Rahimzadeh, Hormat, Schouten, Marcel, Rychlik, Ivan, Cabezas-Reina, Carlos J., Roca, Ana Maria, Nauta, Ferdau, Sahin, Idris, Goffin, Eric, Kanaan, Nada, Labriola, Laura, Devresse, Arnaud, Diaz-Mareque, Anabel, Coca, Armando, de Arriba, Gabriel, Meijers, Björn K. I., Naesens, Maarten, Kuypers, Dirk, Desschans, Bruno, Tonnerlier, Annelies, Wissing, Karl M., Dedinska, Ivana, Pessolano, Giuseppina, Malik, Shafi, Dounousi, Evangelia, Papachristou, Evangelos, Berger, Stefan P., Meijer, Esther, Sanders, Jan Stephan F., Franssen, Casper F. M., Özyilmaz, Akin, Ponikvar, Jadranka Buturović, Pernat, Andreja Marn, Kovac, Damjan, Arnol, Miha, Ekart, Robert, Abrahams, Alferso C., van Zuilen, Arjan D., Meijvis, Sabine C. A., Dolmans, Helma, Esposito, Pasquale, Krzesinski, Jean-Marie, Barahira, Jean Damacène, Gallieni, Maurizio, Martin-Moreno, Paloma Leticia, Guglielmetti, Gabriele, Guzzo, Gabriella, Toapanta, Nestor, Soler, Maria Jose, Luik, Antinus J., van Kuijk, Willi H. M., Stikkelbroeck, Lonneke W. H., Hermans, Marc M. H., Rimsevicius, Laurynas, Righetti, Marco, Heitink-ter Braak, Nicole, Medical Informatics, APH - Aging & Later Life, APH - Quality of Care, APH - Global Health, ACS - Pulmonary hypertension & thrombosis, Nephrology, ACS - Microcirculation, APH - Health Behaviors & Chronic Diseases, Clinical sciences, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, ACS - Diabetes & metabolism, Internal Medicine, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), van der Net, Jeroen B, Essig, Marie, du Buf-Vereijken, Peggy W G, van Ginneken, Betty, Maas, Nanda, van Jaarsveld, Brigit C, Bemelman, Frederike J, Klingenberg-Salahova, Farah, Heenan-Vos, Frederiek, Vervloet, Marc G, Nurmohamed, Azam, Vogt, Liffert, Abramowicz, Daniel, Verhofstede, Sabine, Maoujoud, Omar, Malfait, Thomas, Fialova, Jana, Melilli, Edoardo, Favà, Alexandre, Cruzado, Josep M, Perez, Nuria Montero, Lips, Joy, Krepel, Harmen, Adilovic, Harun, Radulescu, Daniela, Hengst, Maaike, Rydzewski, Andrzej, Braconnier, Philippe, Weis, Daniel, Gellert, Ryszard, Oliveira, João, Alferes, Daniela G, Zakharova, Elena V, Ambuehl, Patrice Max, Walker, Andrea, Lepeytre, Fanny, Rabaté, Clémentine, Rostoker, Guy, Marques, Sofia, Azasevac, Tijana, Majstorovic, Gordana Strazmester, Ten Dam, Marc, Krüger, Thilo, Brzosko, Szymon, Liakopoulos, Vassilios, Zanen, Adriaan L, Logtenberg, Susan J J, Fricke, Lutz, Kuryata, Olexandr, Slebe, Jeroen J P, ElHafeez, Samar Abd, Kemlin, Delphine, van de Wetering, Jacqueline, Reinders, Marlies E J, Hesselink, Dennis A, Kal-van Gestel, J., Eiselt, Jaromir, Kielberger, Lukas, El-Wakil, Hala S, Logan, Ian, Canal, Cristina, Facundo, Carme, Ramos, Ana M, Debska-Slizien, Alicja, Veldhuizen, Nicoline M H, Tigka, Eirini, Konsta, Maria Anna Polyzou, Panagoutsos, Stylianos, Mallamaci, Francesca, Postorino, Adele, Cambareri, Francesco, Matceac, Irina, Covic, Adrian, Groeneveld, J H M, Jousma, Jolanda, van Buren, Marjolijn, Diekmann, Fritz, Oppenheimer, Federico, Blasco, Miquel, Pereira, Tiago Assis, Santos, Augusto Cesar S, Arias-Cabrales, Carlos, Crespo, Marta, Llinàs-Mallol, Laura, Buxeda, Anna, Tàrrega, Carla Burballa, Redondo-Pachon, Dolores, Jimenez, Maria Dolores Arenas, Mendoza-Valderrey, Alberto, Martins, Ana Cristina, Mateus, Catarina, Alvila, Goncalo, Laranjinha, Ivo, Hofstra, Julia M, Siezenga, Machiel A, Franco, Antonio, Arroyo, David, Castellano, Sandra, Manzanos, Sagrario Balda, Haridian Sosa Barrios, R., Lemahieu, Wim, Bartelet, Karlijn, Dirim, Ahmet Burak, Demir, Erol, Sever, Mehmet Sukru, Turkmen, Aydin, Şafak, Seda, Hollander, Daan A M J, Büttner, Stefan, Meziyerh, Soufian, van der Helm, Danny, Mallat, Marko, Bouwsma, Hanneke, Sridharan, Sivakumar, Petrulienė, Kristina, Maloney, Sharon-Rose, Verberk, Iris, van der Sande, Frank M, Christiaans, Maarten H L, Hemmelder, Marc H, Kumar N, Mohan, Di Luca, Marina, Tuğlular, Serhan Z, Ziekenhuis, Martini, Kramer, Andrea B, Beerenhout, Charles, Luik, Peter T, Kerschbaum, Julia, Tiefenthaler, Martin, Watschinger, Bruno, Adema, Aaltje Y, Stepanov, Vadim A, Zulkarnaev, Alexey B, Turkmen, Kultigin, Gandolfini, Ilaria, Maggiore, Umberto, Fliedner, Anselm, Åsberg, Anders, Mjoen, Geir, Miyasato, Hitoshi, de Fijter, Carola W H, Mongera, Nicola, Pini, Stefano, de Biase, Consuelo, Kerckhoffs, Angele, Els van de Logt, Anne, Maas, Rutger, Duivenvoorden, Raphaël, Lebedeva, Olga, Lopez, Veronica, Reichert, Louis J M, Verhave, Jacobien, Titov, Denis, Parshina, Ekaterina V, Zanoli, Luca, Marcantoni, Carmelita, van Kempen, Gijs, van Gils-Verrij, Liesbeth E A, Harty, John C, Meurs, Marleen, Myslak, Marek, Battaglia, Yuri, Lentini, Paolo, den Deurwaarder, Edwin, Stendahl, Maria, Rahimzadeh, Hormat, Schouten, Marcel, Rychlik, Ivan, Cabezas-Reina, Carlos J, Roca, Ana Maria, Nauta, Ferdau, Sahin, İdris, Goffin, Eric, Kanaan, Nada, Labriola, Laura, Devresse, Arnaud, Diaz-Mareque, Anabel, Coca, Armando, de Arriba, Gabriel, Meijers, Björn K I, Naesens, Maarten, Kuypers, Dirk, Desschans, Bruno, Tonnerlier, Annelies, Wissing, Karl M, Dedinska, Ivana, Pessolano, Giuseppina, Malik, Shafi, Dounousi, Evangelia, Papachristou, Evangelos, Berger, Stefan P, Meijer, Esther, Sanders, Jan Stephan F, Franssen, Casper F M, Özyilmaz, Akin, Ponikvar, Jadranka Buturović, Pernat, Andreja Marn, Kovac, Damjan, Arnol, Miha, Ekart, Robert, Abrahams, Alferso C, van Zuilen, Arjan D, Meijvis, Sabine C A, Dolmans, Helma, Esposito, Pasquale, Krzesinski, Jean-Marie, Barahira, Jean Damacène, Gallieni, Maurizio, Martin-Moreno, Paloma Leticia, Guglielmetti, Gabriele, Guzzo, Gabriella, Toapanta, Nestor, Soler, Maria Jose, Luik, Antinus J, van Kuijk, Willi H M, Stikkelbroeck, Lonneke W H, Hermans, Marc M H, Rimševičius, Laurynas, Righetti, Marco, and Heitink-Ter Braak, Nicole

