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Immotile cilia at the ventral node of mouse embryos are required for sensing leftward fluid flow that breaks left-right symmetry of the body. However, the flow-sensing mechanism has long remained elusive. In this work, we show that immotile cilia at the node undergo asymmetric deformation along the dorsoventral axis in response to the flow. Application of mechanical stimuli to immotile cilia by optical tweezers induced calcium ion transients and degradation of Dand5 messenger RNA (mRNA) in the targeted cells. The Pkd2 channel protein was preferentially localized to the dorsal side of immotile cilia, and calcium ion transients were preferentially induced by mechanical stimuli directed toward the ventral side. Our results uncover the biophysical mechanism by which immotile cilia at the node sense the direction of fluid flow.

Cilia and centrosomes of eukaryotic cells play important roles in cell movement, fluid transport, extracellular sensing, and chromosome division. The physiological functions of cilia and centrosomes are generated by their dynamics, motions, and forces controlled by the physical, chemical, and biological environments. How an individual cilium achieves its beat pattern and induces fluid flow is governed by its ultrastructure as well as the coordination of associated molecular motors. Thus, a bottom-up understanding of the physiological functions of cilia and centrosomes from the molecular to tissue levels is required. Correlations between the structure and motion can be understood in terms of mechanics. This review first focuses on cilia and centrosomes at the molecular level, introducing their ultrastructure. We then shift to the organelle level and introduce the kinematics and mechanics of cilia and centrosomes. Next, at the tissue level, we introduce nodal ciliary dynamics and nodal flow, which play crucial roles in the organogenetic process of left-right asymmetry. We also introduce respiratory ciliary dynamics and mucous flow, which are critical for protecting the epithelium from drying and exposure to harmful particles and viruses, i.e., respiratory clearance function. Finally, we discuss the future research directions in this field., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Planktonic microorganisms are ubiquitous in water, and their population dynamics are essential for forecasting the behavior of global aquatic ecosystems. Their population dynamics are strongly affected by these organisms' motility, which is generated by their hair-like organelles, called cilia or flagella. However, because of the complexity of ciliary dynamics, the precise role of ciliary flow in microbial life remains unclear. Here, we have used ciliary hydrodynamics to show that ciliates acquire the optimal propulsion efficiency. We found that ciliary flow highly resists an organism's propulsion and that the swimming velocity rapidly decreases with body size, proportional to the power of minus two. Accordingly, the propulsion efficiency decreases as the cube of body length. By increasing the number of cilia, however, efficiency can be significantly improved, up to 100-fold. We found that there exists an optimal number density of cilia, which provides the maximum propulsion efficiency for all ciliates. The propulsion efficiency in this case decreases inversely proportionally to body length. Our estimated optimal density of cilia corresponds to those of actual microorganisms, including species of ciliates and microalgae, which suggests that now-existing motile ciliates and microalgae have survived by acquiring the optimal propulsion efficiency. These conclusions are helpful for better understanding the ecology of microorganisms, such as the energetic costs and benefits of multicellularity in Volvocaceae, as well as for the optimal design of artificial microswimmers., Competing Interests: The authors declare no competing interest.

To gain insight into the nature of biological synchronization at the microscopic scale, we here investigate the hydrodynamic synchronization between conically rotating objects termed nodal cilia. A mechanical model of three rotating cilia is proposed with consideration of variation in their shapes and geometrical arrangement. We conduct numerical estimations of both near-field and far-field hydrodynamic interactions, and we apply a conventional averaging method for weakly coupled oscillators. In the nonidentical case, the three cilia showed stable locked-phase differences around ±π/2. However, such phase locking also occurred with three identical cilia when allocated in a triangle except for the equilateral triangle. The effects of inhomogeneity in cilia shapes and geometrical arrangement on such asymmetric interaction is discussed to understand the role of biological variation in synchronization via hydrodynamic interactions.

The mechanism by which the two different heads of the ciliary outer dynein arm produce force to translocate the microtubule during beating is still unknown. In this report we use cryo-electron tomography and image processing to analyze the conformational changes and the relative abundance of each conformation of the two dynein heads from mouse respiratory cilia. In the absence of nucleotides the majority of dynein dimers are in the apo form and both heads are tightly packed, whereas they are dissociated and move independently in the presence of nucleotides. The head of the external outer arm dynein heavy chain has a diagonal shift toward both the neighboring B-tubule and the proximal end of the axoneme, while the head of the internal heavy chain shifts only longitudinally toward the proximal end. In the presence of nucleotides a significant number of the dynein dimers have two heads overlapped in the proximal shifting form or overlapped in the apo form. During ciliary bending axonemal dynein translocates microtubules by moving with short steps and two heads stay at the same position longer than cytoplasmic dynein. This demonstrates that the step of the outer arm dynein dimer is not dominated by the hand-over-hand motion, but also indicates the difference between axonemal dynein and cytoplasmic dynein., (Copyright © 2014 Wiley Periodicals, Inc.)

