scholarly journals The path to the 2017 Nobel Prize in Physiology or Medicine

2017 ◽  
Vol 17 (3) ◽  
pp. S1-S13 ◽  
Author(s):  
K. Lalchhandama
Keyword(s):  
Circadian Rhythm ◽  
Nobel Prize ◽  
Clock Gene ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Fruit Fly ◽  
Comprehensive Knowledge ◽  
Health Related ◽  
To Receive ◽  
Per Gene

Jeffrey C. Hall, Michael Rosbash and Michael W. Young are selected to receive the 2017 Nobel Prize in Physiology or Medicine 2017 “for their discoveries of molecular mechanisms controlling the circadian rhythm”. They discovered clock genes and their protein-products that control the circadian rhythm in the fruit fly, Drosophila melanogaster. Starting with their work on the major clock gene period (per) in the 1980s, they subsequently discovered novel genes such as Clock, cry, cycle, dbt, pdp1, per, tim, vri, and their mutations that affect the fruit fly daily behaviours. With the proteins these genes produce, their discoveries have established the understanding of a complex molecular network of clock genes and proteins. This comprehensive knowledge further enrich our perception of circadian rhythm in other animals, including us. Behind this knowledge is the foundation of understanding of many disease and health-related issues concerned with our genetics, hormones, and behaviour. Their discoveries are befitting of the Nobel Prize, but it is a bit of an irony that the pioneer discovers have already died and will forever be denied of their deservedly fame. The epoch-making discovery of per gene was in fact by Seymour Benzer and his student Ronald J. Konopka discovered in 1971. Konopka especially continued as one of the leading scientists, in many of the later discoveries. But life and luck for Nobel fame ran out for them.

Abstract 084: Significant Roles of Hyperglycemia and Obesity in the Disruption of Blood Pressure Circadian Rhythm in Leptin-receptor Mutant Db/db Mice

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Tianfei Hou ◽  
Wen Su ◽  
Ming Gong ◽  
Zhenheng Guo
Keyword(s):  
Blood Pressure ◽  
Circadian Rhythm ◽  
Clock Gene ◽  
Leptin Receptor ◽  
Clock Genes ◽  
The Body ◽  
Diabetic Patients ◽  
Receptor Mutant ◽  
Type 2 Diabetic

Blood pressure (BP) exhibits 24-hour rhythm. Loss of BP oscillation has been found in up to 75% diabetic patients and is associated with increased risks of target organ injuries. However, the mechanisms underlying the disruption of BP circadian rhythm in diabetes remain poorly understood. We and others have demonstrated that type 2 diabetic db/db mice in C57/KsJ background have hypertension and severely disrupted BP circadian rhythm. Since these db/db mice were severely hyperglycemic (>600 mg/dL) as well as obese, it is unclear which factor or both contribute to the disruption of BP oscillation. Moreover, it is unclear whether clock genes are involved in the diabetes associated disruption of BP circadian rhythm. To address these specific questions, we cross bred the leptin receptor mutated db/db mice in the C57BL/KsJ background with PERIOD2::LUCIFERASE knock in mice in C57BL/6J background. At 4-5 months old, the blood glucose in these db/db -Per2 mice was higher than controls (320.3 vs 153 mg/dL) but was significantly lower than the C57/KsJ - db/db mice (608.5 mg/dL). However, the body weight of these db/db -per2 mice was significantly higher than both the C57/KsJ- db/db (66.4 vs 44.8 g) as well as control mice (33.9 g). The metabolic flexibility, which is represented by respiratory exchange ratio and measured using TSE LabMaster Indirect Calorimetry System, was significantly compromised in the db/db -per2 mice when compared to controls. We then determined the BP in the db/db -per2 mice using radiotelemetry under 12: 12 light: dark cycle. The circadian parameters of BP, including period length, amplitude and acrophase were calculated using Chronos-fit software. The results demonstrated that db/db -per2 mice have normal BP value but disrupted BP circadian rhythm, with decreased power of 24h oscillation, diminished amplitude and shifted acrophase. However, the extent of the disruption was significantly less than that we have reported in the C57/KsJ- db/db mice. By using LumiCycle, we are currently investigating the clock gene functions in various tissues including SCN, aorta, liver, and etc isolated from db/db -Per2 mice. In summary, we demonstrated that both hyperglycemia and obesity significantly contribute to the disruption in BP circadian rhythm in db/db mice.