Subjects
Transplantation, COVID-19, infectious diseases, mortality, DIALYSIS PATIENTS, kidney failure, BODY-MASS INDEX, obesity paradox, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], TRANSPLANT, SDG 3 - Good Health and Well-being, Nephrology, ERACODA, reverse epidemiology, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11]
Abstract

Background In the general population with coronavirus disease 2019 (COVID-19), obesity is associated with an increased risk of mortality. Given the typically observed obesity paradox among patients on kidney function replacement therapy (KFRT), especially dialysis patients, we examined the association of obesity with mortality among dialysis patients or living with a kidney transplant with COVID-19. Methods Data from the European Renal Association COVID-19 Database (ERACODA) were used. KFRT patients diagnosed with COVID-19 between 1 February 2020 and 31 January 2021 were included. The association of Quetelet's body mass index (BMI) (kg/m2), divided into: Results In 3160 patients on KFRT (mean age: 65 years, male: 61%), 99 patients were lean, 1151 normal weight (reference), 1160 overweight, 525 obese I and 225 obese II/III. During follow-up of 3 months, 28, 20, 21, 23 and 27% of patients died in these categories, respectively. In the fully adjusted model, the hazard ratios (HRs) for 3-month mortality were 1.65 [95% confidence interval (CI): 1.10, 2.47], 1 (ref.), 1.07 (95% CI: 0.89, 1.28), 1.17 (95% CI: 0.93, 1.46) and 1.71 (95% CI: 1.27, 2.30), respectively. Results were similar among dialysis patients (N = 2343) and among those living with a kidney transplant (N = 817) (Pinteraction = 0.99), but differed by sex (Pinteraction = 0.019). In males, the HRs for the association of aforementioned BMI categories with 3-month mortality were 2.07 (95% CI: 1.22, 3.52), 1 (ref.), 0.97 (95% CI: 0.78. 1.21), 0.99 (95% CI: 0.74, 1.33) and 1.22 (95% CI: 0.78, 1.91), respectively, and in females corresponding HRs were 1.34 (95% CI: 0.70, 2.57), 1 (ref.), 1.31 (95% CI: 0.94, 1.85), 1.54 (95% CI: 1.05, 2.26) and 2.49 (95% CI: 1.62, 3.84), respectively. Conclusion In KFRT patients with COVID-19, on dialysis or a kidney transplant, obesity is associated with an increased risk of mortality at 3 months. This is in contrast to the obesity paradox generally observed in dialysis patients. Additional studies are required to corroborate the sex difference in the association of obesity with mortality.

Published
2022

15. COVID-19-related mortality in kidney transplant and haemodialysis patients

Author

Goffin, Eric, Candellier, Alexandre, Vart, Priya, Noordzij, Marlies, Arnol, Miha, Covic, Adrian, Lentini, Paolo, Malik, Shafi, Reichert, Louis J., Sever, Mehmet S., Watschinger, Bruno, Jager, Kitty J., Gansevoort, Ron T., van der Net, Jeroen B., Essig, Marie, du Buf-Vereijken, Peggy W. G., van Ginneken, Betty, Vogt, Liffert, van Jaarsveld, Brigit C., Bemelman, Frederike J., Klingenberg-Salahova, Farah, Heenan-Vos, Frederiek, Vervloet, Marc G., Nurmohamed, Azam, Abramowicz, Daniel, Verhofstede, Sabine, Maoujoud, Omar, Malfait, Thomas, Avitum, B. Braun, Fialova, Jana, Melilli, Edoardo, Favà, Alexandre, Cruzado, Josep M., Perez, Nuria Montero, Lips, Joy, Krepel, Harmen, Adilovic, Harun, Hengst, Maaike, Rydzewski, Andrzej, Gellert, Ryszard, Oliveira, João, Alferes, Daniela G., Zakharova, Elena V., Ambuehl, Patrice Max, Walker, Andrea, Winzeler, Rebecca, Lepeytre, Fanny, Rabaté, Clémentine, Rostoker, Guy, Marques, Sofia, Azasevac, Tijana, Katicic, Dajana, ten Dam, Marc, Krüger, Thilo, Brzosko, Szymon, Zanen, Adriaan L., Logtenberg, Susan J. J., Fricke, Lutz, Slebe, Jeroen J. P., Kemlin, Delphine, van de Wetering, Jacqueline, Reinders, Marlies E. J., Eiselt, Jaromir, Kielberger, Lukas, el-Wakil, Hala S., Verhoeven, Martine A. M., Canal, Cristina, Facundo, Carme, Ramos, Ana M., Debska-Slizien, Alicja, Veldhuizen, Nicoline M. H., Tigka, Eirini, Konsta, Maria Anna Polyzou, Panagoutsos, Stylianos, Mallamaci, Francesca, Matceac, Irina, Nistor, Ionut, Cordos, Monica, Groeneveld, J. H. M., Jousma, Jolanda, van Buren, Marjolijn, Elhafeez, Samar Abd, Diekmann, Fritz, Pereira, Tiago Assis, Santos, Augusto Cesar S., Arias-Cabrales, Carlos, Crespo, Marta, Llinàs-Mallol, Laura, Buxeda, Anna, Tàrrega, Carla Burballa, Redondo-Pachon, Dolores, Jimenez, Maria Dolores Arenas, Hofstra, Julia M., Franco, Antonio, Arroyo, David, Rodríguez-Ferrero, Maria Luisa, Manzanos, Sagrario Balda, Barrios, R. Haridian Sosa, Ávila, Gonçalo, Laranjinha, Ivo, Mateus, Catarina, Lemahieu, Wim, Dirim, Ahmet Burak, Demir, Erol, Å afak, Seda, Turkmen, Aydin, Hollander, Daan A. M. J., Büttner, Stefan, de Vries, Aiko P. J., Meziyerh, Soufian, van der Helm, Danny, Mallat, Marko, Bouwsma, Hanneke, Sridharan, Sivakumar, Petruliene, Kristina, Maloney, Sharon-Rose, Verberk, Iris, van der Sande, Frank M., Christiaans, Maarten H. L., Hemmelder, Marc, Kumar, Mohan N., di Luca, Marina, Tuǧlular, Serhan Z., Kramer, Andrea, Beerenhout, Charles, Luik, Peter T., Kerschbaum, Julia, Tiefenthaler, Martin, Adema, Aaltje Y., Stepanov, Vadim A., Zulkarnaev, Alexey B., Turkmen, Kultigin, Fliedner, Anselm, Åsberg, Anders, Mjoen, Geir, Miyasato, Hitoshi, de Fijter, Carola W. H., Mongera, Nicola, Pini, Stefano, de Biase, Consuelo, Duivenvoorden, Raphaël, Hilbrands, Luuk, Kerckhoffs, Angele, Maas, Rutger, Lebedeva, Olga, Lopez, Veronica, Verhave, Jacobien, Titov, Denis, Parshina, Ekaterina V., Zanoli, Luca, Marcantoni, Carmelita, van Gils-Verrij, Liesbeth E. A., Harty, John C., Meurs, Marleen, Myslak, Marek, Battaglia, Yuri, den Deurwaarder, Edwin, Stendahl, Maria, Rahimzadeh, Hormat, Schouten, Marcel, Rychlik, Ivan, Cabezas-Reina, Carlos J., Roca, Ana Maria, Nauta, Ferdau, Kanaan, Nada, Labriola, Laura, Devresse, Arnaud, Diaz-Mareque, Anabel, Coca, Armando, Meijers, Björn K. I., Naesens, Maarten, Kuypers, Dirk, Desschans, Bruno, Tonnelier, Annelies, Wissing, Karl M., de Arriba, Gabriel, Dedinska, Ivana, Pessolano, Giuseppina, Gandolfini, Ilaria, Maggiore, Umberto, Papachristou, Evangelos, Franssen, Casper F. M., Berger, Stefan P., Meijer, Esther, Özyilmaz, Akin, Sanders, Jan Stephan F., Ponikvar, Jadranka Buturović, Pernat, Andreja Marn, Kovac, Damjan, Ekart, Robert, Abrahams, Alferso C., Molenaar, Femke M., van Zuilen, Arjan D., Meijvis, Sabine C. A., Dolmans, Helma, Tantisattamos, Ekamol, Esposito, Pasquale, Krzesinski, Jean-Marie, Barahira, Jean Damacène, Gallieni, Maurizio, Sabiu, Gianmarco, Martin-Moreno, Paloma Leticia, Guglielmetti, Gabriele, Guzzo, Gabriella, Toapanta, Nestor, Luik, Antinus J., van Kuijk, Willi H. M., Stikkelbroeck, Lonneke W. H., Hermans, Marc M. H., Rimsevicius, Laurynas, Righetti, Marco, Islam, Mahmud, Braak, Nicole Heitink-Ter, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Internal Medicine, Clinical sciences, Nephrology, ACS - Diabetes & metabolism, AII - Inflammatory diseases, AII - Infectious diseases, Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Medical Informatics, ACS - Pulmonary hypertension & thrombosis, APH - Aging & Later Life, APH - Quality of Care, ACS - Microcirculation, APH - Health Behaviors & Chronic Diseases, and APH - Global Health

