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6. Lifetime Prediction as Result of Calculated Component Loads from Available System Data

Author

Wöll, Lothar, Jacobs, Georg, Kramer, Achim, Cavas-Martínez, Francisco, Series Editor, Chaari, Fakher, Series Editor, Gherardini, Francesco, Series Editor, Haddar, Mohamed, Series Editor, Ivanov, Vitalii, Series Editor, Kwon, Young W., Series Editor, Trojanowska, Justyna, Series Editor, Liyanage, Jayantha P., editor, Amadi-Echendu, Joe, editor, and Mathew, Joseph, editor

Published
2020
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9. Guidelines for Genome-Scale Analysis of Biological Rhythms

Author

Hughes, Michael E, Abruzzi, Katherine C, Allada, Ravi, Anafi, Ron, Arpat, Alaaddin Bulak, Asher, Gad, Baldi, Pierre, de Bekker, Charissa, Bell-Pedersen, Deborah, Blau, Justin, Brown, Steve, Ceriani, M Fernanda, Chen, Zheng, Chiu, Joanna C, Cox, Juergen, Crowell, Alexander M, DeBruyne, Jason P, Dijk, Derk-Jan, DiTacchio, Luciano, Doyle, Francis J, Duffield, Giles E, Dunlap, Jay C, Eckel-Mahan, Kristin, Esser, Karyn A, FitzGerald, Garret A, Forger, Daniel B, Francey, Lauren J, Fu, Ying-Hui, Gachon, Frédéric, Gatfield, David, de Goede, Paul, Golden, Susan S, Green, Carla, Harer, John, Harmer, Stacey, Haspel, Jeff, Hastings, Michael H, Herzel, Hanspeter, Herzog, Erik D, Hoffmann, Christy, Hong, Christian, Hughey, Jacob J, Hurley, Jennifer M, de la Iglesia, Horacio O, Johnson, Carl, Kay, Steve A, Koike, Nobuya, Kornacker, Karl, Kramer, Achim, Lamia, Katja, Leise, Tanya, Lewis, Scott A, Li, Jiajia, Li, Xiaodong, Liu, Andrew C, Loros, Jennifer J, Martino, Tami A, Menet, Jerome S, Merrow, Martha, Millar, Andrew J, Mockler, Todd, Naef, Felix, Nagoshi, Emi, Nitabach, Michael N, Olmedo, Maria, Nusinow, Dmitri A, Ptáček, Louis J, Rand, David, Reddy, Akhilesh B, Robles, Maria S, Roenneberg, Till, Rosbash, Michael, Ruben, Marc D, Rund, Samuel SC, Sancar, Aziz, Sassone-Corsi, Paolo, Sehgal, Amita, Sherrill-Mix, Scott, Skene, Debra J, Storch, Kai-Florian, Takahashi, Joseph S, Ueda, Hiroki R, Wang, Han, Weitz, Charles, Westermark, Pål O, Wijnen, Herman, Xu, Ying, Wu, Gang, Yoo, Seung-Hee, Young, Michael, Zhang, Eric Erquan, Zielinski, Tomasz, and Hogenesch, John B

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Cancer, Bioengineering, Human Genome, Genetics, Generic health relevance, Biostatistics, Circadian Rhythm, Computational Biology, Genome, Genomics, Humans, Metabolomics, Proteomics, Software, Statistics as Topic, Systems Biology, circadian rhythms, diurnal rhythms, computational biology, functional genomics, systems biology, guidelines, biostatistics, RNA-seq, ChIP-seq, proteomics, metabolomics, Physiology, Neurosciences, Medical Physiology, Neurology & Neurosurgery, Zoology, Biological psychology
Abstract

Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding "big data" that are conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome-scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them.

