Circadian Rhythm of Output from Neurones in the Eye of Aplysia: II. Effects of Cold Pulses on a Population of Coupled Oscillators

1977 ◽  
Vol 70 (1) ◽  
pp. 167-181
Author(s):  
JACK A. BENSON ◽  
JON W. JACKLET
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Coupled Oscillators ◽  
Phase Point ◽  
Frequency Curve ◽  
Phase Angle Difference ◽  
Long Duration ◽  
Large Phase ◽  
East West ◽  
Frequency Curves

1. The circadian clock that controls CAP frequency was stopped at or near its lowest phase point by long duration cold pulses of 6 °C. On return to normal recording temperature (15 °C), the rhythm was always reinitiated from this phase point. 2. Following long cold pulses, there was often a transient peak of CAP activity lasting 2-6 h. It is thought that this was an effect of rise in temperature after prolonged cooling and not an effect on the clock itself. 3. Twelve h cold pulses, spanning the rhythm peak, caused phase delays. 9 °C pulses caused small delays (e.g. 1.7 h) while large phase delays (e.g. 6.7 h) followed pulses of 5 °C. Some pulses at an intermediate temperature (8.5 °C) caused abnormal post-pulse cycles lasting several days, and resulting in very large phase delays (10–14 n). 4. The abnormal CAP frequency curves following 12 h cold pulses of 8.5 °C spanning the rhythm peak are interpreted as rhythm splits. It is postulated that part of the population of coupled oscillators comprising the circadian clock was slightly delayed by the cold pulse, while the other part was driven further towards the “stopped” state, thus producing a large phase angle difference between the two subpopulations. These drew one another back into phase during several cycles to reform a normal circadian rhythm. 5. It is hypothesized that the circadian oscillations of the two subpopulations did not sum to produce the observed CAP frequency curve; rather the level of CAP output was controlled by whichever subpopulation was discharging at the higher frequency. Note: Laboratory of Sensory Sciences, University of Hawaii at Manoa, 1993 East-West Road, Honolulu, Hawaii 96822, U.S.A.

Circadian Rhythm of Output from Neurones in the Eye of Aplysia: III. Effects of Light on Clock and Receptor Output Measured in the Optic Nerve

1977 ◽  
Vol 70 (1) ◽  
pp. 183-194
Author(s):  
JACK A. BENSON ◽  
JON W. JACKLET
Keyword(s):  
Circadian Rhythm ◽  
Optic Nerve ◽  
Circadian Clock ◽  
Light Pulse ◽  
Temperature Sensitivity ◽  
Phase Point ◽  
Light Onset ◽  
Constant Illumination ◽  
Light Pulses ◽  
East West

1. The circadian rhythm of CAP frequency recorded from the optic nerve of isolated eyes at 15 °C was damped out by constant illumination (1100 lux) after several cycles of the rhythm. During illumination (LL) the rhythm was skewed with a rapid rising phase and slow falling phase, and the period was decreased by about 1 h. It is postulated that the circadian clock was stopped by LL at its lowest phase point, and that following cessation of LL, the rhythm was reinitiated from this phase point after a latency of 6-8 h. 2. For light pulses of 80 lux and 1100 lux, the photoresponse of the dark-adapted eye to 20 min light pulses applied beginning at 2 h intervals was not influenced by the circadian clock. At 5 lux there was a periodicity in the magnitude of the photoresponse, in phase with the circadian rhythm of spontaneous CAP production. 3. Small CAPs of non-circadian frequency were recorded together with normal CAPs in about 10% of records of output from isolated eyes. The cells producing the small CAPs had a different temperature sensitivity from those producing normal CAPs. The response of these cells to short light pulses consisted of a phasic burst of activity at light onset, followed by silence during the remainder of the short light pulse, and for 1 or 2 min following cessation of illumination. These small CAPs may be the activity either of H-type receptors or of secondary cells desynchronized from the major population. Note: Laboratory of Sensory Sciences, University of Hawaii at Manoa, 1993 East-West Road, Honolulu, Hawaii 96822, U.S.A.

