L’agence internationale de recherche sur le cancer (IARC) a indiqué que le travail posté qui provoquait une disruption circadienne était probablement cancérogène chez l’Homme. Ainsi, une perturbation expérimentale sévère du système circadien accélère-t elle la progression tumorale et pourrait favoriser la cancérogénèse. Durant ma thèse, j’ai démontré que la disruption circadienne résultant d’une mutation ou d’une mise au silence des gènes de l’horloge Per ou Cry accélérait la cancérogénèse hépatique induite par la diéthylnitrosamine, en favorisant l’instabilité génomique, la prolifération cellulaire, et l’inflammation. J’ai montré que l’alimentation programmée ou la dexaméthasone modifiaient la régulation circadienne de ces trois caractéristiques du cancer, suggérant ainsi qu’une intervention thérapeutique ciblant le système circadien pourrait prévenir la cancérogénèse. J’ai ainsi mis en évidence le contrôle circadien de trois mécanismes moléculaires de la cancérogenèse précoce et proposé deux interventions ciblant l’horloge circadienne dans un but de prévention de la cancérogenèse. / The International Agency for Research on Cancer (IARC) concluded that “shift-work that involves circadian disruption is probably carcinogenic to humans”. Severe disruption alteration accelerated tumor progression and enhanced carcinogenesis. During my PhD, I demonstrated that circadian disruption resulting from mutation of Per and Cry clock genes accelerated liver carcinogenesis induced by diethylnitrosamine through promoting genomic instability, cellular proliferation, and inflammation. I showed that meal timing or dexamethasone altered circadian regulation of these three characteristics of cancer, suggesting a therapeutic intervention targeting the circadian system could prevent carcinogenesis. I have thus demonstrated the circadian control of three molecular mechanisms of early carcinogenesis and proposed two interventions targeting the circadian clock for liver carcinogenesis prevention.

Over the past decades, decision making under risk has garnered a great amount of attention both in the field of economics and psychology. Although state-dependent variabilities of risk taking are well-documented, little is known about the effects of a person’s preferred time of day, or chronotype, in risky decision making. Under circumstances of circadian mismatch (e.g., when an “early bird” makes decisions in the evening), research suggests that decision making may reflect a greater reliance on heuristics, such as using stereotypes in social judgments. However, the effects of circadian mismatch on heuristics in risky decision making are relatively unexplored. This paper looks into the effects of circadian mismatch on the reflection effect: a behavioral bias in financial decision making, wherein individuals are risk averse when facing potential gains, and risk seeking when facing potential losses. Participants will be randomly assigned to their circadian matched or circadian mismatched conditions and will play a series of financial gambling tasks with real monetary incentives. This study predicts that the reflection effect will be exacerbated in circadian mismatched individuals as compared to matched participants. Exploring such an effect could have real-world implications on decision making under risk by providing critical knowledge about the effects of time of day on our susceptibility to behavioral biases. It could therefore point to the existence of a more optimal time of day to engage in such critical decision making.

Shift work is commonplace in many fields that require around-the-clock employee coverage. There is ample evidence that two-tier shift work can detrimentally affect health and functioning. The purpose of this study was to understand the impact of three-tier shift schedules on physical and mental health and community functioning, a concept which refers to activities and behaviors performed by individuals or groups within a system. This study used a qualitative phenomenological design, and community functioning and recovery theory were central to the conceptual framework. In-depth interviews were used to explore the perceptions of three-tier shift workers on their functioning, relationships, mental health, physical health, and safety. Special attention was paid to sleep, using restoration theory, which indicates that sufficient sleep is necessary to avoid mental and physical breakdown. The data were organized into themes, and epoché and bracketing were used during the interviews and data analysis. The results of the study add to the literature on how three-tier shift schedules affect employees. Emergent themes included overwhelmingly negative perceptions of three-tier shift workers on their health and safety, difficulty adjusting to the three-tier shift schedule, negative impact on workers' personal lives, negative impact on workers' mental health, negative impact on workers' physical health, and negative impact on workers' performance and safety. These findings could lead to positive social change through policy creation on healthier shift schedules, which could result in healthier employees, stronger family units, and safer roads and worksites.