Subjects
medicine.medical_specialty, kidney, Original Article - Dialysis, medicine.medical_treatment, infectious diseases, law.invention, Kidney Failure, SDG 3 - Good Health and Well-being, Renal Dialysis, Risk Factors, law, Internal medicine, medicine, Humans, COVID-19, dialysis, mortality, transplantation, Registries, Renal replacement therapy, Chronic, AcademicSubjects/MED00340, Kidney transplantation, Dialysis, Transplantation, SARS-CoV-2, business.industry, Kidney Transplantation/adverse effects, Hazard ratio, medicine.disease, Kidney Transplantation, Intensive care unit, Comorbidity, Transplant Recipients, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Kidney Failure, Chronic/therapy, Nephrology, Kidney Failure, Chronic, Hemodialysis, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business
Abstract

BACKGROUND AND AIMS: Studies examining kidney failure patients with COVID-19 reported higher mortality in hemodialysis patients than in kidney transplant recipients. However, hemodialysis patients are often older and have more comorbidities. This study investigated the association of type of kidney replacement therapy with COVID-19 severity adjusting for differences in characteristics. METHOD: Data were retrieved from the European Renal Association COVID-19 Database (ERACODA), which includes kidney replacement therapy patients diagnosed with COVID-19 from all over Europe. We included all kidney transplant recipients and hemodialysis patients who presented between February 1st and December 1st 2020 and had complete information reason for COVID-19 screening and vital status at day 28. The diagnosis of COVID-19 was made based on a PCR of a nasal or pharyngeal swab specimens and/or COVID-19 compatible findings on a lung CT scan. The association of kidney transplantation or hemodialysis with 28-day mortality was examined using Cox proportional-hazards regression models adjusted for age, sex, frailty and comorbidities. Additionally, this association was investigated in the subsets of patients that were screened because of symptoms or have had routine screening. RESULTS: A total of 1,670 patients (496 functional kidney transplant recipients and 1,174 hemodialysis patients) were examined. 16.9% of kidney transplant recipients and 23.9% of hemodialysis patients died within 28 days of presentation. In an unadjusted model, the risk of 28-day mortality was 33% lower in kidney transplant recipients compared with hemodialysis patients (hazard ratio (HR): 0.67, 95% CI: 0.52, 0.85). However, in an age, sex and frailty adjusted model, the risk of 28-day mortality was 29% higher in kidney transplant recipients (HR=1.29, 95% CI: 1.00, 1.68), whereas in a fully adjusted model the risk was even 43% higher (HR=1.43, 95% CI: 1.06, 1.93). This association in patients who were screened because of symptoms (n=1,145) was similar (fully adjusted model HR=1.46, 95% CI: 1.05, 2.04). Results were similar when other endpoints were studied (e.g. risk for hospitalization, ICU admission or mortality beyond 28 days) as well as across subgroups. Only age was found to interact significantly, suggesting that the increased mortality risk associated with kidney transplantation was especially present in elderly subjects. CONCLUSION: In this study, kidney transplant recipients had a greater risk of a more severe course of COVID-19 compared with hemodialysis patients when adjusted for age, sex and comorbidities.

