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Collective migration of epithelial cells is a fundamental process in multicellular pattern formation. As they expand their territory, cells are exposed to various physical forces generated by cell–cell interactions and the surrounding microenvironment. While the physical stress applied by neighbouring cells has been well studied, little is known about how the niches that surround cells are spatio-temporally remodelled to regulate collective cell migration and pattern formation. Here, we analysed how the spatio-temporally remodelled extracellular matrix (ECM) alters the resistance force exerted on cells so that the cells can expand their territory. Multiple microfabrication techniques, optical tweezers, as well as mathematical models were employed to prove the simultaneous construction and breakage of ECM during cellular movement, and to show that this modification of the surrounding environment can guide cellular movement. Furthermore, by artificially remodelling the microenvironment, we showed that the directionality of collective cell migration, as well as the three-dimensional branch pattern formation of lung epithelial cells, can be controlled. Our results thus confirm that active remodelling of cellular microenvironment modulates the physical forces exerted on cells by the ECM, which contributes to the directionality of collective cell migration and consequently, pattern formation., Hagiwara et al. investigate how spatio-temporally remodeled ECM alters the resistance force exerted on cells using microfabrication techniques, optical tweezers and mathematical models. The authors demonstrate that active remodeling of the microenvironment modulates force exerted on cells by the ECM, contributing to directionality and pattern formation.

SummaryTilling patterns are observed in many biological structures. Hexagonal tilling, commonly observed in the compound eyes of wild-type Drosophila, is dominant in nature; this dominance can probably be attributed to physical restrictions such as structural robustness, minimal boundary length, and space filling efficiency. Surprisingly, tetragonal tiling patterns are also observed in some Drosophila small eye mutants and aquatic crustaceans. Herein, geometrical tessellation is shown to determine the ommatidial tiling patterns. In small eye mutants, the hexagonal pattern is transformed into a tetragonal pattern as the relative positions of neighboring ommatidia are stretched along the dorsal-ventral axis. Hence, the regular distribution of ommatidia and their uniform growth collectively play an essential role in the establishment of tetragonal and hexagonal tiling patterns in compound eyes.

Tiling patterns are observed in many biological structures. The compound eye is an interesting example of tiling and is often constructed by hexagonal arrays of ommatidia, the optical unit of the compound eye. Hexagonal tiling may be common due to mechanical restrictions such as structural robustness, minimal boundary length, and space-filling efficiency. However, some insects exhibit tetragonal facets.

Planar cell polarity (PCP) regulates the orientation of external structures. A core group of proteins that includes Frizzled forms the heart of the PCP regulatory system. Other PCP mechanisms that are independent of the core group likely exist, but their underlying mechanisms are elusive. Here, we show that tissue flow is a mechanism governing core group-independent PCP on the Drosophila notum. Loss of core group function only slightly affects bristle orientation in the adult central notum. This near-normal PCP results from tissue flow-mediated rescue of random bristle orientation during the pupal stage. Manipulation studies suggest that tissue flow can orient bristles in the opposite direction to the flow. This process is independent of the core group and implies that the apical extracellular matrix functions like a “comb” to align bristles. Our results reveal the significance of cooperation between tissue dynamics and extracellular substances in PCP establishment.

We present a new method, Multi-Ancestry Meta-Analysis (MAMA), which combines genome-wide association study (GWAS) summary statistics from multiple populations to produce new summary statistics for each population, identifying novel loci that would not have been discovered in either set of GWAS summary statistics alone. In simulations, MAMA increases power with less bias and generally lower type-1 error rate than other multi-ancestry meta-analysis approaches. We apply MAMA to 23 phenotypes in East-Asian- and European-ancestry populations and find substantial gains in power. In an independent sample, novel genetic discoveries from MAMA replicate strongly.