Bibliography: leaves 168-187. / viii, a-f, 187, [51] leaves, [12] leaves of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Investigates the environmental control of seasonal reproduction and the role of the pineal in the transmission of multiple environmental signals to the reproductive axis. The principle species studied was the highly seasonal native Australian bush rat, Rattus fuscipes greyi. / Thesis (Ph.D.)--University of Adelaide, Dept. of Obstetrics and Gynaecology, 1994

Sialylation is an important carbohydrate modification of glycoconjugates, which introduces sialic acids (SA). The relatively large nine-carbon, negatively charged sugars are typically located at the termini of carbohydrate chains. SA's are often required for functionally important molecular and cellular interactions including virus-host interactions, tumor progression and malignancy, immune system development and function, and nervous system development and function. However, the study of sialylation in vertebrates, including man, encounters serious obstacles associated with the complexity of vertebrates' biology and limitations of available experimental approaches. Drosophila is a useful model system with many advantages including quick generation time, a large number of progeny, simplified glycosylation and neurophysiology, and ease of genetic manipulations. The primary focus of this thesis is on the functions of Drosophila melanogaster CMP sialic acid synthetase (DmCSAS) and sialyltransferase (DSiaT) in the central nervous system (CNS). A combination of genetic, immunostaining, and neurobiology approaches were used to characterize the functions of DmCSAS and DSiaT in Drosophila. This investigation revealed the expression of DmCSAS and suggested that it plays an important role in a specialized and developmentally regulated process in the nervous system of Drosophila. Further experiments examined sub-cellular localization of DmCSAS revealing that this protein has a complex mostly Golgi-associated distribution within the cell in vivo. I discovered a novel link between Drosophila sialylation and circadian rhythm regulation. I also characterized the electrophysiological phenotypes of DmCSAS mutants and compared them to the corresponding defects associated with DSiaT mutations. My experiments also revealed that the relationship between DmCSAS and DSiaT are more complex than originally thought; these genes may have independent functions while also participating in the same pathway. Taken together, these results elucidate the sialylation pathway in Drosophila and shed more light on the role of sialylation in the nervous system. My experiments provide a unique evolutionary perspective on the sialylation pathway in animals and suggest that the neural function of SA in Drosophila can be conserved in vertebrates, including humans.

Thesis (M.S.)--Uniformed Services University of the Health Sciences, 2005. / Typescript (photocopy).