scholarly journals PER2 Circadian Oscillation Sensitizes Esophageal Cancer Cells to Chemotherapy

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 266
Author(s):  
Juan Alfonso Redondo ◽  
Romain Bibes ◽  
Alizée Vercauteren Drubbel ◽  
Benjamin Dassy ◽  
Xavier Bisteau ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Circadian Rhythm ◽  
Survival Rate ◽  
Circadian Clock ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Response To Therapy ◽  
Circadian Oscillation ◽  
Resistance To Therapy

Esophageal squamous cell carcinoma (eSCC) accounts for more than 85% cases of esophageal cancer worldwide and the 5-year survival rate associated with metastatic eSCC is poor. This low survival rate is the consequence of a complex mechanism of resistance to therapy and tumor relapse. To effectively reduce the mortality rate of this disease, we need to better understand the molecular mechanisms underlying the development of resistance to therapy and translate that knowledge into novel approaches for cancer treatment. The circadian clock orchestrates several physiological processes through the establishment and synchronization of circadian rhythms. Since cancer cells need to fuel rapid proliferation and increased metabolic demands, the escape from circadian rhythm is relevant in tumorigenesis. Although clock related genes may be globally repressed in human eSCC samples, PER2 expression still oscillates in some human eSCC cell lines. However, the consequences of this circadian rhythm are still unclear. In the present study, we confirm that PER2 oscillations still occur in human cancer cells in vitro in spite of a deregulated circadian clock gene expression. Profiling of eSCC cells by RNAseq reveals that when PER2 expression is low, several transcripts related to apoptosis are upregulated. Consistently, treating eSCC cells with cisplatin when PER2 expression is low enhances DNA damage and leads to a higher apoptosis rate. Interestingly, this process is conserved in a mouse model of chemically-induced eSCC ex vivo. These results therefore suggest that response to therapy might be enhanced in esophageal cancers using chronotherapy.

scholarly journals Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

2021 ◽  
Vol 22 (2) ◽  
pp. 676
Author(s):  
Andy W. C. Man ◽  
Huige Li ◽  
Ning Xia
Keyword(s):  
Circadian Rhythm ◽  
Cardiovascular Diseases ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Therapeutic Target ◽  
Environmental Changes ◽  
Clock Genes ◽  
Vascular System ◽  
Peripheral Tissues ◽  
Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: A sense of time of the glucocorticoid circadian clock: from the ontogeny to the diagnosis of Cushing’s syndrome

2018 ◽  
Vol 179 (1) ◽  
pp. R1-R18 ◽  
Author(s):  
Ayrton Custodio Moreira ◽  
Sonir Rauber Antonini ◽  
Margaret de Castro
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Clock Genes ◽  
Circadian Variation ◽  
Circadian System ◽  
Feedback Loops ◽  
Adrenal Axis ◽  
Sense Of Time ◽  
Pituitary Adrenal Axis ◽  
Hierarchical Manner

The circadian rhythm of glucocorticoids has long been recognised within the last 75 years. Since the beginning, researchers have sought to identify basic mechanisms underlying the origin and emergence of the corticosteroid circadian rhythmicity among mammals. Accordingly, Young, Hall and Rosbash, laureates of the 2017 Nobel Prize in Physiology or Medicine, as well as Takahashi’s group among others, have characterised the molecular cogwheels of the circadian system, describing interlocking transcription/translation feedback loops essential for normal circadian rhythms. Plasma glucocorticoid circadian variation depends on the expression of intrinsic clock genes within the anatomic components of the hypothalamic–pituitary–adrenal axis, which are organised in a hierarchical manner. This review presents a general overview of the glucocorticoid circadian clock mechanisms, highlighting the ontogeny of the pituitary–adrenal axis diurnal rhythmicity as well as the involvement of circadian rhythm abnormalities in the physiopathology and diagnosis of Cushing’s disease.