Published
2021

16. Sex differences in COVID-19 mortality risk in patients on kidney function replacement therapy

Author

Vart, Priya, Duivenvoorden, Raphaël, Adema, Aaltje, Covic, Adrian, Finne, Patrik, Braak, Nicole Heijtink-ter, Laine, Kaisa, Noordzij, Marlies, Schouten, Marcel, Jager, Kitty J., Gansevoort, Ron T., van der Net, Jeroen B., Essig, Marie, du Buf-Vereijken, Peggy W. G., van Ginneken, Betty, Maas, Nanda, van Jaarsveld, Brigit C., Bemelman, Frederike J., Klingenberg-Salahova, Farah, Heenan-Vos, Frederiek, Vervloet, Marc G., Nurmohamed, Azam, Vogt, Liffert, Abramowicz, Daniel, Verhofstede, Sabine, Maoujoud, Omar, Malfait, Thomas, Fialova, Jana, Melilli, Edoardo, Favà, Alexandre, Cruzado, Josep M., Perez, Nuria Montero, Lips, Joy, Krepel, Harmen, Adilovic, Harun, Radulescu, Daniela, Hengst, Maaike, Konings, Constantijn, Rydzewski, Andrzej, Braconnier, Philippe, Weis, Daniel, Gellert, Ryszard, Oliveira, João, Alferes, Daniela G., Zakharova, Elena V., Ambühl, Patrice Max, Guidotti, Rebecca, Walker, Andrea, Lepeytre, Fanny, Rabaté, Clémentine, Rostoker, Guy, Marques, Sofia, Azasevac, Tijana, Majstorovic, Gordana Strazmester, Katicic, Dajana, ten Dam, Marc, Krüger, Thilo, Brzosko, Szymon, Liakopoulos, Vassilios, Zanen, Adriaan L., Logtenberg, Susan J. J., Fricke, Lutz, Kuryata, Olexandr, Slebe, Jeroen J. P., ElHafeez, Samar Abd, Kemlin, Delphine, van de Wetering, Jacqueline, Reinders, Marlies E. J., Hesselink, Dennis A., Kal-van Gestel, J., Eiselt, Jaromir, Kielberger, Lukas, El-Wakil, Hala S., Verhoeven, Martine, Logan, Ian, Canal, Cristina, Facundo, Carme, Ramos, Ana M., Debska-Slizien, Alicja, Veldhuizen, Nicoline M. H., Tigka, Eirini, Konsta, Maria Anna Polyzou, Panagoutsos, Stylianos, Mallamaci, Francesca, Postorino, Adele, Cambareri, Francesco, Matceac, Irina, Nistor, Ionut, Groeneveld, J. H.M., Jousma, Jolanda, van Buren, Marjolijn, Diekmann, Fritz, Oppenheimer, Federico, Blasco, Miquel, Pereira, Tiago Assis, Santos, Augusto Cesar S., Arias-Cabrales, Carlos, Crespo, Marta, Llinàs-Mallol, Laura, Buxeda, Anna, Tàrrega, Carla Burballa, Redondo-Pachon, Dolores, Jimenez, Maria Dolores Arenas, Mendoza-Valderrey, Alberto, Martins, Ana Cristina, Mateus, Catarina, Alvila, Goncalo, Laranjinha, Ivo, Hofstra, Julia M., Siezenga, Machiel A., Franco, Antonio, Arroyo, David, Castellano, Sandra, Rodríguez-Ferrero, Maria Luisa, Manzanos, Sagrario Balda, Barrios, R. Haridian Sosa, Lemahieu, Wim, Bartelet, Karlijn, Dirim, Ahmet Burak, Demir, Erol, Sever, Mehmet Sukru, Turkmen, Aydin, Şafak, Seda, Hollander, Daan A. M. J., Büttner, Stefan, de Vries, Aiko P. J., Meziyerh, Soufian, van der Helm, Danny, Mallat, Marko, Bouwsma, Hanneke, Sridharan, Sivakumar, Petrulienė, Kristina, Maloney, Sharon-Rose, Verberk, Iris, van der Sande, Frank M., Christiaans, Maarten H. L., Hemmelder, Marc H., MohanKumar, N., Di Luca, Marina, Tuğlular, Serhan Z., Kramer, Andrea B., Beerenhout, Charles, Luik, Peter T., Kerschbaum, Julia, Tiefenthaler, Martin, Watschinger, Bruno, Stepanov, Vadim A., Zulkarnaev, Alexey B., Turkmen, Kultigin, Gandolfini, Ilaria, Maggiore, Umberto, Fliedner, Anselm, Åsberg, Anders, Mjoen, Geir, Miyasato, Hitoshi, de Fijter, Carola W. H., Mongera, Nicola, Pini, Stefano, de Biase, Consuelo, Kerckhoffs, Angele, van de Logt, Anne Els, Maas, Rutger, Hilbrands, Luuk B., Lebedeva, Olga, Lopez, Veronica, Reichert, Louis J. M., Verhave, Jacobien, Titov, Denis, Parshina, Ekaterina V., Zanoli, Luca, Marcantoni, Carmelita, van Kempen, Gijs, van Gils-Verrij, Liesbeth E. A., Harty, John C., Meurs, Marleen, Myslak, Marek, Battaglia, Yuri, Lentini, Paolo, den Deurwaarder, Edwin, Stendahl, Maria, Rahimzadeh, Hormat, Rychlik, Ivan, Cabezas-Reina, Carlos J., Roca, Ana Maria, Nauta, Ferdau, Sahin, İdris, Goffin, Eric, Kanaan, Nada, Labriola, Laura, Devresse, Arnaud, Diaz-Mareque, Anabel, Coca, Armando, de Arriba, Gabriel, Meijers, Björn K. I., Naesens, Maarten, Kuypers, Dirk, Desschans, Bruno, Tonnerlier, Annelies, Wissing, Karl M., Dedinska, Ivana, Pessolano, Giuseppina, Malik, Shafi, Dounousi, Evangelia, Papachristou, Evangelos, Berger, Stefan P., Sanders, Jan Stephan F., Franssen, Casper F. M., Özyilmaz, Akin, Ponikvar, Jadranka Buturović, Pernat, Andreja Marn, Kovac, Damjan, Arnol, Miha, Ekart, Robert, Abrahams, Alferso C., Molenaar, Femke M., van Zuilen, Arjan D., Meijvis, Sabine C. A., Dolmans, Helma, Tantisattamo, Ekamol, Esposito, Pasquale, Krzesinski, Jean-Marie, Barahira, Jean Damacène, Gallieni, Maurizio, Martin-Moreno, Paloma Leticia, Guglielmetti, Gabriele, Guzzo, Gabriella, Toapanta, Nestor, Soler, Maria Jose, Luik, Antinus J., van Kuijk, Willi H. M., Stikkelbroeck, Lonneke W. H., Hermans, Marc M. H., Rimševičius, Laurynas, Righetti, Marco, Islam, Mahmud, Clinical sciences, Nephrology, Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Medical Informatics, APH - Aging & Later Life, APH - Quality of Care, APH - Global Health, ACS - Pulmonary hypertension & thrombosis, AII - Inflammatory diseases, ACS - Microcirculation, APH - Health Behaviors & Chronic Diseases, Internal Medicine, Department of Medicine, Clinicum, University of Helsinki, Helsinki University Hospital Area, ACS - Diabetes & metabolism, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, and UCL - (SLuc) Service de néphrologie

Subjects
Male, kidney, Transplant, infectious diseases, Kidney, All institutes and research themes of the Radboud University Medical Center, COVID‐19, Renal Dialysis, Risk Factors, risk factors, Humans, Eracoda, Aged, Sex Characteristics, Multidisciplinary, Dialysis patients, Kidney Transplantation/adverse effects, COVID-19, Middle Aged, Kidney Transplantation, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Nephrology, 3121 General medicine, internal medicine and other clinical medicine, mortality risk, Immunosuppressive Agents/therapeutic use, Female, Immunosuppressive Agents
Abstract

In the general population with COVID-19, the male sex is an established risk factor for mortality, in part due to a more robust immune response to COVID-19 in women. Because patients on kidney function replacement therapy (KFRT) have an impaired immune response, especially kidney transplant recipients due to their use of immunosuppressants, we examined whether the male sex is still a risk factor for mortality among patients on KFRT with COVID-19. From the European Renal Association COVID-19 Database (ERACODA), we examined patients on KFRT with COVID-19 who presented between February 1st, 2020, and April 30th, 2021. 1204 kidney transplant recipients (male 62.0%, mean age 56.4 years) and 3206 dialysis patients (male 61.8%, mean age 67.7 years) were examined. Three-month mortality in kidney transplant recipients was 16.9% in males and 18.6% in females (p = 0.31) and in dialysis patients 27.1% in males and 21.9% in females (p = 0.001). The adjusted HR for the risk of 3-month mortality in males (vs females) was 0.89 (95% CI 65, 1.23, p = 0.49) in kidney transplant recipients and 1.33 (95% CI 1.13, 1.56, p = 0.001) in dialysis patients (pinteraction = 0.02). In a fully adjusted model, the aHR for the risk of 3-month mortality in kidney transplant recipients (vs. dialysis patients) was 1.39 (95% CI 1.02, 1.89, p = 0.04) in males and 2.04 (95% CI 1.40, 2.97, p interaction = 0.02). In patients on KFRT with COVID-19, the male sex is not a risk factor for mortality among kidney transplant recipients but remains a risk factor among dialysis patients. The use of immunosuppressants in kidney transplant recipients, among other factors, may have narrowed the difference in the immune response to COVID-19 between men and women, and therefore reduced the sex difference in COVID-19 mortality risk.