Published
2017

10. Circadian period is compensated for repressor protein turnover rates in single cells.

Author

Gabriel, Christian H., del Olmo, Marta, Widini, Arunya Rizki, Roshanbin, Rashin, Woyde, Jonas, Hamza, Ebrahim, Gutu, Nica-Nicoleta, Zehtabian, Amin, Ewers, Helge, Granada, Adrian, Herzel, Hanspeter, and Kramer, Achim

Subjects
FLUORESCENT proteins, PROTEIN stability, CHIMERIC proteins, MESSENGER RNA, MOLECULAR clock
Abstract

Most mammalian cells have molecular circadian clocks that generate widespread rhythms in transcript and protein abundance. While circadian clocks are robust to fluctuations in the cellular environment, little is known about the mechanisms by which the circadian period compensates for fluctuating metabolic states. Here, we exploit the heterogeneity of single cells both in circadian period and a metabolic parameter--protein stability--to study their interdependence without the need for genetic manipulation. We generated cells expressing key circadian proteins (CRYPTOCHROME1/2 (CRY1/2) and PERIOD1/2 (PER1/2)) as endogenous fusions with fluorescent proteins and simultaneously monitored circadian rhythms and degradation in thousands of single cells. We found that the circadian period compensates for fluctuations in the turnover rates of circadian repressor proteins and uncovered possible mechanisms using a mathematical model. In addition, the stabilities of the repressor proteins are circadian phase dependent and correlate with the circadian period in a phase-dependent manner, in contrast to the prevailing model. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Circadian rhythms in septic shock patients

Author

Lachmann, Gunnar, Ananthasubramaniam, Bharath, Wünsch, Viktor A., Scherfig, Lara-Marie, von Haefen, Clarissa, Knaak, Cornelia, Edel, Andreas, Ehlen, Lukas, Koller, Barbara, Goldmann, Anton, Herzel, Hanspeter, Kramer, Achim, and Spies, Claudia

Published
2021
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19. Circadian protein expression patterns in healthy young adults

Author

Specht, Adrien, primary, Kolosov, German, additional, Cederberg, Katie L.J., additional, Bueno, Flavia, additional, Arrona-Palacios, Arturo, additional, Pardilla-Delgado, Enmanuelle, additional, Ruiz-Herrera, Noelia, additional, Zitting, Kirsi-Marja, additional, Kramer, Achim, additional, Zeitzer, Jamie M., additional, Czeisler, Charles A., additional, Duffy, Jeanne F., additional, and Mignot, Emmanuel, additional

Published
2023
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28. High-accuracy determination of internal circadian time from a single blood sample

Author

Wittenbrink, Nicole, Ananthasubramaniam, Bharath, Munch, Mirjam, Koller, Barbara, Maier, Bert, Weschke, Charlotte, Bes, Frederik, de Zeeuw, Jan, Nowozin, Claudia, Wahnschaffe, Amely, Wisniewski, Sophia, Zaleska, Mandy, Bartok, Osnat, Ashwal-Fluss, Reut, Lammert, Hedwig, Herzel, Hanspeter, Hummel, Michael, Kadener, Sebastian, Kunz, Dieter, and Kramer, Achim

Subjects
Medical care -- Innovations, Circadian rhythms -- Health aspects, Medical research, Health care industry
Abstract

BACKGROUND. The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism, and behavior, and it is essential to health. Whereas therapy adapted to time of day is increasingly reported to be highly successful, it needs to be personalized, since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors, including genetic predisposition, age, sex, environmental light levels, and season. An easy and convenient diagnostic tool is currently missing. METHODS. To establish a validated test, we followed a 3-stage biomarker development strategy: (a) using circadian transcriptomics of blood monocytes from 12 individuals in a constant routine protocol combined with machine learning approaches, we identified biomarkers for internal time; and these biomarkers (b) were migrated to a clinically relevant gene expression profiling platform (NanoString) and (c) were externally validated using an independent study with 28 early or late chronotypes. RESULTS. We developed a highly accurate and simple assay (BodyTime) to estimate the internal circadian time in humans from a single blood sample. Our assay needs only a small set of blood-based transcript biomarkers and is as accurate as the current gold standard method, dim-light melatonin onset, at smaller monetary, time, and sample-number cost. CONCLUSION. The BodyTime assay provides a new diagnostic tool for personalization of health care according to the patient's circadian clock. FUNDING. This study was supported by the Bundesministerium fur Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany., Introduction Many fundamental aspects of human physiology, metabolism, and behavior display 24-hour rhythms. These are found at all levels--from cells, tissues, and organs to the entire organism (for a review [...]