Abstract 3: Cellular Contributions of the Circadian Clock in Atherogenesis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Xueling Li ◽  
Ling Ruan ◽  
Austin Bentley ◽  
Stephen Haigh ◽  
Yuqing Huo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Circadian Rhythm ◽  
Circadian Clock ◽  
Cell Types ◽  
No Production ◽  
Light Cycle ◽  
Lipid Uptake ◽  
Enhanced Production ◽  
The Impact

Atherosclerosis is a leading cause of death despite the improvements in lipid and blood pressure control. The circadian clock, a molecular network of genes and proteins that controls 24-hour timing, has emerged to have a surprising role in the control of metabolic and vascular function. Herein we examined the impact of circadian rhythm dysfunction in atherogenesis by implementation of vascular transplant and PCSK9 based approaches to induce accelerated lesion development in mice. We find that atherogenesis is exacerbated in Bmal1-KO aortic grafts immersed in the hypercholesterolemic milieu of ApoE -/- mice. To assess if atherosclerosis was ‘circadian rhythm dependent’ we subjected wild-type mice to a shortened light cycle (4L/4D) and induced atherosclerosis by intravenous injection of a human PCSK-9 adeno associated virus. Atherosclerosis in the jet-lagged PCSK-9 mice was robustly increased relative to the atherosclerosis observed in WT mice on a normal light cycle (12L/12D), providing further evidence that circadian rhythm and the circadian clock contribute to atherosclerosis. However, atherosclerosis is a complex disease that is the net result of interplay between intrinsic (vascular cells) and extrinsic mechanisms (metabolism, blood pressure, and hormones) and the importance of clock function in individual cell types is poorly understood. We found that deletion or silencing of key circadian transcription factors resulted in an enhanced inflammatory and pro-oxidant phenotype with diminished NO production and greater lipid uptake in both macrophages and endothelial cells. Loss of circadian function in smooth muscle cells similarly resulted in enhanced production of reactive oxygen species and greater cell proliferation. Surprising, the silencing of Bmal2 in endothelial cells resulted in greater lipid uptake in oxLDL treated HAEC as well as increased expression of markers of autophagy, suggesting that Bmal2 may orchestrate numerous output functions in different cell types. In conclusion, we find that the circadian clock and circadian rhythm have a profound impact on atherosclerosis, to influence vascular cell inflammatory and lipid uptake responses, and identify an unexpectedly prominent role for the side-partner of Bmal1, Bmal2.

scholarly journals “Gut Microbiota-Circadian Clock Axis” in Deciphering the Mechanism Linking Early-Life Nutritional Environment and Abnormal Glucose Metabolism

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Liyuan Zhou ◽  
Lin Kang ◽  
Xinhua Xiao ◽  
Lijing Jia ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Circadian Rhythm ◽  
Gut Microbiota ◽  
Circadian Clock ◽  
Early Life ◽  
Metabolic Diseases ◽  
Clock Genes ◽  
Early Stage ◽  
Adult Life ◽  
Metabolic Memory

The prevalence of diabetes mellitus (DM) has been increasing dramatically worldwide, but the pathogenesis is still unknown. A growing amount of evidence suggests that an abnormal developmental environment in early life increases the risk of developing metabolic diseases in adult life, which is referred to as the “metabolic memory” and the Developmental Origins of Health and Disease (DOHaD) hypothesis. The mechanism of “metabolic memory” has become a hot topic in the field of DM worldwide and could be a key to understanding the pathogenesis of DM. In recent years, several large cohort studies have shown that shift workers have a higher risk of developing type 2 diabetes mellitus (T2DM) and worse control of blood glucose levels. Furthermore, a maternal high-fat diet could lead to metabolic disorders and abnormal expression of clock genes and clock-controlled genes in offspring. Thus, disorders of circadian rhythm might play a pivotal role in glucose metabolic disturbances, especially in terms of early adverse nutritional environments and the development of metabolic diseases in later life. In addition, as a peripheral clock, the gut microbiota has its own circadian rhythm that fluctuates with periodic feeding and has been widely recognized for its significant role in metabolism. In light of the important roles of the gut microbiota and circadian clock in metabolic health and their interconnected regulatory relationship, we propose that the “gut microbiota-circadian clock axis” might be a novel and crucial mechanism to decipher “metabolic memory.” The “gut microbiota-circadian clock axis” is expected to facilitate the future development of a novel target for the prevention and intervention of diabetes during the early stage of life.