Published
2022

18. Clinical, Functional, and Mental Health Outcomes in Kidney Transplant Recipients 3 Months After a Diagnosis of COVID-19

Author

Duivenvoorden, Raphaël, Vart, Priya, Noordzij, Marlies, Soares Dos Santos, Augusto C., Zulkarnaev, Alex B., Franssen, Casper F. M., Kuypers, Dirk, Demir, Erol, Rahimzadeh, Hormat, Kerschbaum, Julia, Jager, Kitty J., Turkmen, Kultigin, Hemmelder, Marc H., Schouten, Marcel, Rodríguez-Ferrero, María Luisa, Crespo, Marta, Gansevoort, Ron T., Hilbrands, Luuk B., van der Net, Jeroen B., Essig, Marie, du Buf-Vereijken, Peggy W. G., van Ginneken, Betty, Maas, Nanda, Vogt, Liffert, van Jaarsveld, Brigit C., Bemelman, Frederike J., Klingenberg-Salahova, Farah, Heenan-Vos, Frederiek, Vervloet, Marc G., Nurmohamed, Azam, Abramowicz, Daniel, Verhofstede, Sabine, Maoujoud, Omar, Malfait, Thomas, Fialova, Jana, Melilli, Edoardo, Favà, Alexandre, Cruzado, Josep M., Montero Perez, Nuria, Lips, Joy, Krepel, Harmen, Adilovic, Harun, Hengst, Maaike, Konings, Constantijn, Rydzewski, Andrzej, Braconnier, Philippe, Weis, Daniel, Gellert, Ryszard, Oliveira, João, Alferes, Daniela G., Radulescu, Daniela, Zakharova, Elena V., Ambuehl, Patrice Max, Guidotti, Rebecca, Walker, Andrea, Lepeytre, Fanny, Rabaté, Clémentine, Rostoker, Guy, Marques, Sofia, Azasevac, Tijana, Strazmester Majstorovic, Gordana, Katicic, Dajana, ten Dam, Marc, Krüger, Thilo, Brzosko, Szymon, Liakopoulos, Vassilios, Zanen, Adriaan L., Logtenberg, Susan J. J., Fricke, Lutz, Kuryata, Olexandr, Slebe, Jeroen J. P., Abd Elhafeez, Samar, Kemlin, Delphine, van de Wetering, Jacqueline, Reinders, Marlies E. J., Hesselink, Dennis A., Kal-van Gestel, J., Eiselt, Jaromir, Kielberger, Lukas, el-Wakil, Hala S., Verhoeven, Martine, Logan, Ian, Canal, Cristina, Facundo, Carme, Ramos, Ana M., Debska-Slizien, Alicja, Veldhuizen, Nicoline M. H., Tigka, Eirini, Polyzou Konsta, Maria Anna, Panagoutsos, Stylianos, Mallamaci, Francesca, Postorino, Adele, Cambareri, Francesco, Matceac, Irina, Nistor, Ionut, Covic, Adrian, Groeneveld, J. H. M., Jousma, Jolanda, van Buren, Marjolijn, Diekmann, Fritz, Oppenheimer, Federico, Blasco, Miquel, Assis Pereira, Tiago, Arias-Cabrales, Carlos, Llinàs-Mallol, Laura, Buxeda, Anna, Tàrrega, Carla Burballa, Redondo-Pachon, Dolores, Jimenez, Maria Dolores Arenas, Mendoza-Valderrey, Alberto, Martins, Ana Cristina, Mateus, Catarina, Alvila, Goncalo, Laranjinha, Ivo, Hofstra, Julia M., Siezenga, Machiel A., Franco, Antonio, Arroyo, David, Castellano, Sandra, Balda Manzanos, Sagrario, Sosa Barrios, R. Haridian, Lemahieu, Wim, Bartelet, Karlijn, Burak Dirim, Ahmet, Sukru Sever, Mehmet, Turkmen, Aydin, Şafak, Seda, Hollander, Daan A. M. J., Büttner, Stefan, de Vries, Aiko P. J., Meziyerh, Soufian, van der Helm, Danny, Mallat, Marko, Bouwsma, Hanneke, Sridharan, Sivakumar, Petruliene, Kristina, Maloney, Sharon-Rose, Verberk, Iris, van der Sande, Frank M., Christiaans, Maarten H. L., Mohan Kumar, N., di Luca, Marina, Tuǧlular, Serhan Z., Kramer, Andrea, Beerenhout, Charles, Luik, Peter T., Tiefenthaler, Martin, Watschinger, Bruno, Adema, Aaltje Y., Stepanov, Vadim A., Gandolfini, Ilaria, Maggiore, Umberto, Fliedner, Anselm, Åsberg, Anders, Mjoen, Geir, Miyasato, Hitoshi, de Fijter, Carola W. H., Mongera, Nicola, Pini, Stefano, de Biase, Consuelo, Kerckhoffs, Angele, van de Logt, Anne Els, Maas, Rutger, Lebedeva, Olga, Lopez, Veronica, Reichert, Louis J. M., Verhave, Jacobien, Titov, Denis, Parshina, Ekaterina V., Zanoli, Luca, Marcantoni, Carmelita, van Kempen, Gijs, van Gils-Verrij, Liesbeth E. A., Harty, John C., Meurs, Marleen, Myslak, Marek, Battaglia, Yuri, Lentini, Paolo, den Deurwaarder, Edwin, Stendahl, Maria, Rychlik, Ivan, Cabezas-Reina, Carlos J., Maria Roca, Ana, Nauta, Ferdau, Sahin, İdris, Goffin, Eric, Kanaan, Nada, Labriola, Laura, Devresse, Arnaud, Diaz-Mareque, Anabel, Coca, Armando, de Arriba, Gabriel, Meijers, Björn K. I., Naesens, Maarten, Desschans, Bruno, Tonnerlier, Annelies, Wissing, Karl M., Dedinska, Ivana, Pessolano, Giuseppina, Malik, Shafi, Dounousi, Evangelia, Papachristou, Evangelos, Berger, Stefan P., Meijer, Esther, Sanders, Jan Stephan F., Özyilmaz, Akin, Buturović Ponikvar, Jadranka, Marn Pernat, Andreja, Kovac, Damjan, Arnol, Miha, Ekart, Robert, Abrahams, Alferso C., Molenaar, Femke M., van Zuilen, Arjan D., Meijvis, Sabine C. A., Dolmans, Helma, Tantisattamo, Ekamol, Esposito, Pasquale, Krzesinski, Jean-Marie, Barahira, Jean Damacène, Gallieni, Maurizio, Martin-Moreno, Paloma Leticia, Guglielmetti, Gabriele, Guzzo, Gabriella, Toapanta, Nestor, Jose Soler, Maria, Luik, Antinus J., van Kuijk, Willi H. M., Stikkelbroeck, Lonneke W. H., Hermans, Marc M. H., Rimsevicius, Laurynas, Righetti, Marco, Islam, Mahmud, Heitink-ter Braak, Nicole, Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Medical Informatics, ACS - Pulmonary hypertension & thrombosis, APH - Aging & Later Life, APH - Quality of Care, APH - Global Health, Nephrology, ACS - Diabetes & metabolism, Internal Medicine, Interne Geneeskunde, RS: Carim - V02 Hypertension and target organ damage, and Clinical sciences

