Background: Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer. Methods: Lung cancer patients (. n=. 62, 34 female) were within 5. years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis. Results: The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively " flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=. .009). Cortisol slope also predicted survival time from initial diagnosis (. p=. .012). Flattened profiles were linked with male gender (. t=. 2.04, df=. 59, p=. .046) and low total and cytotoxic T cell lymphocyte counts (. r=. -.39 and -.30, p=. .004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival. Conclusions: Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

Background: Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer. Methods: Lung cancer patients (. n=. 62, 34 female) were within 5. years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis. Results: The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively " flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=. .009). Cortisol slope also predicted survival time from initial diagnosis (. p=. .012). Flattened profiles were linked with male gender (. t=. 2.04, df=. 59, p=. .046) and low total and cytotoxic T cell lymphocyte counts (. r=. -.39 and -.30, p=. .004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival. Conclusions: Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

Postpartum depression (PPD) remains a serious mood disorder without a known etiology. PPD has a prevalence of 7-15% in the general population. Women with a history of a mood disorder are at an even higher risk for the development of PPD. Work over the last few decades has established a strong association between circadian rhythm and sleep disturbances and mood disorders, such as Major Depressive Disorder (MDD) and Bipolar Disorder (BD). Despite the breadth of evidence associating circadian rhythm disruption and depressive mood episodes, literature establishing a connection between circadian rhythms and changes in mood across the perinatal period is lacking. The work outlined in this thesis aimed to address this gap by examining the association between circadian rhythm and sleep disturbances across the perinatal period and their association with changes in mood in women at high and low risk of PPD development. A total of 87 women were studied, 45 healthy controls and 42 women with a mood history. Women were interviewed during the third trimester of pregnancy and between six to twelve weeks postpartum. Sleep and circadian rhythms were measured using both subjectively with self-reported questionnaires and objectively with actigraphy. Our results show that women at high and low risk showed higher disruption differ in subjective circadian rhythmicity, as well as in both subjective and objective parameters of sleep. Specifically, women at high risk for postpartum were found to have lower sleep efficiency, as measured by actigraphy, in the postpartum. In addition, subjective and objective parameters of sleep and circadian rhythms are associated with changes in depressive symptoms across the perinatal period. Our findings suggest that stabilizing circadian rhythms and improving sleep quality throughout the perinatal period can prevent postpartum mood worsening, particularly for those women at greatest risk. / Thesis / Master of Science (MSc)

Tumorigenesis is the result of uncontrolled cell growth due to the deregulation of cell cycle checkpoints 1. Period 2 (Per2) is a tumor suppressor that oscillate in expression in a 24-hour cycle 2, 3. Here, we show that Per2 interacts with the tumor suppressor protein p53. Both G1 and G2 checkpoint pathways involve a p53 dependent pathway which can trigger the cell to go through cell arrest or programmed cell death4. Understanding all the mitigating factors involved in regulating cell cycle progression under DNA damage can offer a better idea in how cells become immortal. Initially discovered through screening of a human liver cDNA library, the novel interaction between p53-Per2 was further documented using co-precipitation. Interestingly, under genotoxic stress conditions, p53 and Per2 were not found to bind which leads us to suspect that Per2 does not affect active p53 which may possibly be due to post translational modifications of its active state. Furthermore we investigated p53's ability to act as a transcription factor in the presence of Per2, showing that the Per2-p53 complex prevents p53 from binding to DNA. This implies that the tetramerization of p53 may also be another factor in Per2's ability to bind to p53. A truncated p53 lacking the last 30 amino acids that theoretically increase p53's ability to form a tetramer showed a drastic reduction in binding to Per2 5, 6. On the other hand, p53 lacking the tetramerization domain showed binding similar to wildtype. Consequently we speculate that the ability of Per2 to modulate p53 and act as a tumor suppressor protein may be dependent on either the post translational modifications of p53 or its oligomeric state. / Master of Science