CORTISOL CIRCADIAN RHYTHM AND INSULIN RESISTANCE IN MUSCLE: EFFECT OF DOSING AND TIMING OF HYDROCORTISONE EXPOSURE ON INSULIN SENSITIVITY IN SYNCHRONIZED MUSCLE CELLS.

2020 ◽  
Author(s):  
Mariarosaria Negri ◽  
Claudia Pivonello ◽  
Chiara Simeoli ◽  
Gilda Di Gennaro ◽  
Mary Anna Venneri ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Circadian Rhythm ◽  
Insulin Sensitivity ◽  
Circadian Clock ◽  
Insulin Signaling ◽  
Clock Genes ◽  
Muscle Cells ◽  
C2c12 Cells ◽  
Circadian Expression

Introduction/Aim: Circadian rhythm disruption is emerging as a risk factor for metabolic disorders and particularly, alterations in clock genes circadian expression have been shown to influence insulin sensitivity. Recently, the reciprocal interplay between the circadian clock machinery and HPA axis has been largely demonstrated: the circadian clock may control the physiological circadian endogenous glucocorticoids secretion and action; glucocorticoids, in turn, are potent regulator of the circadian clock and their inappropriate replacement has been associated with metabolic impairment. The aim of the current study was to investigate in vitro the interaction between the timing-of-the-day exposure to different hydrocortisone (HC) concentrations on muscle insulin sensitivity. Methods: Serum-shock synchronized mouse skeletal muscle C2C12 cells were exposed to different HC concentrations recapitulating the circulating daily physiological cortisol profile (standard cortisol profile), the circulating daily cortisol profile that reached in adrenal insufficient (AI) patients treated with once-daily MR-HC (flat cortisol profile) and treated with thrice-daily of conventional IR-HC (steep cortisol profile). The 24 hrs spontaneous oscillation of the clock genes in synchronized C2C12 cells was used to align the timing for in vitro HC exposure (Bmal1 acrophase, midphase and bathyphase) with the reference times of cortisol peaks in AI treated with IR-HC (8 am, 1 pm, 6 pm). A panel of 84 insulin sensitivity related genes and intracellular insulin signaling proteins were analyzed by RT-qPCR and western blot, respectively. Results: Only the steep profile, characterized by a higher HC exposure during Bmal1 bathyphase, produced significant downregulation in 21 insulin sensitivity-related genes. Among these, Insr, Irs1, Irs2, Pi3kca and Adipor2 were downregulated when compared the flat to the standard or steep profile. Reduced intracellular IRS1 Tyr608, AKT Ser473, AMPK Thr172 and ACC Ser79 phosphorylations were also observed. Conclusions: The current study demonstrated that is late-in-the-day cortisol exposure that modulates insulin sensitivity-related genes expression and intracellular insulin signaling in skeletal muscle cells.

Mammalian Circadian Clock and Its Resetting

Physiology ◽  
1991 ◽  
Vol 6 (3) ◽  
pp. 129-134
Author(s):  
H Illnerova
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Complex Structure ◽  
Day Length ◽  
Circadian Pacemaker ◽  
Melatonin Production

Data on resetting circadian rhythm in melatonin production suggest a complex structure of the underlying pacemaker and explain why the circadian pacemaker functions also as a calendar measuring day length. The pacemaker is entrainable not only by light but by various drugs as well.

An Approximate Law of Survivorship and Other Notes on the Use of Frequency Curves in Actuarial Statistics

1934 ◽  
Vol 65 (1) ◽  
pp. 1-36 ◽  
Author(s):  
W. Palin Elderton
Keyword(s):  
Frequency Curve ◽  
Frequency Curves

LET EX be the exposed to risk at age x; F (x, 0) be the ordinate at x of a frequency curve used instead of Ex : the frequency curve is not necessarily a graduation of Ex. but may be and in some circumstances will be;

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