Subjects
kidney transplant, Adult, Kidney Disease, Outcome Assessment, Renal and urogenital, infectious diseases, Medical and Health Sciences, clinical, DISEASE, All institutes and research themes of the Radboud University Medical Center, Rare Diseases, SDG 3 - Good Health and Well-being, 7.1 Individual care needs, Clinical Research, Outcome Assessment, Health Care, Humans, Retrospective Studies, Transplantation, SARS-CoV-2, MORTALITY, Rehabilitation, COVID-19, mental health outcomes, survive, Organ Transplantation, Original Clinical Science—General, Middle Aged, SOLID-ORGAN TRANSPLANT, Kidney Transplantation, Transplant Recipients, DIALYSIS PATIENTS, Health Care, functional, Intensive Care Units, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Good Health and Well Being, Nephrology, ERACODA, ERACODA Collaborators, Surgery, Management of diseases and conditions, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11]
Abstract

BACKGROUND: Kidney transplant patients are at high risk for coronavirus disease 2019 (COVID-19)-related mortality. However, limited data are available on longer-term clinical, functional, and mental health outcomes in patients who survive COVID-19.METHODS: We analyzed data from adult kidney transplant patients in the European Renal Association COVID-19 Database who presented with COVID-19 between February 1, 2020, and January 31, 2021.RESULTS: We included 912 patients with a mean age of 56.7 (±13.7) y. 26.4% were not hospitalized, 57.5% were hospitalized without need for intensive care unit (ICU) admission, and 16.1% were hospitalized and admitted to the ICU. At 3 mo follow-up survival was 82.3% overall, and 98.8%, 84.2%, and 49.0%, respectively, in each group. At 3 mo follow-up biopsy-proven acute rejection, need for renal replacement therapy, and graft failure occurred in the overall group in 0.8%, 2.6%, and 1.8% respectively, and in 2.1%, 10.6%, and 10.6% of ICU-admitted patients, respectively. Of the surviving patients, 83.3% and 94.4% reached their pre-COVID-19 physician-reported functional and mental health status, respectively, within 3 mo. Of patients who had not yet reached their prior functional and mental health status, their treating physicians expected that 79.6% and 80.0%, respectively, still would do so within the coming year. ICU admission was independently associated with a low likelihood to reach prior functional and mental health status.CONCLUSIONS: In kidney transplant recipients alive at 3-mo follow-up, clinical, physician-reported functional, and mental health recovery was good for both nonhospitalized and hospitalized patients. Recovery was, however, less favorable for patients who had been admitted to the ICU.

Published
2022

19. Listeria monocytogenes requires cellular respiration for NAD+ regeneration and pathogenesis

Author

Rivera-Lugo, Rafael, primary, Deng, David, primary, Anaya-Sanchez, Andrea, additional, Tejedor-Sanz, Sara, additional, Tang, Eugene, additional, Reyes Ruiz, Valeria M, additional, Smith, Hans B, additional, Titov, Denis V, additional, Sauer, John-Demian, additional, Skaar, Eric P, additional, Ajo-Franklin, Caroline M, additional, Portnoy, Daniel A, additional, and Light, Samuel H, additional

Published
2022
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21. Author response: Listeria monocytogenes requires cellular respiration for NAD+ regeneration and pathogenesis

Author

Rivera-Lugo, Rafael, primary, Deng, David, primary, Anaya-Sanchez, Andrea, additional, Tejedor-Sanz, Sara, additional, Tang, Eugene, additional, Reyes Ruiz, Valeria M, additional, Smith, Hans B, additional, Titov, Denis V, additional, Sauer, John-Demian, additional, Skaar, Eric P, additional, Ajo-Franklin, Caroline M, additional, Portnoy, Daniel A, additional, and Light, Samuel H, additional

Published
2022
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23. Listeria monocytogenes requires cellular respiration for NAD+ regeneration and pathogenesis

Author

Rivera-Lugo, Rafael, primary, Deng, David, additional, Anaya-Sanchez, Andrea, additional, Tejedor-Sanz, Sara, additional, Reyes Ruiz, Valeria M, additional, Smith, Hans B, additional, Titov, Denis V, additional, Sauer, John-Demian, additional, Skaar, Eric P, additional, Ajo-Franklin, Caroline M, additional, Portnoy, Daniel A, additional, and Light, Samuel H, additional

Published
2021
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30. Physical bioenergetics: Energy fluxes, budgets, and constraints in cells.

Author

Xingbo Yang, Heinemann, Matthias, Howard, Jonathon, Huber, Greg, Iyer-Biswas, Srividya, Le Treut, Guillaume, Lynch, Michael, Montooth, Kristi L., Needleman, Daniel J., Pigolotti, Simone, Rodenfels, Jonathan, Ronceray, Pierre, Shankar, Sadasivan, Tavassoly, Iman, Thutupalli, Shashi, Titov, Denis V., Jin Wang, and Foster, Peter J.

Subjects
FLUX (Energy), BIOENERGETICS, CYTOLOGY, ENERGY metabolism, OPEN-ended questions
Abstract

Cells are the basic units of all living matter which harness the flow of energy to drive the processes of life. While the biochemical networks involved in energy transduction are well-characterized, the energetic costs and constraints for specific cellular processes remain largely unknown. In particular, what are the energy budgets of cells? What are the constraints and limits energy flows impose on cellular processes? Do cells operate near these limits, and if so how do energetic constraints impact cellular functions? Physics has provided many tools to study nonequilibrium systems and to define physical limits, but applying these tools to cell biology remains a challenge. Physical bioenergetics, which resides at the interface of nonequilibrium physics, energy metabolism, and cell biology, seeks to understand how much energy cells are using, how they partition this energy between different cellular processes, and the associated energetic constraints. Here we review recent advances and discuss open questions and challenges in physical bioenergetics. [ABSTRACT FROM AUTHOR]

Published
2021
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31. Renin-Angiotensin System Blockers and the Risk of COVID-19–Related Mortality in Patients with Kidney Failure