Molecular Mechanisms of Circadian Rhythm inLotus japonicusandArabidopsis thalianaAre Sufficiently Compatible to Regulate Heterologous Core Clock Genes Robustly

2012 ◽  
Vol 76 (12) ◽  
pp. 2332-2334 ◽  
Author(s):  
Hanayo UEOKA-NAKANISHI ◽  
Takafumi YAMASHINO ◽  
Kai ISHIDA ◽  
Mari KAMIOKA ◽  
Norihito NAKAMICHI ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Molecular Mechanisms ◽  
Clock Genes

scholarly journals Machine Learning and In-Vivo Expression Analyses Reveal Circadian Clock Features Predictive of Anxiety in Humans

2021 ◽  
Author(s):  
Aziz Zafar ◽  
Rebeccah Overton ◽  
Ziad Attia ◽  
Ahmet Ay ◽  
Krista Ingram
Keyword(s):  
Machine Learning ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Clock Gene ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Anxiety Symptoms ◽  
Circadian Phase ◽  
Functional Studies

Abstract Mood disorders, including anxiety, are associated with disruptions in circadian rhythms and are linked to polymorphisms in circadian clock genes. Molecular mechanisms underlying these connections may be direct—via transcriptional activity of clock genes on downstream mood pathways in the brain, or indirect—via clock gene influences on the phase and amplitude of circadian rhythms which, in turn, modulate physiological processes influencing mood. Employing machine learning combined with statistical approaches, we explored clock genotype combinations that predict risk for anxiety symptoms in a deeply phenotyped population. We identified multiple novel circadian genotypes predictive of anxiety, with the PER3B-AG/CRY1-CG genotype being the strongest predictor of anxiety risk in males. Molecular chronotyping, using clock gene expression oscillations, revealed that advanced circadian phase and robust circadian amplitudes are associated with high levels of anxiety symptoms. Further analyses revealed that individuals with advanced phases and pronounced circadian misalignment were at higher risk for severe anxiety symptoms. Our results support both direct and indirect influences of clock gene variants on mood: while sex-specific clock genotype combinations predictive of anxiety symptoms suggest direct effects on mood pathways, the mediation of PER3B effects on anxiety via diurnal preference measures and the association of circadian phase with anxiety symptoms provide evidence for indirect effects of the molecular clockwork on mood. Unraveling the complex molecular mechanisms underlying the links between circadian physiology and mood is essential to identifying the core clock genes to target in future functional studies, thereby advancing the development of non-invasive treatments for anxiety-related disorders.

scholarly journals The value of interdisciplinary research: lessons from the 2017 Nobel Prize in chronobiology

2018 ◽  
Vol 12 (1) ◽  
pp. 25-28
Author(s):  
Jadwiga M. Giebultowicz
Keyword(s):  
Nobel Prize ◽  
Molecular Mechanisms ◽  
Biological Clock ◽  
Basic Research ◽  
Fruit Fly ◽  
Short Review ◽  
Model Organisms ◽  
Biological Clocks ◽  
Daily Rhythms ◽  
Interdisciplinary Work