Published
2018
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35. Effects of early vs. late time-restricted eating on 24-hour glucose profiles and internal circadian time

Author

Peters, Beeke, additional, Schwarz, Julia, additional, Schuppelius, Bettina, additional, Ottawa, Agnieszka, additional, Koppold, Daniela A., additional, Int-Veen, Tillman, additional, Manlik, Tanja, additional, Arnrich, Bert, additional, Pfeiffer, Andreas, additional, Michalsen, Andreas, additional, Kramer, Achim, additional, Steckhan, Nico, additional, and Pivovarova-Ramich, Olga, additional

Published
2023
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37. Alternative polyadenylation factor CPSF6 regulates temperature compensation of the mammalian circadian clock

Author

Schmal, Christoph, Maier, Bert, Ashwal-Fluss, Reut, Bartok, Osnat, Finger, Anna-Marie, Bange, Tanja, Koutsouli, Stella, Robles, Maria S., Kadener, Sebastian, Herzel, Hanspeter, Kramer, Achim, Schmal, Christoph, Maier, Bert, Ashwal-Fluss, Reut, Bartok, Osnat, Finger, Anna-Marie, Bange, Tanja, Koutsouli, Stella, Robles, Maria S., Kadener, Sebastian, Herzel, Hanspeter, and Kramer, Achim

Abstract

A defining property of circadian clocks is temperature compensation, characterized by the resilience of their near 24-hour free-running periods against changes in environmental temperature within the physiological range. While temperature compensation is evolutionary conserved across different taxa of life and has been studied within many model organisms, its molecular underpinnings remain elusive. Posttranscriptional regulations such as temperature-sensitive alternative splicing or phosphorylation have been described as underlying reactions. Here, we show that knockdown of cleavage and polyadenylation specificity factor subunit 6 (CPSF6), a key regulator of 3′-end cleavage and polyadenylation, significantly alters circadian temperature compensation in human U-2 OS cells. We apply a combination of 3′-end-RNA-seq and mass spectrometry–based proteomics to globally quantify changes in 3′ UTR length as well as gene and protein expression between wild-type and CPSF6 knockdown cells and their dependency on temperature. Since changes in temperature compensation behavior should be reflected in alterations of temperature responses within one or all of the 3 regulatory layers, we statistically assess differential responses upon changes in ambient temperature between wild-type and CPSF6 knockdown cells. By this means, we reveal candidate genes underlying circadian temperature compensation, including eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)., Peer Reviewed

Published
2023

38. A conditional Smg6 mutant mouse model reveals circadian clock regulation through the nonsense-mediated mRNA decay pathway

Author

Katsioudi, Georgia; https://orcid.org/0000-0001-7007-9832, Dreos, René; https://orcid.org/0000-0002-0816-7775, Arpa, Enes S; https://orcid.org/0000-0001-9685-5115, Gaspari, Sevasti; https://orcid.org/0000-0002-0596-4840, Liechti, Angelica; https://orcid.org/0000-0002-0166-0639, Sato, Miho; https://orcid.org/0000-0001-9321-8487, Gabriel, Christian H; https://orcid.org/0000-0003-2081-1743, Kramer, Achim; https://orcid.org/0000-0001-9671-6078, Brown, Steven A; https://orcid.org/0000-0001-5511-568X, Gatfield, David; https://orcid.org/0000-0001-5114-2824, Katsioudi, Georgia; https://orcid.org/0000-0001-7007-9832, Dreos, René; https://orcid.org/0000-0002-0816-7775, Arpa, Enes S; https://orcid.org/0000-0001-9685-5115, Gaspari, Sevasti; https://orcid.org/0000-0002-0596-4840, Liechti, Angelica; https://orcid.org/0000-0002-0166-0639, Sato, Miho; https://orcid.org/0000-0001-9321-8487, Gabriel, Christian H; https://orcid.org/0000-0003-2081-1743, Kramer, Achim; https://orcid.org/0000-0001-9671-6078, Brown, Steven A; https://orcid.org/0000-0001-5511-568X, and Gatfield, David; https://orcid.org/0000-0001-5114-2824

