Circadian Clock and Hypoxia.

The timing of life on Earth is remarkable: between individuals of the same species, a highly similar temporal pattern is observed, with shared periods of activity and inactivity each day. At the individual level, this means that over the course of a single day, a person alternates between two states. They are either upright, active, and communicative or they lie down in a state of (un)consciousness called sleep where even the characteristic of neuronal signals in the brain shows distinctive properties. The circadian clock governs both of these time stamps-activity and (apparent) inactivity-making them come and go consistently at the same approximate time each day. This behavior thus represents the meeting of two pervasive systems: the circadian clock and metabolism. In this article, we will describe what is known about how the circadian clock anticipates daily changes in oxygen usage, how circadian clock regulation may relate to normal physiology, and to hypoxia and ischemia that can result from pathologies such as myocardial infarction and stroke.

The circadian clock of the bacterium B. subtilis evokes properties of complex, multicellular circadian systems.

Circadian clocks are pervasive throughout nature, yet only recently has this adaptive regulatory program been described in nonphotosynthetic bacteria. Here, we describe an inherent complexity in the Bacillus subtilis circadian clock. We find that B. subtilis entrains to blue and red light and that circadian entrainment is separable from masking through fluence titration and frequency demultiplication protocols. We identify circadian rhythmicity in constant light, consistent with the Aschoff's rule, and entrainment aftereffects, both of which are properties described for eukaryotic circadian clocks. We report that circadian rhythms occur in wild isolates of this prokaryote, thus establishing them as a general property of this species, and that its circadian system responds to the environment in a complex fashion that is consistent with multicellular eukaryotic circadian systems.

Rhythmic Spatial Self-Organization of Bacterial Colonies.

Bacteria display a remarkable capacity to organize themselves in space and time within biofilms. Traditionally, the spatial organization of biofilms has been dissected vertically; however, biofilms can exhibit complex, temporally structured, two-dimensional radial patterns while spreading on a surface. Kahl and colleagues report a ring pattern that indicates the alternating redox metabolism of P. aeruginosa biofilms under light/dark cycles. Does the presence of a rhythmic, daily phenotype imply a circadian rhythm? Here, we highlight several examples of rhythmic patterns reported in the literature for surface-colonizing multicellular assemblies and discuss the conceptual requirements for proving the presence of a prokaryotic circadian clock behind pattern formation.

A circadian clock in a nonphotosynthetic prokaryote.

Circadian clocks create a 24-hour temporal structure, which allows organisms to occupy a niche formed by time rather than space. They are pervasive throughout nature, yet they remain unexpectedly unexplored and uncharacterized in nonphotosynthetic bacteria. Here, we identify in Bacillus subtilis circadian rhythms sharing the canonical properties of circadian clocks: free-running period, entrainment, and temperature compensation. We show that gene expression in B. subtilis can be synchronized in 24-hour light or temperature cycles and exhibit phase-specific characteristics of entrainment. Upon release to constant dark and temperature conditions, bacterial biofilm populations have temperature-compensated free-running oscillations with a period close to 24 hours. Our work opens the field of circadian clocks in the free-living, nonphotosynthetic prokaryotes, bringing considerable potential for impact upon biomedicine, ecology, and industrial processes.

Clocks, Viruses, and Immunity: Lessons for the COVID-19 Pandemic.

Circadian rhythms are evolutionarily conserved anticipatory systems that allow the host to prepare and respond to threats in its environment. This article summarizes a European Biological Rhythms Society (EBRS) workshop held in July 2020 to review current knowledge of the interplay between the circadian clock and viral infections to inform therapeutic strategies against SARS-CoV-2 and COVID-19. A large body of work supports the role of the circadian clock in regulating various aspects of viral replication, host responses, and associated pathogenesis. We review the evidence describing the multifaceted role of the circadian clock, spanning host susceptibility, antiviral mechanisms, and host resilience. Finally, we define the most pressing research questions and how our knowledge of chronobiology can inform key translational research priorities.

Are There Circadian Clocks in Non-Photosynthetic Bacteria?

Circadian clocks in plants, animals, fungi, and in photosynthetic bacteria have been well-described. Observations of circadian rhythms in non-photosynthetic Eubacteria have been sporadic, and the molecular basis for these potential rhythms remains unclear. Here, we present the published experimental and bioinformatical evidence for circadian rhythms in these non-photosynthetic Eubacteria. From this, we suggest that the timekeeping functions of these organisms will be best observed and studied in their appropriate complex environments. Given the rich temporal changes that exist in these environments, it is proposed that microorganisms both adapt to and contribute to these daily dynamics through the process of temporal mutualism. Understanding the timekeeping and temporal interactions within these systems will enable a deeper understanding of circadian clocks and temporal programs and provide valuable insights for medicine and agriculture.

Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders.

Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention.

Full UPF3B function is critical for neuronal differentiation of neural stem cells.

BACKGROUND: Mutation in the UPF3B gene on chromosome X is implicated in neurodevelopmental disorders including X-linked intellectual disability, autism and schizophrenia. The protein UPF3B is involved in the nonsense-mediated mRNA decay pathway (NMD) that controls mRNA stability and functions in the prevention of the synthesis of truncated proteins. RESULTS: Here we show that NMD pathway components UPF3B and UPF1 are down-regulated during differentiation of neural stem cells into neurons. Using tethered function assays we found that UPF3B missense mutations described in families with neurodevelopmental disorders reduced the activity of UPF3B protein in NMD. In neural stem cells, UPF3B protein was detected in the cytoplasm and in the nucleus. Similarly in neurons, UPF3B protein was detected in neurites, the somatic cytoplasm and in the nucleus. In both cell types nuclear UPF3B protein was enriched in the nucleolus. Using GFP tagged UPF3B proteins we found that the missense mutations did not affect the cellular localisation. Expression of missense mutant UPF3B disturbed neuronal differentiation and reduced the complexity of the branching of neurites. Neuronal differentiation was similarly affected in the presence of the NMD inhibitor Amlexanox. The expression of mutant UPF3B proteins lead to a subtle increase in mRNA levels of selected NMD targets. CONCLUSIONS: Together our findings indicate that, despite the down-regulation of NMD factors, functional NMD is critical for neuronal differentiation. We propose that the neurodevelopmental phenotype of UPF3B missense mutation is caused by impairment of NMD function altering neuronal differentiation.