Since 1901, the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of humanity. The 2017 Nobel Prize in Physiology or Medicine was awarded jointly to Jeffrey C. Hall, Michael Rosbash and Michael W. Young “for their discoveries of molecular mechanisms controlling the circadian rhythm.” It may be surprising to learn that those three scientists dedicated their entire careers to research on the fruit fly, Drosophila melanogaster. However, as their studies progressed, it became increasingly clear that the mechanism of the biological clock that they discovered in Drosophila is very similar to a timekeeping mechanism present in mammals, including humans. Through interdisciplinary work between scientists performing basic research on model organisms and doctors working in medical schools, we have learned over time that daily rhythms support human health while disruption of these rhythms is associated with a range of pathological disorders such as cardiovascular problems, metabolic, neurological, and many other diseases. This short review will highlight critical milestones on the way to understanding biological clocks, focusing on the roles played by the three Nobel Prize winners.

scholarly journals Integrated RNA-seq Analysis Indicates Asynchrony in Clock Genes between Tissues under Spaceflight

Life ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 196
Author(s):  
Shin-ichiro Fujita ◽  
Lindsay Rutter ◽  
Quang Ong ◽  
Masafumi Muratani
Keyword(s):  
Clock Gene ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Rna Seq ◽  
Space Biology ◽  
Gene Expressions ◽  
Peripheral Tissues ◽  
Unique Approach ◽  
Lifestyle Related Diseases ◽  
Biology Research

Rodent models have been widely used as analogs for estimating spaceflight-relevant molecular mechanisms in human tissues. NASA GeneLab provides access to numerous spaceflight omics datasets that can potentially generate novel insights and hypotheses about fundamental space biology when analyzed in new and integrated fashions. Here, we performed a pilot study to elucidate space biological mechanisms across tissues by reanalyzing mouse RNA-sequencing spaceflight data archived on NASA GeneLab. Our results showed that clock gene expressions in spaceflight mice were altered compared with those in ground control mice. Furthermore, the results suggested that spaceflight promotes asynchrony of clock gene expressions between peripheral tissues. Abnormal circadian rhythms are associated not only with jet lag and sleep disorders but also with cancer, lifestyle-related diseases, and mental disorders. Overall, our findings highlight the importance of elucidating the causes of circadian rhythm disruptions using the unique approach of space biology research to one day potentially develop countermeasures that benefit humans on Earth and in space.

scholarly journals Activation of the clock gene TIMELESS by H3k27 acetylation promotes colorectal cancer tumorigenesis by binding to Myosin-9

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Meng Cao ◽  
Yi Wang ◽  
Yijing Xiao ◽  
Dandan Zheng ◽  
Chunchun Zhi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clock Gene ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Clock Genes ◽  
Tumor Development ◽  
Creb Binding Protein ◽  
Functional Studies

Abstract Background Colorectal cancer (CRC) is a common tumor characterized by its high mortality. However, the underlying molecular mechanisms that drive CRC tumorigenesis are unclear. Clock genes have important roles in tumor development. In the present study, the expression and functions of clock gene TIMELESS (encoding the Timeless protein) in CRC were investigated. Methods Immunohistochemistry, cell proliferation, migration, invasion, EMT and xenograft tumor experiments were used to prove the function of Timeless in the tumorigenesis of CRC. Immunoprecipitation, mass spectrometry, Immunofluorescence and Chromatin immunoprecipitation (ChIP) were utilized to clarify the mechanism of Timeless in regulating CRC tumorigenesis. Results We found that Timeless was upregulated in CRC tissues compared with corresponding normal tissues and its expression was closely associated with the TNM stages and overall survival of CRC patients. Functional studies demonstrated that Timeless promoted the proliferation, invasion, and EMT of CRC cells in vitro and in vivo. Mechanistic investigations showed that Timeless activated the β-catenin signal pathway by binding to Myosin-9, which binds to β-catenin to induce its nuclear translocation. The upregulation of Timeless was attributed to CREB-binding protein (CBP)/p300-mediated H3K27 acetylation of the promoter region of Timeless. Conclusion Timeless regulates the tumorigenesis of CRC by binding to and regulating myosin-9, suggesting Timeless might be a potential prognostic biomarker and therapeutic target for CRC.