Author

Soler, Maria Jose, Noordzij, Marlies, Abramowicz, Daniel, de Arriba, Gabriel, Basile, Carlo, van Buren, Marjolijn, Covic, Adrian, Crespo, Marta, Duivenvoorden, Raphaël, Massy, Ziad A., Ortiz, Alberto, Sanchez, J. Emilio, Petridou, Emily, Stevens, Kate, White, Colin, Vart, Priya, Gansevoort, Ron T., van der Net, Jeroen B., Essig, Marie, du Buf-Vereijken, Peggy W.G., van Ginneken, Betty, Maas, Nanda, Vogt, Liffert, van Jaarsveld, Brigit C., Jager, Kitty J., Bemelman, Frederike J., Klingenberg-Salahova, Farah, Heenan-Vos, Frederiek, Vervloet, Marc G., Nurmohamed, Azam, Verhofstede, Sabine, Maoujoud, Omar, Malfait, Thomas, Fialova, Jana, Melilli, Edoardo, Favà, Alexandre, Cruzado, Josep M., Perez, Nuria Montero, Lips, Joy, Krepel, Harmen, Adilovic, Harun, Hengst, Maaike, Rydzewski, Andrzej, Gellert, Ryszard, Oliveira, João, Alferes, Daniela G., Zakharova, Elena V., Ambuehl, Patrice Max, Winzeler, Rebecca, Lepeytre, Fanny, Rabaté, Clémentine, Rostoker, Guy, Marques, Sofia, Azasevac, Tijana, Katicic, Dajana, Dam, Marc ten, Krüger, Thilo, Brzosko, Szymon, van Zanen, A.L., Logtenberg, Susan J.J., Fricke, Lutz, Slebe, Jeroen J.P., Kemlin, Delphine, van de Wetering, Jacqueline, Reinders, Marlies E.J., Eiselt, Jaromir, Kielberger, Lukas, El-Wakil, Hala S., ElHafeez, Samar Abd, Canal, Cristina, Facundo, Carme, Ramos, Ana M., Debska-Slizien, Alicja, Veldhuizen, Nicoline M.H., Panagoutsos, Stylianos, Matceac, Irina, Nistor, Ionut, Cordos, Monica, Groeneveld, J.H.M, Jousma, Jolanda, Diekmann, Fritz, Pereira, Tiago Assis, Santos, Augusto Cesar S., Arias-Cabrales, Carlos, Llinàs-Mallol, Laura, Buxeda, Anna, Tàrrega, Carla Burballa, Redondo-Pachon, Dolores, Arenas Jimenez, Maria Dolores, Hofstra, Julia M., Franco, Antonio, Arroyo, David, Rodríguez-Ferrero, Maria Luisa, Manzanos, Sagrario Balda, Sosa Barrios, R. Haridian, Lemahieu, Wim, Bartelet, Karlijn, Dirim, Ahmet Burak, Demir, Erol, Sever, Mehmet Sukru, Turkmen, Aydin, Hollander, Daan A.M.J., Büttner, Stefan, de Vries, Aiko P.J., Meziyerh, Soufian, van der Helm, Danny, Mallat, Marko, Bouwsma, Hanneke, Sridharan, Sivakumar, Petruliene, Kristina, Maloney, Sharon-Rose, Verberk, Iris, van der Sande, Frank M., Christiaans, Maarten H.L., Hemmelder, Marc, Di Luca, Marina, Tuğlular, Serhan Z., Beerenhout, Charles, Luik, Peter T., Kerschbaum, Julia, Tiefenthaler, Martin, Watschinger, Bruno, Adema, Aaltje Y., Stepanov, Vadim A., Zulkarnaev, Alexey B., Turkmen, Kultigin, Fliedner, Anselm, Åsberg, Anders, Mjoen, Geir, Miyasato, Hitoshi, de Fijter, Carola W.H., Pini, Stefano, de Biase, Consuelo, Hilbrands, Luuk, Kerckhoffs, Angele, van de Logt, Anne Els, Maas, Rutger, Lebedeva, Olga, Lopez, Veronica, Reichert, Louis J.M., Verhave, Jacobien, Titov, Denis, Parshina, Ekaterina V., Zanoli, Luca, Marcantoni, Carmelita, van Gils-Verrij, Liesbeth E.A., Harty, John C., Meurs, Marleen, Myslak, Marek, Battaglia, Yuri, Lentini, Paolo, den Deurwaarder, Edwin, Stendahl, Maria, Rahimzadeh, Hormat, Schouten, Marcel, Rychlik, Ivan, Cabezas-Reina, Carlos J., Roca, Ana Maria, Nauta, Ferdau, Goffin, Eric, Kanaan, Nada, Labriola, Laura, Devresse, Arnaud, Diaz-Mareque, Anabel, Coca, Armando, Meijers, Björn K.I., Naesens, Maarten, Kuypers, Dirk, Desschans, Bruno, Tonnerlier, Annelies, Wissing, Karl M., Dedinska, Ivana, Pessolano, Giuseppina, Gandolfini, Ilaria, Maggiore, Umberto, Malik, Shafi, Papachristou, Evangelos, Franssen, Casper F.M., Berger, Stefan P., Meijer, Esther, Sanders, Jan Stephan F., Ponikvar, Jadranka Buturović, Pernat, Andreja Marn, Kovac, Damjan, Arnol, Miha, Ekart, Robert, Abrahams, Alferso C., Molenaar, Femke M., van Zuilen, Arjan D., Meijvis, Sabine C.A., Dolmans, Helma, Esposito, Pasquale, Krzesinski, Jean-Marie, Barahira, Jean Damacène, Gallieni, Maurizio, Martin-Moreno, Paloma Leticia, Guglielmetti, Gabriele, Guzzo, Gabriella, Luik, Antinus J., van Kuijk, Willi H.M., Stikkelbroeck, Lonneke W.H., Hermans, Marc M.H., Rimsevicius, Laurynas, Righetti, Marco, Islam, Mahmud, and Braak, Nicole Heitink-ter

Published
2021
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33. Anti-inflammaging effects of human alpha-1 antitrypsin

Author

Yuan, Ye, primary, DiCiaccio, Benedetto, additional, Li, Ying, additional, Elshikha, Ahmed S., additional, Titov, Denis, additional, Brenner, Brian, additional, Seifer, Lee, additional, Pan, Hope, additional, Karic, Nurdina, additional, Akbar, Mohammad A., additional, Lu, Yuanqing, additional, Song, Sihong, additional, and Zhou, Lei, additional

Published
2017
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37. Homozygous deletion inMICU1presenting with fatigue and lethargy in childhood

Author

Lewis-Smith, David, primary, Kamer, Kimberli J., additional, Griffin, Helen, additional, Childs, Anne-Marie, additional, Pysden, Karen, additional, Titov, Denis, additional, Duff, Jennifer, additional, Pyle, Angela, additional, Taylor, Robert W., additional, Yu-Wai-Man, Patrick, additional, Ramesh, Venkateswaran, additional, Horvath, Rita, additional, Mootha, Vamsi K., additional, and Chinnery, Patrick F., additional

Published
2016
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39. Anti‐inflammaging effects of human alpha‐1 antitrypsin.