Although we inhale air that contains many harmful substances, including, for example, dust and viruses, these small particles are trapped on the surface of the tracheal lumen and transported towards the larynx by cilia-generated flow. The transport phenomena are affected not only by the time- and space-average flow field but also by the fluctuation of the flow. Because flow fluctuation has received little attention, we investigated it experimentally in mice. To understand the origin of flow fluctuation, we first measured the distribution of ciliated cells in the trachea and individual ciliary motions. We then measured the detailed flow field using a confocal micro-PTV system. Strong flow fluctuations were observed, caused by the unsteadiness of the ciliary beat and the spatial inhomogeneity of ciliated cells. The spreading of particles relative to the bulk motion became diffusive if the time scale was sufficiently larger than the beat period. Finally, we quantified the effects of flow fluctuation on bulk flow by evaluating the Peclet number of the system, which indicated that the directional transport was an order of magnitude larger than the isotropic diffusion. These results are important in understanding transport phenomena in the airways on a cellular scale.

Rotational movement of mouse node cilia generates leftward fluid flow in the node cavity, playing an important role in left-right determination in the embryo. Although rotation of numerous cilia was believed necessary to trigger the determination, recent reports indicate the action of two cilia to be sufficient. We examine cooperative cilia movement via hydrodynamic interaction. Results show cilia to be cooperative, having phases locked in a certain relation; a system with a pair of nonidentical cilia can achieve phase-locked states more easily than one with a pair of identical cilia.

Rotational movement of isolated single cilia in mice embryo was investigated, which generates leftward fluid flow in the node cavity and plays an important role in left-right determination. The leftward unidirectional flow results from tilting of the rotational axis of the cilium to the posterior side. By combining computational fluid dynamics with experimental observations, we demonstrate that the leftward stroke can be more effective than expected for cases in which cilia tilting alone is considered with the no-slip condition under constant driving torque. Our results suggest that the driving torque is asymmetric.

Mucociliary clearance on the surface of the tracheal lumen is an important component of lung defense against dust mites and viruses. However, the axonemal structure that achieves effective ciliary motion, and the mechanisms by which discretely distributed ciliary cells generate directional flow are unknown. In this study, we examined individual ciliary motion with 7- to 9-nm spatial precision by labeling the ciliary tip with quantum dots and detected an asymmetric beating pattern. Cryo-electron tomography revealed that the densities of two inner dynein arms were missing from at least 2 doublet microtubules in the axonemal structure. Although the flow directions generated by individual ciliated cells were unsteady and diverse, the time- and space-averaged velocity field was found to be directional. These results indicate that the asymmetric ciliary motion is driven by the asymmetric axonemal structure, and it generates overall directional flow from the lungs to the oropharynx on sparsely distributed ciliated cells., From the Clinical Editor: The authors of this study utilized quantum dots in determining the kinetics of ciliary motion in mouse respiratory cilia with 7- to 9-nm spatial precision., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The fluid dynamics of microswimmers has received attention from the fields of microbiology, microrobotics, and active matter. Microorganisms have evolved organelles termed cilia for propulsion through liquids. Each cilium periodically performs effective and recovery strokes, creating a metachronal wave as a whole and developing a propulsive force. One well-established mathematical model of ciliary swimming is the squirmer model, which focuses on surface squirming velocities. This model is also useful when studying active colloids and droplets. The squirmer model has been recently used to investigate the behaviors of microswimmers in complex environments, their collective dynamics, and the characteristics of active fluids. Efforts have also been made to broaden the range of applications beyond the assortment permitted by the squirmer model, which was established to specifically represent ciliary flow and incorporate biological features. The stress swimmer model imposes stresses above the cell body surface that enforce the no-slip condition. The ciliated swimmer model precisely reproduces the behaviors of each cilium that engages in mutual hydrodynamic interactions. Mathematical models have improved our understanding of various microbial phenomena, including cell–cell and cell–wall interactions and energetics. Here, I review recent advances in the hydrodynamics of ciliary swimming and then discuss future challenges. [ABSTRACT FROM AUTHOR]

Abstract: Mucociliary clearance on the surface of the tracheal lumen is an important component of lung defense against dust mites and viruses. However, the axonemal structure that achieves effective ciliary motion, and the mechanisms by which discretely distributed ciliary cells generate directional flow are unknown. In this study, we examined individual ciliary motion with 7- to 9-nm spatial precision by labeling the ciliary tip with quantum dots and detected an asymmetric beating pattern. Cryo-electron tomography revealed that the densities of two inner dynein arms were missing from at least 2 doublet microtubules in the axonemal structure. Although the flow directions generated by individual ciliated cells were unsteady and diverse, the time- and space-averaged velocity field was found to be directional. These results indicate that the asymmetric ciliary motion is driven by the asymmetric axonemal structure, and it generates overall directional flow from the lungs to the oropharynx on sparsely distributed ciliated cells. From the Clinical Editor: The authors of this study utilized quantum dots in determining the kinetics of ciliary motion in mouse respiratory cilia with 7- to 9-nm spatial precision. [Copyright &y& Elsevier]