Night work is inherent in working processes in hospitals and may have repercussions on the health of workers. Among these, stands out for the nursing care practice uninterrupted. Thus, beyond the specific implications of the process of nursing care, night service workers are exposed to typical repercussions of this shift. This study had as its object: the effects of night work in nursing and guiding question: what are the effects of night work for workers of Nursing intensive care units? In this sense, aimed to know the effects of night work for workers of these units. This is a qualitative, descriptive. The study included thirteen nursing workers of adult intensive care units and cardiology in a public hospital in the state of Rio Grande do Sul was used as a tool to semistructured data collection interview, which took place from October to November 2013. Data were analyzed according to thematic content analysis proposed by Minayo. It is reiterated that the ethical aspects of Resolution Nº 466/2012 of the National Health Council. As results were seen three categories emerged: Perceptions of nursing about the night work in the Intensive Care Unit; Physical, psychological and social effects of night work on Unit and Intensive Care; Strategies used by shift workers in Intensive Care Units in response to suffering. It was found in the statements of these workers that night work can promote both experiences of pleasure and satisfaction as dissatisfaction and suffering. This study reveals corroborating previous researches that night work reflected both in health and in social, family and emotional life of nursing workers. However, despite realize these effects, participants prefer to stay in this shift, due to personal, family and financial needs. It was evident that the workers, in most cases, they use individual and collective strategies in order to stay healthy in the workplace, even though they often do not perceive them. It is considered, based on the findings of this study, it is essential that hospitals develop health prevention and promotion of quality of life of workers nocturnal Nursing programs, as well as moments of integration between management, workers and institutional directions, promoting dialogue and sharing of knowledge and experiences in order that this employee feels valued and welcomed at it on your desktop. / O trabalho noturno é inerente ao processo laboral em instituições hospitalares e pode apresentar repercussões na saúde dos trabalhadores. Dentre esses, destaca-se os da Enfermagem pela prática assistencial ininterrupta. Com isso, além das implicações específicas do processo assistencial da Enfermagem, os trabalhadores do serviço noturno ficam expostos a repercussões típicas desse turno de trabalho. Este estudo teve como objeto: as repercussões do trabalho noturno na Enfermagem e como questão norteadora: quais as repercussões do trabalho noturno para trabalhadores de Enfermagem de Unidades de Cuidados Intensivos? Nesse sentido, objetivou conhecer as repercussões do trabalho noturno aos trabalhadores destas unidades. Trata-se de uma pesquisa qualitativa, de caráter analítico e descritivo. Participaram do estudo treze trabalhadores de Enfermagem das Unidades de Cuidados Intensivos Adulto e Cardiológica de um hospital público do interior do estado do Rio Grande do Sul. Utilizou-se a entrevista semiestruturada como instrumento de coleta de dados, a qual ocorreu no período de outubro a novembro de 2013. Os dados foram analisados segundo a análise de conteúdo temática proposta por Minayo. Reitera-se que foram atendidos os aspectos éticos da Resolução Nº 466/2012 do Conselho Nacional de Saúde. Como resultados emergiram três categorias: Percepções dos trabalhadores de Enfermagem acerca do trabalho noturno em Unidade de Cuidados Intensivos; Repercussões físicas, psíquicas e sociais do trabalho noturno em Unidade de Cuidados Intensivos e Estratégias utilizadas pelos trabalhadores noturnos de Unidades de Cuidados Intensivos frente ao sofrimento. Constatou-se nos depoimentos destes trabalhadores que o trabalho noturno pode promover tanto vivências de prazer e satisfação quanto de insatisfação e sofrimento. Este estudo revela que o trabalho noturno repercute tanto na saúde, como na vida social, familiar e emocional dos trabalhadores de Enfermagem. No entanto, apesar de perceberem estas repercussões, os participantes preferem permanecer neste turno de trabalho, em função de suas necessidades pessoais, familiares e financeiras. Evidenciou-se que os trabalhadores, na maioria das vezes, utilizam-se de estratégias individuais e coletivas, no intuito de se manterem saudáveis no seu ambiente de trabalho, mesmo que muitas vezes, não as percebam. Considera-se, a partir dos achados deste estudo, ser fundamental que as instituições hospitalares desenvolvam programas de prevenção à saúde e promoção da qualidade de vida dos trabalhadores noturnos da Enfermagem, assim como, momentos de integração entre chefias, direções institucionais e trabalhadores, promovendo o diálogo e o compartilhar de conhecimentos e vivências, no intuito de que este trabalhador se sinta valorizado no que faz e acolhido no seu ambiente de trabalho.