Author

Yuan, Ye, DiCiaccio, Benedetto, Li, Ying, Elshikha, Ahmed S., Titov, Denis, Brenner, Brian, Seifer, Lee, Pan, Hope, Karic, Nurdina, Akbar, Mohammad A., Lu, Yuanqing, Song, Sihong, and Zhou, Lei

Subjects
TRYPSIN inhibitors, INFLAMMATION, DROSOPHILA, OSTEOPOROSIS, PROTEIN expression
Abstract

Summary: Inflammaging plays an important role in most age‐related diseases. However, the mechanism of inflammaging is largely unknown, and therapeutic control of inflammaging is challenging. Human alpha‐1 antitrypsin (hAAT) has immune‐regulatory, anti‐inflammatory, and cytoprotective properties as demonstrated in several disease models including type 1 diabetes, arthritis, lupus, osteoporosis, and stroke. To test the potential anti‐inflammaging effect of hAAT, we generated transgenic Drosophila lines expressing hAAT. Surprisingly, the lifespan of hAAT‐expressing lines was significantly longer than that of genetically matched controls. To understand the mechanism underlying the anti‐aging effect of hAAT, we monitored the expression of aging‐associated genes and found that aging‐induced expressions of Relish (NF‐ĸB orthologue) and Diptericin were significantly lower in hAAT lines than in control lines. RNA‐seq analysis revealed that innate immunity genes regulated by NF‐kB were significantly and specifically inhibited in hAAT transgenic Drosophila lines. To confirm this anti‐inflammaging effect in human cells, we treated X‐ray‐induced senescence cells with hAAT and showed that hAAT treatment significantly decreased the expression and maturation of IL‐6 and IL‐8, two major factors of senescence‐associated secretory phenotype. Consistent with results from Drosophila,RNA‐seq analysis also showed that hAAT treatment significantly inhibited inflammation related genes and pathways. Together, our results demonstrated that hAAT significantly inhibited inflammaging in both Drosophila and human cell models. As hAAT is a FDA‐approved drug with a confirmed safety profile, this novel therapeutic potential may make hAAT a promising candidate to combat aging and aging‐related diseases. [ABSTRACT FROM AUTHOR]

Published
2018
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43. Back Cover: Synthesis of Multivalent Carbohydrate‐Centered Glycoclusters as Nanomolar Ligands of the Bacterial Lectin LecA from Pseudomonas aeruginosa (Chem. Eur. J. 28/2013)

Author

Gening, Marina L., primary, Titov, Denis V., additional, Cecioni, Samy, additional, Audfray, Aymeric, additional, Gerbst, Alexey G., additional, Tsvetkov, Yury E., additional, Krylov, Vadim B., additional, Imberty, Anne, additional, Nifantiev, Nikolay E., additional, and Vidal, Sébastien, additional

Published
2013
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45. Linear and cyclic oligo-β-(1→6)-D-glucosamines: Synthesis, conformations, and applications for design of a vaccine and oligodentate glycoconjugates

Author

Gening, Marina L., primary, Tsvetkov, Yury E., additional, Titov, Denis V., additional, Gerbst, Alexey G., additional, Yudina, Olga N., additional, Grachev, Alexey A., additional, Shashkov, Alexander S., additional, Vidal, Sébastien, additional, Imberty, Anne, additional, Saha, Tanmoy, additional, Kand, Dnyaneshwar, additional, Talukdar, Pinaki, additional, Pier, Gerald B., additional, and Nifantiev, Nikolay E., additional

Published
2013
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46. XPB, a subunit of TFIIH, is a target of the natural product triptolide

Author

Titov, Denis V, primary, Gilman, Benjamin, additional, He, Qing-Li, additional, Bhat, Shridhar, additional, Low, Woon-Kai, additional, Dang, Yongjun, additional, Smeaton, Michael, additional, Demain, Arnold L, additional, Miller, Paul S, additional, Kugel, Jennifer F, additional, Goodrich, James A, additional, and Liu, Jun O, additional

Published
2011
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49. Linear and cyclic oligo-β-(1 → 6)-D-glucosamines: Synthesis, conformations, and applications for design of a vaccine and oligodentate glycoconjugates.

Author

Gening, Marina L., Tsvetkov, Yury E., Titov, Denis V., Gerbst, Alexey G., Yudina, Olga N., Grachev, Alexey A., Shashkov, Alexander S., Vidal, Sébastien, Imberty, Anne, Saha, Tanmoy, Kand, Dnyaneshwar, Talukdar, Pinaki, Pier, Gerald B., and Nifantiev, Nikolay E.

Subjects
GLUCOSAMINE synthase, GLYCOCONJUGATES, POLYSACCHARIDES, PATHOGENIC bacteria, STAPHYLOCOCCUS aureus, CARBOHYDRATES, SYNTHETIC vaccines
Abstract

Poly-β-(1 → 6)-N-acetyl-D-glucosamine is an exopolysaccharide secreted by numerous pathogenic bacteria, including Staphylococcus aureus, Escherichia coli, Yersinia pestis, Bordetella pertussis, Acinetobacter baumannii, Burkholderia spp., and others. A convergent approach was developed for the synthesis of oligosaccharide fragments consisting of 5, 7, 9, and 11 glucosamine or N-acetylglucosamine units and for the preparation of five nona-β-(1 → 6)-D-glucosamines with various N-acetylation patterns. Penta- and nonaβ-(1 → 6)-D-glucosamines conjugated to protein carriers through a specially developed sulfhydryl linker proved to be highly immunogenic in mice and rabbits and elicited antibodies that mediated opsonic killing of multiple strains of S. aureus (including methicillin-resistant S. aureus, MRSA) and E. coli, and protected against S. aureus skin abscesses and lethal E. coli and B. cenocepacia peritonitis. These findings provide a basis for the construction of a unique semisynthetic vaccine against multiple bacterial targets. Conformational studies by means of special NMR experiments and computer modeling revealed that the oligo-β-(1 → 6)-D-glucosamine chain exists mostly in a helix-like conformation, where the terminal monosaccharides are arranged close to each other. Owing to this feature, oligoglucosamines consisting of 2 to 7 residues easily form products of cycloglycosylation. Cyclooligo-β-(1 → 6)-D-glucosamines represent a new family of functionalized cyclic oligosaccharides. Owing to their molecular architectonics, these compounds are convenient scaffolds for the design of conjugates with defined valency, symmetry, flexibility, and function. [ABSTRACT FROM AUTHOR]

Published
2013
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50. Analyzing protein kinase dynamics in living cells with FRET reporters

Author

Ni, Qiang, Titov, Denis V., and Zhang, Jin

Subjects
*PROTEIN kinases, *PHOSPHOTRANSFERASES, *ENERGY transfer, *FORCE & energy
Abstract

Abstract: Genetically encoded reporters based on fluorescence resonance energy transfer (FRET) are being developed for analyzing spatiotemporal dynamics of kinase activities in living cells, as the activities of this class of enzymes are often dynamically regulated and spatially compartmentalized within specific signaling context. Here we describe a general modular design and engineering strategies for the development of activity reporters for kinases of interest, using A-kinase activity reporter (AKAR) as an illustrative example. Discussed here are basic structure of such reporters, design considerations, reporter gene construction, cellular and in vitro characterization. Strategies for improving specificity, dynamic range or sensitivity, reversibility and integrity of the reporter as well as basic methods for live-cell time-lapse imaging using these reporters are summarized. Discussion of using this approach in the study of MAPK cascades is also provided. These FRET-based kinase activity reporters, along with analogous probes based on alternative designs, provide real-time tracking of kinase dynamics with subcellular resolution, which should complement other methods and offer great opportunities to delineate the molecular mechanisms underlying the complex regulation of kinases. [Copyright &y& Elsevier]

Published
2006
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