Circadian rhythms are periodic physiological events that recur about every 24 hours. The word circadian derives from the Latin words <i>circ</i>a "about" and <i>dies</i> "day". The importance of circadian rhythms is well recognized in many different organisms' survival as well as in human physiology. It was in the 1950's that scientists demonstrated the existence of an endogenous biological clock, and that the clock is temperature compensated. However, the molecular mechanism of circadian rhythms began to come clear only after the discovery of the period (per) gene in Drosophila melanogaster in 1971, and the frequency (frq) gene in Neurospora crassa in 1973. Since the breakthrough discoveries of the per and frq genes and their mutants (short period mutants, perS or frq1, frq2; and long period mutants perL or frq3, frq7), molecular biologists have discovered other crucial components of the mechanism of circadian rhythms. Currently, there are about a dozen identified circadian genes in Drosophila melanogaster. The consensus idea of the mechanism is that it involves two-interlocked feedback loops largely based on transcription-translation controls. However, based on our mathematical models and analysis, we propose that there is also an autocatalytic effect based on proteolysis and stabilization of PER proteins. Based on the dynamics of multiple steady states and limit cycle oscillation, we propose an alternative mechanism for robust temperature compensation. We start with a simple model in order to understand the core dynamics of the clock mechanism, and move to a more comprehensive model. In both cases, we use bifurcation analysis as a tool to understand the dynamics of the system. With our model, we propose hypotheses to be tested in Neurospora crassa. / Ph. D.

Circadian clocks are internal timekeepers that allow organisms to anticipate and exploit predictable daily changes in their environment, aiding survival. Clock-driven rhythms, such as asexual spore development (conidiation) in Neurospora crassa, show temperature compensated periodicity that persists in constant conditions and can be reset by environmental time cues. This ability of circadian clocks to maintain a constant period and phase of behaviour over a range of temperatures is important, and whilst much of the machinery making up the circadian clock is known, the mechanism that underpins temperature compensation is not well understood. Further, it is unknown how the clock can control conidiation in the face of changing temperatures. To investigate possible mechanisms underlying temperature compensation, I first explored how compensation may arise within the central clock machinery using a comprehensive dynamic model of the Neurospora crassa circadian clock. This clock incorporates key components of the clock, and I introduced known temperature-sensitive component changes based on experimental observations. This analysis indicated that temperature-dependent changes in the binding of CK-1a to the FRQ-FRH complex may be pivotal in the temperature compensation mechanism. Previous work has highlighted the importance of the blue-light photoreceptor VIVID (VVD), as VVD knockout strains show a temperature-dependent delay in the phase of peak conidiation. Next I explored this potential role using a theoretical output model. By incorporating regulation of this pathway by VVD, I found that VVD may contribute to phase control by increasing expression of genes or proteins that peak early on in the output pathway. RNA-Seq experiments were carried out to assess the contribution of VVD to the overall transcriptomic profile of Neurospora. The analysis highlighted several key genes through which VVD may regulate the conidiation pathway, including the clock-controlled genes eas and ccg-9, which both show temperature- and strain-dependent changes in expression patterns over the time course of conidiation. In conclusion, VVD may indeed have an important role in the temperature compensation of output pathways, though further work is needed to assess the specific
contributions of genes highlighted by my RNA-Seq analysis to the compensatory mechanism.

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Subjective feeling, or mood, is not just a product of situational and dispositional factors, but is also based in part on underlying circadian rhythms. Notably, accumulating evidence suggests that circadian patterning is limited to positive affect, possibly as an adaptive manifestation of an appetitive motivational system. Furthermore, dispositional factors may influence the observed patterning, such as blunting the rhythm in positive affect when depression is present. The present study sought to examine further these phenomenon at an individual-level, as well as to explore circadian and affective interactions at a couple-level for perhaps the first time by monitoring mood, interpersonal interactions, sleep, activity, and light in 31 bed-sharing cohabitating couples over the course of 7 days. Participants' depression, well-being, relationship satisfaction, and morningness-eveningness were also assessed. Systematic daily patterning was found in all three measures of affect, and was moderated by depression, well-being, and morningness-eveningness. Within-couple affective synchrony (covariation) was positively associated with relationship satisfaction, within-couple morningness-eveningness similarity, and synchrony of sleep timing. Finally, day-to-day within-couple sleep timing synchrony predicted the tenor of the following day's partner interactions and affect. These data provide further evidence of potentially important interactions between sleep, circadian, affective processes both within- and between-individuals.

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