Posto que a Saúde do Trabalhador tenha se consolidado como uma política pública de saúde nas últimas décadas, mas ainda em fase de estruturação de sua rede, o tensionamento de uma discussão acerca da legitimidade da integralidade nas práticas de saúde do trabalhador, momento oportuno à aproximação com a cronobiologia, à luz da saúde coletiva. Esta dissertação visa analisar a presença da integralidade nas práticas de cuidado e de vigilância na Saúde do Trabalhador e a possíveis associações com o campo de conhecimento das propriedades temporais e interseccionalidades com a saúde coletiva e saúde pública. Foi realizada uma pesquisa documental de publicações oficiais do Ministério da Saúde brasileiro referentes à Política de Saúde do Trabalhador, fichas de notificações de acidentes e de agravos relacionados ao trabalho e pesquisa bibliográfica das revisões sistemáticas existentes sobre saúde do trabalhador e cronobiologia, indexadas nas bases de dados Foram pesquisadas as bases de dados eletrônicas (de janeiro de 1975 até dezembro de 2016): MEDLINE/PubMed, Lilacs, Scielo, Cochrane Library e Handsearch via Scirius. No desenvolvimento desta pesquisa a concepção da integralidade se afirmou como conceito entrelaçador a fim de aproximar o tema da cronobiologia com as prática em Saúde do Trabalhador - e não somente da racionalidade médica da saúde ocupacional. Os principais domínios analisados, devido a repercussões da dessincronização foram: integralidade da política de Saúde do Trabalhador brasileira; legislação e jornada de trabalho; implicações neoplásicas e cardiovasculares; classe de trabalhadores; agravos da saúde mental e associações com a desregulação circadiana; alterações no sono, estado de alerta e ocorrência de acidentes. Como resultado, verificou-se que a interação dos fatores do processo de adaptação/dessincronização ao trabalho noturno/rotativo repercute na vida social, familiar e na saúde do trabalhador. Não foi encontrado consenso quanto ao tempo de exposição para aparecimento de sinais de alterações circadianas. Tanto as fichas de notificação de acidente relacionado ao trabalho quanto documentos oficiais da Política de Saúde do Trabalhador não consideram os tópicos acima relacionados. Sugere-se a inclusão do tema nas discussões da Rede Nacional de Atenção Integral à Saúde do Trabalhador e nas práticas de cuidado e de vigilância à saúde do trabalhador, assim como a criação de linha de cuidado que atenda a assistência multiprofissional, acolhimento, vinculação e responsabilização da equipe pelo cuidado do usuário em todos os níveis. Esta pesquisa não busca cessar essa discussão, mas sim iniciá-la, a fim de suscitar outras pesquisas e práticas sobre o tema em prol da Saúde Coletiva. É importante ressaltar que o processo de desenvolvimento de uma política nacional de saúde do trabalhador deve considerar os preceitos da gestão do cuidado em saúde e estar pautado na autonomia do usuário. / Since Worker's Health has consolidated as a public health policy and structured its network in the last decades, the tension of a discussion about the legitimacy of integrality in the health practices of the worker and its appropriation with chronobiology and collective health It is necessary. This dissertation goals to analyze the presence of integrality in care and vigilance practices in Worker 's Health and associations with the field of knowledge of temporal properties and intersectionalities with collective and public health, by means of documentary and empirical analysis. The main areas analyzed were the integrality of the Brazilian Worker's Health policy, legislation; neoplastic and cardiovascular implications to work activity; specificities in the class of workers; mental health associations with circadian dysregulation; changes in sleep, in the alert state and occurrence of accidents. It was verified that the interaction of the factors of the adaptation / desynchronization process to the nocturnal / rotating work has repercussions on the social, family life and health of the worker. The main repercussions of circadian desynchronization on the worker's life were: alterations in sleep and alertness, work accidents, metabolic and cardiovascular alterations, socio-temporal disorders, stress, behavioral and mood changes, cardiometabolic diseases, eating disorders, neoplastic diseases, accidents of work and of route. No consensus was found regarding the time of exposure for signs of circadian changes. Both the work-related accident notification sheets and official Worker Health Policy documents do not consider the above topics. It is suggested that the topic be included in the discussions of the National Network of Integral Attention to Worker's Health and in Brazilian care and surveillance practices, as well as the creation of a care line that addresses multiprofessional assistance, reception, liaison and accountability of the team through user care at all levels. This research does not seek to stop this discussion, but to initiate it, in order to elicit other research and practices on the subject in favor of Collective Health. It is important to emphasize that the process of developing a national worker health policy must consider the precepts of health care management and be guided by the autonomy of the user. In the development of this research, the concept of integrality was affirmed as an interlacing concept in order to bring the subject of chronobiology closer to practices in Worker's Health - and not only the medical rationality of occupational health.