scholarly journals Mechanism of circadian clock. The 2017 Nobel Prize in physiology or medicine

Kosmos ◽  
2018 ◽  
Vol 67 (2) ◽  
pp. 245-249
Author(s):  
Jadwiga M. Giebultowicz
Keyword(s):  
Nobel Prize ◽  
Molecular Mechanisms ◽  
Biological Clock ◽  
Basic Research ◽  
Fruit Fly ◽  
Short Review ◽  
Model Organisms ◽  
Biological Clocks ◽  
Medical Doctors ◽  
Daily Rhythms

Since 1901, the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of humanity. The 2017 Nobel Prize in Physiology or Medicine was awarded jointly to Jeffrey C. Hall, Michael Rosbash and Michael W. Young “for their discoveries of molecular mechanisms controlling the circadian rhythm.” It may be surprising to learn that those three scientists dedicated their entire careers to research on the fruit fly, Drosophila melanogaster. However, as their studies progressed, it became increasingly clear that the mechanism of the biological clock that they discovered in Drosophila is very similar to a timekeeping mechanism present in mammals, including humans. Through interdisciplinary work between scientists performing basic research on model organisms and medical doctors, we have learned over time that daily rhythms support human health while disruption of these rhythms is associated with a range of pathological disorders such as cardiovascular problems, metabolic, neurological, and many other diseases. This short review highlights critical milestones on the way to understanding biological clocks, focusing on the roles played by the three Nobel Prize winners.

scholarly journals Circadian Clock Component BMAL1 in the Paraventricular Nucleus Regulates Glucose Metabolism

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4487
Author(s):  
Masanori Nakata ◽  
Parmila Kumari ◽  
Rika Kita ◽  
Nanako Katsui ◽  
Yuriko Takeuchi ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Paraventricular Nucleus ◽  
Clock Gene ◽  
Clock Genes ◽  
Circadian Variation ◽  
Glucose And Lipid Metabolism ◽  
Clock Component

It is suggested that clock genes link the circadian rhythm to glucose and lipid metabolism. In this study, we explored the role of the clock gene Bmal1 in the hypothalamic paraventricular nucleus (PVN) in glucose metabolism. The Sim1-Cre-mediated deletion of Bmal1 markedly reduced insulin secretion, resulting in impaired glucose tolerance. The pancreatic islets’ responses to glucose, sulfonylureas (SUs) and arginine vasopressin (AVP) were well maintained. To specify the PVN neuron subpopulation targeted by Bmal1, the expression of neuropeptides was examined. In these knockout (KO) mice, the mRNA expression of Avp in the PVN was selectively decreased, and the plasma AVP concentration was also decreased. However, fasting suppressed Avp expression in both KO and Cre mice. These results demonstrate that PVN BMAL1 maintains Avp expression in the PVN and release to the circulation, possibly providing islet b-cells with more AVP. This action helps enhance insulin release and, consequently, glucose tolerance. In contrast, the circadian variation of Avp expression is regulated by feeding, but not by PVN BMAL1.

Organization of endogenous clocks in insects

2005 ◽  
Vol 33 (5) ◽  
pp. 957-961 ◽  
Author(s):  
C. Helfrich-Förster
Keyword(s):  
Drosophila Melanogaster ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Fruit Fly ◽  
Circadian Clocks ◽  
Rhythm Generation ◽  
Similarities And Differences ◽  
The Brain ◽  
Master Clock

Insect and mammalian circadian clocks show striking similarities. They utilize homologous clock genes, generating self-sustained circadian oscillations in distinct master clocks of the brain, which then control rhythmic behaviour. The molecular mechanisms of rhythm generation were first uncovered in the fruit fly Drosophila melanogaster, whereas cockroaches were among the first animals where the brain master clock was localized. Despite many similarities, there exist obvious differences in the organization and functioning of insect master clocks. These similarities and differences are reviewed on a molecular and anatomical level.

Sign in / Sign up

Export Citation Format

Share Document