Chrono-pharmaceutical approaches to optimize dosing regimens based on the circadian clock machinery

Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at different administration times. The “circadian clock” is an endogenous timing system that broadly regulates metabolism, physiology and behavior. In mammals, this clock governs the oscillatory expression of the majority of genes with a period length of approximately 24 h. Genetic studies have revealed that molecular components of the circadian clock regulate the expression of genes responsible for the sensitivity to drugs and their disposition. The circadian control of pharmacodynamics and pharmacokinetics enables ‘chrono-pharmaceutical’ applications, namely drug administration at appropriate times of day to optimize the therapeutic index (efficacy vs. toxicity). On the other hand, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity. Currently, novel therapeutic approaches are facilitated by the development of chemical compound targeted to key proteins that cause circadian exacerbation of disease events. This review presents an overview of the current understanding of the role of the circadian biological clock in regulating drug efficacy and disease conditions, and also describes the importance of identifying the difference in the circadian machinery between diurnal and nocturnal animals to select the most appropriate times of day to administer drugs in humans.

The connection of polymorphism and diurnal changes of the biological clock gene expression with the risk of progression of primary open-angle glaucoma

The purpose of this work is to study the connection betweengenetic factors (polymorphism and expression of key genes of the biological clock (KGBC), key genes controlled by KGBC, melatonin receptors) and the diurnal oscillation of melatonin in patients with stable and progressing primary open-angle glaucoma. Materials and methods. The study involved 115 patients aged 53–86 (averagely, 68.8 ± 7.9 years) with stable and progressive glaucoma. All patients underwent primary ophthalmological examination, tested for diurnal body temperature profile, intraocular pressure (IOP), melatonin (by the DLMO protocol) and were typed for key genes of the biological clock using the real-time polymerase chain reaction. We studied the sleep phase shift to later hours in carriers of the G-allele of the melatonin receptor gene during the progression of glaucoma. Results. The study of the clinical and genotypic features of the POAG course revealed phasal shifts of the circadian rhythms of body temperature, IOP, salivary melatonin levels and sleep phases which contributed to the progression of glaucomatous optic neuropathy. Certain polymorphic variants of genes contribute to individual frequent manifestations of desynchronosis. The clock rs1801260 and MTNR1B rs10830963 gene polymorphism was found to be related to disturbances in melatonin production and sleep phase. Conclusion. Complex manifestations of circadian desynchronization accompanying the progressive course of glaucoma are the late phase of rhythms and a decrease in sleep duration, body temperature, salivary melatonin and IOP, internal desynchronization between IOP and body temperature, IOP and sleep, evening dyslipidemia. The revealed patterns open up prospects for future studies of the relationship between polymorphism and daily changes of the expression of key genes in the biological clock with the risk of progression of primary open angle glaucoma.

GUN4 Affects the Circadian Clock and Seedlings Adaptation to Changing Light Conditions

The chloroplast is a key organelle for photosynthesis and perceiving environmental information. GENOME UNCOUPLED 4 (GUN4) has been shown to be required for the regulation of both chlorophyll synthesis, reactive oxygen species (ROS) homeostasis and plastid retrograde signaling. In this study, we found that growth of the gun4 mutant was significantly improved under medium strong light (200 μmol photons m−2s−1) compared to normal light (100 μmol photons m−2s−1), in marked contrast to wild-type (WT). Further analysis revealed that GUN4 interacts with SIGNAL RECOGNITION PARTICLE 54 KDA SUBUNIT (SRP43) and SRP54. RNA-seq analysis indicated that the expression of genes for light signaling and the circadian clock is altered in gun4 compared with (WT). qPCR analysis confirmed that the expression of the clock genes CLOCK-RELATED 1 (CCA1), LATE ELONGATION HYPOCOTYL (LHY), TIMING OF CAB EXPRESSION 1 (TOC1) and PSEUDO RESPONSE REGULATOR 7 (PRR7) is significantly changed in the gun4 and srp54 mutants under normal and medium strong light conditions. These results suggest that GUN4 may coordinate the adaptation of plants to changing light conditions by regulating the biological clock, although it is not clear whether the effect is direct or indirect.

Effect of diurnal changes on the auditory working memory in individuals with normal hearing

The human circadian rhythmicity is an internal biological clock mechanism that enables them to effectively perform tasks during a particular time of the day, due to which they exhibit diurnal effects. The morningness-eveningness questionnaire classifies individuals as definitely morning, moderately morning, intermediate, moderately evening, and definitely evening type individuals based on their active performance during different times of the day. Literature show variations in visual, memory, audition, and other cognitive tasks throughout the day in every individual. The current study aimed to document the diurnal effects on auditory working memory, a phenomenon crucial for learning and academic outcomes and holds its role in various clinical and research fields. Thirty-two participants were enrolled (21 females and 11 males) and were classified based on the morningness-eveningness questionnaire. The Auditory Working Memory tests were carried out during the morning and evening for all the participants. Based on a parametric paired t-test, results reveal no significant differences between morning time and evening time across moderately morning, intermediate, and moderately evening groups implying that working memory is a higher-order function that shows no or negligible diurnal effects, unlike other lower-order functions like temporal processing of auditory signals.

DESIGN FRAMEWORK FOR LIGHTING AND OCCUPATIONAL WELL-BEING IN UNDERGROUND SPACES: CASE STUDY IN PYHÄSALMI MINE

In underground spaces, lack of daylight may produce disorders in the biological clock of workers and have many negative physiological and psychological effects. Besides the traditional means of illumination, new LED lighting technologies, which allow the dynamic changes of the lighting intensity and spectral composition of white light, provide means to support workers’ daily rhythm with circadian lighting. The effects of lighting, however, are not only physiological, and there are several other factors related to lighting as a design task while the human experience of light is multifaceted. This paper illustrates the design problematics of lighting environment of underground workspaces through a case study project in Pyhäsalmi mine, Finland. The paper proposes a holistic design framework for lighting, which supports occupational well-being in underground spaces, based on the results from the case study with realized intelligent lighting pilot environment where user experiences were evaluated with semi-structural interviews.

Age and Happiness

Contrary to the common belief that the age-happiness relationship is mountain shape (the middle aged being happier than children and the aged), it is really largely U shape, with the middle aged (at around mid 30’s or 40’s) least happy. The increase from around 60 to 70’s is particularly clear. However, happiness becomes lower over the last few years of illness before passing away. The decline in happiness from around 12 years old and the trough in happiness level around middle ages may partly be explained by the delay in sleep–wake cycles of teenagers, causing conflict with their mostly middle-aged parents. Recognizing the evolutionary ultimate explanation for this delay advanced here, the society should delay start hours for high schools to fit in with the delayed biological clock of teenagers.