Computational modelling elucidates the mechanism of ciliary regulation in health and disease

<p>Abstract</p> <p>Background</p> <p>Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood. We develop a detailed systems model for calcium, membrane potential and cyclic nucleotide-dependent ciliary motility regulation.</p> <p>Results</p> <p>The model describes the intimate relationship between calcium and potassium ionic concentrations inside and outside of cilia with membrane voltage and, for the first time, describes a novel type of ciliary excitability which plays the major role in ciliary movement regulation. Our model describes a mechanism that allows ciliary excitation to be robust over a wide physiological range of extracellular ionic concentrations. The model predicts the existence of several dynamic modes of ciliary regulation, such as the generation of intraciliary Ca²⁺spike with amplitude proportional to the degree of membrane depolarization, the ability to maintain stable oscillations, monostable multivibrator regimes, all of which are initiated by variability in ionic concentrations that translate into altered membrane voltage.</p> <p>Conclusions</p> <p>Computational investigation of the model offers several new insights into the underlying molecular mechanisms of ciliary pathologies. According to our analysis, the reported dynamic regulatory modes can be a physiological reaction to alterations in the extracellular environment. However, modification of the dynamic modes, as a result of genetic mutations or environmental conditions, can cause a life threatening pathology.</p

Expression of Interest for a Phase-II LHCb Upgrade: Opportunities in flavour physics, and beyond, in the HL-LHC era

A Phase-II Upgrade is proposed for the LHCb experiment in order to take full advantage of the flavour-physics opportunities at the HL-LHC, and other topics that can be studied with a forward spectrometer. This Upgrade, which will be installed in Long Shutdown 4 of the LHC (2030), will build on the strengths of the current experiment and the Phase-I Upgrade, but will consist of re-designed sub-systems that can operate at a luminosity of 2×1034cm−2s−1, ten times that of the Phase-I Upgrade detector. New and improved detector components will increase the intrinsic performance of the experiment in certain key areas. In particular the installation of a tungsten sampling electromagnetic calorimeter will widen LHCb's capabilities for decays involving π0 and η mesons, electrons, and photons from loop-level penguin processes. The physics motivation is presented, and the prospects for operating the LHCb Interaction Point at high luminosity are assessed. The challenges for the detector are described and possible solutions are discussed. Finally, the key R\&amp;D areas are summarised, together with a set of initial modifications suitable for implementation during Long Shutdown 3 (2024--2026)