Tuning the Mammalian Circadian Clock: Robust Synergy of Two Loops

The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary clocks throughout the body. Its molecular constituents form an intracellular network which dictates circadian time and regulates clock-controlled genes. These clock-controlled genes are involved in crucial biological processes including metabolism and cell cycle regulation. Its malfunction can lead to disruption of biological rhythms and cause severe damage to the organism. The detailed mechanisms that govern the circadian system are not yet completely understood. Mathematical models can be of great help to exploit the mechanism of the circadian circuitry. We built a mathematical model for the core clock system using available data on phases and amplitudes of clock components obtained from an extensive literature search. This model was used to answer complex questions for example: how does the degradation rate of Per affect the period of the system and what is the role of the ROR/Bmal/REV-ERB (RBR) loop? Our findings indicate that an increase in the RNA degradation rate of the clock gene Period (Per) can contribute to increase or decrease of the period - a consequence of a non-monotonic effect of Per transcript stability on the circadian period identified by our model. Furthermore, we provide theoretical evidence for a potential role of the RBR loop as an independent oscillator. We carried out overexpression experiments on members of the RBR loop which lead to loss of oscillations consistent with our predictions. These findings challenge the role of the RBR loop as a merely auxiliary loop and might change our view of the clock molecular circuitry and of the function of the nuclear receptors (REV-ERB and ROR) as a putative driving force of molecular oscillations

Effects of ventricular rate regularization pacing on quality of life and symptoms in patients with atrial fibrillation (Atrial fibrillation symptoms mediated by pacing to mean rates [AF SYMPTOMS Study])

The aim of this study was to investigate the effect of the Ventricular Response Pacing (VRP) algorithm, which regularizes ventricular rate during atrial fibrillation (AF), on symptoms, quality of life, and functional capacity. VRP regularizes the ventricular rate during AF without increasing the mean ventricular rate, thereby reducing the severity of AF-related symptoms in patients with persistent AF. However, VRP did not improve general quality of life (Medical Outcomes Study 36-item Short-Form General Health Survey), the performance of routine activities (Duke Activity Status Index), or functional capacity (hall walk) in patients with AF. © 2004 by Excerpta Medica, Inc.link_to_subscribed_fulltex

Paternal knockdown of (cytosine‐5‐)‐methyltransferase ( ) increases offspring susceptibility to infection in red flour beetles

Schulz NKE, Mohamed FF, Lo LK, Peuß R, de Buhr MF, Kurtz J. Paternal knockdown of (cytosine‐5‐)‐methyltransferase ( ) increases offspring susceptibility to infection in red flour beetles. Insect Molecular Biology. 2022;31(6):711-721.Intergenerational effects from fathers to offspring are increasingly reported from diverse organisms, but the underlying mechanisms remain speculative. Paternal trans‐generational immune priming (TGIP) was demonstrated in the red flour beetleTribolium castaneum: non‐infectious bacterial exposure of fathers protects their offspring against an infectious challenge for at least two generations. Epigenetic processes, such as cytosine methylation of nucleic acids, have been proposed to enable transfer of information from fathers to offspring. Here we studied a potential role in TGIP of theDnmt2gene (renamed asTrdmt1in humans), which encodes a highly conserved enzyme that methylates different RNAs, including specific cytosines of a set of tRNAs.Dnmt2has previously been reported to be involved in intergenerational epigenetic inheritance in mice and protection against viruses in fruit flies. We first studied gene expression and found thatDnmt2is expressed in various life history stages and tissues ofT. castaneum, with high expression in the reproductive organs. RNAi‐mediated knockdown ofDnmt2in fathers was systemic, slowed down offspring larval development and increased mortality of the adult offspring upon bacterial infection. However, these effects were independent of bacterial exposure of the fathers. In conclusion, our results point towards a role ofDnmt2for paternal effects, while elucidation of the mechanisms behind paternal TGIP needs further studies