Circadian clocks are biological timekeepers that help maintain an organism’s behavior and physiological state optimally timed to the Earth’s day/night cycle. To do this, these internal pacemakers must accurately keep track of time. Equally importantly, they must be able to adjust their oscillations in response to external time cues to remain properly synchronized with the environment, and correctly anticipate environmental changes. When the internal clock is offset from its surrounding day/night cycle, clinically relevant disruptions develop, ranging from inconveniences such as jet-lag to more severe problems such as sleep disorders or mood disorders. In this work, I have used the fruit fly, Drosophila melanogaster, as a model organism to investigate how light and temperature can synchronize circadian systems. My initial studies centered on an intracellular photoreceptor, CRYPTOCHROME (CRY). CRY is a blue light photoreceptor previously identified as a major component of the primary light-input pathway into the Drosophila circadian clock. We used molecular techniques to show that after light-activation, CRY binds to the key circadian molecule TIMELESS (TIM). This interaction irreversibly targets TIM, but not CRY, for degradation. Further studies characterizing a newly isolated cry mutant, crym, showed that the carboxyl-terminus of CRY is not necessary for CRY’s ability to impart photic information to the molecular clock. Instead, the C-terminus appears to be necessary for normal CRY stability and protein-protein interactions. Thus, we conclude that in contrast to previous reports on CRYs of other species, where the C-terminal domain was required for transduction of photic information, the C-terminus of DrosophilaCRY has a purely modulatory function. During the second part of my dissertation work, I focused my studies on circadian thermoreception. While the effects of light in synchronization of the Drosophilaclock to environmental cycles have been extensively characterized, significantly less is known about temperature input pathways into the circadian pacemaker. I have used two approaches to look at how temperature affects the circadian system. First, I conducted a series of behavioral analyses looking at how locomotor rhythms can be phase-shifted in response to temperature cycles. By examining the behavior of genetically ablated flies, we determined that the well-characterized neurons controlling morning and evening surges of activity during light/dark cycles are also implicated in morning and evening behaviors under temperature cycles. However, we also find evidence of cells that contribute to modulating afternoon and evening behavior specifically under temperature cycles. These data contribute to a growing number of studies in the field suggesting that pacemaker cells may play different roles under various environmental conditions. Additionally, we provide data showing that intercellular communication plays an important role in regulating circadian response to temperature cycles. When the morning oscillator is absent or attenuated, the evening cells respond abnormally quickly to temperature cycles. My work thus provides information on the roles of different cell groups during temperature cycles, and suggests that beyond simply synchronizing individual oscillating cells, intercellular network activity may also have a role in modulating proper response to environmental time cues. Finally, I present some preliminary work looking at effects of temperature on known circadian molecules. Using a combination of in vivo and cell culture techniques, I have found that TIM protein levels decrease at higher temperatures. My cell culture data suggest that this is a proteasome-independent degradation event. As TIM is also a key molecule in the light-input pathway, the stability of TIM proteins may be a key point of integration for light and temperature input pathways. While additional research needs to be conducted to confirm these effects in vivoin wild-type flies, these preliminary results identify a possible avenue for further study. Taken together, my work has contributed new data on both molecular and neuronal substrates involved in processing light and temperature inputs into the Drosophila circadian clock.

Most organisms, from cyanobacteria to humans are equipped with circadian clocks. These endogenous and self-sustained pacemakers allow organisms to adapt their physiology and behavior to daily environmental variations, and to anticipate them. The circadian clock is synchronized by environmental cues (i.e. light and temperature fluctuations). The fruit fly, Drosophila melanogaster, is well established as a model for the study of circadian rhythms. Molecular mechanisms of the Drosophilacircadian clock are conserved in mammals. Using genetic screens, several essential clock proteins (PER, TIM, CLK, CYC, DBT, SGG and CK-II) were identified in flies. Homologs of most of these proteins are also involved in generating mammalian circadian rhythms. In addition, there are only six neuronal groups in the adult fly brain (comprising about 75 pairs of cells) that express high levels of clock genes. The simplicity of this system is ideal for the study of the neural circuitry underlying behavior. The first half of this dissertation focuses on a genetic screen designed to identify novel genes involved in the circadian light input pathway. The screen was based on previous observations that a mutation in the circadian photoreceptor CRYPTOCHROME (CRY) allows flies to remain rhythmic in constant light (LL), while wild type flies are usually arrhythmic under this condition. 2000 genes were overexpressed and those that showed a rhythmic behavior in LL (like crymutants) were isolated. The candidate genes isolated in the screen present a wide variety of biological functions. These include genes involved in protein degradation, signaling pathways, regulation of transcription, and even a pacemaker gene. In this dissertation, I describe work done in order to validate and characterize such candidates. The second part of this dissertation focuses on identifying the pacemaker neurons that drive circadian rhythms in constant light (LL) when the pacemaker gene period is overexpressed. We found that a subset of pacemaker neurons, the DN1s, is responsible for driving rhythms in constant light. This attractive finding reveals a novel role for the DN1s in driving behavioral rhythms under constant conditions and suggests a mechanism for seasonal adaptation in Drosophila.