Proper organ development often requires nuclei to move to a specific position within the cell. To determine how nuclear positioning affects left-right (LR) development in the Drosophila anterior midgut (AMG), we developed a surface-modeling method to measure and describe nuclear behavior at stages 13-14, captured in three-dimensional time-lapse movies. We describe the distinctive positioning and a novel collective nuclear behavior by which nuclei align LR symmetrically along the anterior-posterior axis in the visceral muscles that overlie the midgut and are responsible for the LR-asymmetric development of this organ. Wnt4 signaling is crucial for the collective behavior and proper positioning of the nuclei, as are myosin II and the LINC complex, without which the nuclei fail to align LR symmetrically. The LR-symmetric positioning of the nuclei is important for the subsequent LR-asymmetric development of the AMG. We propose that the bilaterally symmetrical positioning of these nuclei may be mechanically coupled with subsequent LR-asymmetric morphogenesis., Summary: The distinctive positioning and a novel collective nuclear behavior by which nuclei align left-right (LR) symmetrically in the Drosophila anterior midgut are responsible for the LR-asymmetric development of this organ.

Collective migration of epithelial cells is a fundamental process in multi-cellular pattern formation. As they expand their territory, cells are exposed to various physical forces generated by cell-cell interactions and the surrounding microenvironment. While the physical stress applied by neighbouring cells has been well studied, little is known about how the niches that surround cells are spatio-temporally remodelled to regulate collective cell migration and pattern formation. Here, we analysed how the spatio-temporally remodelled extracellular matrix (ECM) alters the resistance force exerted on cells so that the cells can expand their territory. Multiple microfabrication techniques, optical tweezers, as well as mathematical models were employed to prove the simultaneous construction and breakage of ECM during cellular movement, and to show that this modification of the surrounding environment can guide cellular movement. Furthermore, by artificially remodelling the microenvironment, we showed that the directionality of collective cell migration, as well as the three dimensional branch pattern formation of lung epithelial cells, can be controlled. Our results thus confirm that active remodelling of cellular microenvironment modulates the physical forces exerted on cells by the ECM, which contributes to the directionality of collective cell migration and consequently, pattern formation.

Individual cells migrate toward the direction of the cell polarity generated by interior or exterior factors. Under situations without guides such as chemoattractants, they migrate randomly. On the other hand, it has been observed that cell groups lead to systematic collective cell migrations. For example, Dictyostelium discoideum and Madin-Darby canine kidney (epithelial) cells exhibit typical collective cell migration patterns such as uniformly directional migration and rotational migration. In particular, it has been suggested from experimental investigations that rotational migrations are intimately related to morphogenesis of organs and tissues in several species. Thus, it is conjectured that collective cell migrations are controlled by universal mechanisms of cells. In this paper, we review actual experimental data related to collective cell migrations on dishes and show that our self-propelled particle model based on the cell polarity can accurately represent actual migration behaviors. Furthermore, we show that collective cell migration modes observed in our model are robust.

Adult height was one of the earliest putative examples of polygenic adaptation in human. By constructing polygenic height scores using effect sizes and frequencies from hundreds of genomic loci robustly associated with height, it was reported that Northern Europeans were genetically taller than Southern Europeans beyond neutral expectation. However, this inference was recently challenged. Sohail et al. and Berg et al. showed that the polygenic signature disappeared if summary statistics from UK Biobank (UKB) were used in the analysis, suggesting that residual uncorrected stratification from large-scale consortium studies was responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population. In the present study, we re-examined this question, focusing on one of the shortest European populations, the Sardinians, as well as on the mainland European populations in general. We found that summary statistics from UKB significantly correlate with population structure in Europe. To further alleviate concerns of biased ascertainment of GWAS loci, we examined height-associated loci from the Biobank of Japan (BBJ). Applying frequency-based inference over these height-associated loci, we showed that the Sardinians remain significantly shorter than expected (~ 0.35 standard deviation shorter than CEU based on polygenic height scores, P = 1.95e-6). We also found the trajectory of polygenic height scores decreased over at least the last 10,000 years when compared to the British population (P = 0.0123), consistent with a signature of polygenic adaptation at height-associated loci. Although the same approach showed a much subtler signature in mainland European populations, we found a clear and robust adaptive signature in UK population using a haplotype-based statistic, tSDS, driven by the height-increasing alleles (P = 4.8e-4). In summary, by examining frequencies at height loci ascertained in a distant East Asian population, we further supported the evidence of polygenic adaptation at height-associated loci among the Sardinians. In mainland Europeans, we also found an adaptive signature, although becoming more pronounced only in haplotype-based analysis.