Abstract

Nonsense-mediated messenger RNA (mRNA) decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in physiological control of mRNA stability have emerged, possible functions in mammalian physiology in vivo remain unclear. Here, we created a conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein. We find that NMD down-regulation affects the function of the circadian clock, a system known to require rapid mRNA turnover. Specifically, we uncover strong lengthening of free-running circadian periods for liver and fibroblast clocks and direct NMD regulation of Cry2 mRNA, encoding a key transcriptional repressor within the rhythm-generating feedback loop. Transcriptome-wide changes in daily mRNA accumulation patterns in the entrained liver, as well as an altered response to food entrainment, expand the known scope of NMD regulation in mammalian gene expression and physiology.

Published
2023

39. Investigation of drivetrain dynamics on low-μ ground using the brush model

Author

Yang, Jianing, Jacobs, Georg, and Kramer, Achim

Abstract

This paper aims to investigate the influence of the low-friction ground on off-highway drivetrain dynamics. A comprehensive vehicle simulation model is established for this purpose. This vehicle model consists of three parts: the torsional drivetrain model, the vehicle body model of longitudinal dynamics and the tyre model with slip behaviour. To correctly reflect tyre slip behaviour, the brush model, which features a physical description of the tyre-ground contact patch, is applied. A group of simulations is carried out on the complete vehicle model, mainly from two perspectives: drivetrain eigen-modes and drivetrain transient response. For the drivetrain eigen-mode analysis, different tyre slip states and the transition process between these two states are taken into consideration. For the drivetrain transient response, the vehicle is assumed to drive over a patch of low-μ ground. The drivetrain oscillation is analysed, and factors such as driving speed and low-μ ground length are investigated.

Published
2024
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46. A conditional Smg6 mutant mouse model reveals circadian clock regulation through the nonsense-mediated mRNA decay pathway

Author

Katsioudi, Georgia, Dreos, René, Arpa, Enes S, Gaspari, Sevasti, Liechti, Angelica, Sato, Miho, Gabriel, Christian H, Kramer, Achim, Brown, Steven A, Gatfield, David, University of Zurich, and Gatfield, David

Subjects
1000 Multidisciplinary, 570 Life sciences, biology, 10050 Institute of Pharmacology and Toxicology, 610 Medicine & health, Animals, Mice, Circadian Clocks/genetics, Codon, Nonsense/genetics, Nonsense Mediated mRNA Decay, RNA Processing, Post-Transcriptional, RNA, Messenger/genetics, RNA, Messenger/metabolism, Transcription Factors/metabolism
Abstract

Nonsense-mediated messenger RNA (mRNA) decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in physiological control of mRNA stability have emerged, possible functions in mammalian physiology in vivo remain unclear. Here, we created a conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein. We find that NMD down-regulation affects the function of the circadian clock, a system known to require rapid mRNA turnover. Specifically, we uncover strong lengthening of free-running circadian periods for liver and fibroblast clocks and direct NMD regulation of Cry2 mRNA, encoding a key transcriptional repressor within the rhythm-generating feedback loop. Transcriptome-wide changes in daily mRNA accumulation patterns in the entrained liver, as well as an altered response to food entrainment, expand the known scope of NMD regulation in mammalian gene expression and physiology.

Published
2023
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49. Global disruption of the circadian clock impairs bone regeneration in a standardized murine fracture model

Author

Jahn, Denise, Witte, Jason, Köhli, Paul, Rahmani, Adibeh, Otto, Ellen, Finger, Anna-Marie, Duda, Georg N., Kramer, Achim, Keller, Johannes, and Tsitsilonis, Serafeim

Subjects
circadian rhythm, Bmal1, fracture, circadian clock, Medicine and health, healing, bone
Abstract

Objectives: The circadian clock controls fundamental physiological processes, such as body temperature, metabolic activity, and hormonal balance. In many tissues, more than 10 percent of genes are expressed in a circadian manner, indicating a pivotal role in both physiological and pathological processes. [for full text, please go to the a.m. URL]

Published
2022
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