One of the fundamental processes of morphogenesis is dome formation, but many parts of the mechanisms has been unexplored. Previous in vitro studies showed that osmotic gradient is the driving factor of the dome formation. However, these investigations were performed without extracellular matrix (ECM), which provides structural support to morphogenesis. With the use of ECM, we observed that basal hypertonic stress induced stable domes in vitro that have not been seen in previous studies. These domes developed from the ECM swelling via aquaporin water transport activity. Based on computer simulation, uneven swelling, with a positive feedback between extending cell and enhanced water transport, was a cause for dome formation. These results indicate that osmotic gradient induces dome morphogenesis via both enhanced water transport activity and subsequent ECM swelling.

The external organs of holometabolous insects are generated through two consecutive processes: the development of imaginal primordia and their subsequent transformation into the adult structures. During the latter process, many different phenomena at the cellular level (e.g. cell shape changes, cell migration, folding and unfolding of epithelial sheets) contribute to the drastic changes observed in size and shape. Because of this complexity, the logic behind the formation of the 3D structure of adult external organs remains largely unknown. In this report, we investigated the metamorphosis of the horn in the Japanese rhinoceros beetle Trypoxylus dichotomus. The horn primordia is essentially a 2D epithelial cell sheet with dense furrows. We experimentally unfolded these furrows using three different methods and found that the furrow pattern solely determines the 3D horn structure, indicating that horn formation in beetles occurs by two distinct processes: formation of the furrows and subsequently unfolding them. We postulate that this developmental simplicity offers an inherent advantage to understanding the principles that guide 3D morphogenesis in insects.

SummaryIn Drosophila, planar cell polarity (PCP) molecules such as Dachsous (Ds) may function as global directional cues directing the asymmetrical localization of PCP core proteins such as Frizzled (Fz). However, the relationship between Ds asymmetry and Fz localization in the eye is opposite to that in the wing, thereby causing controversy regarding how these two systems are connected. Here, we show that this relationship is determined by the ratio of two Prickle (Pk) isoforms, Pk and Spiny-legs (Sple). Pk and Sple form different complexes with distinct subcellular localizations. When the amount of Sple is increased in the wing, Sple induces a reversal of PCP using the Ds-Ft system. A mathematical model demonstrates that Sple is the key regulator connecting Ds and the core proteins. Our model explains the previously noted discrepancies in terms of the differing relative amounts of Sple in the eye and wing.

Previous studies on adaptive behaviour in single-celled organisms have given hints to the origin of their memorizing capacity. Here we report evidence that a protozoan ciliateTetrahymenahas the capacity to learn the shape and size of its swimming space. Cells confined in a small water droplet for a short period were found to recapitulate circular swimming trajectories upon release. The diameter of the circular trajectories and their duration reflected the size of the droplet and the period of confinement. We suggest a possible mechanism for this adaptive behaviour based on a Ca2+channel. In our model, repeated collisions with the walls of a confining droplet result in a slow rise in intracellular calcium that leads to a long-term increase in the reversal frequency of the ciliary beat.

Large amounts of radioactive substances were released into the environment from the Fukushima Dai-ichi Nuclear Power Plants in eastern Japan as a consequence of the great earthquake (M 9.0) and tsunami of 11 March 2011. Radioactive substances discharged into the atmosphere first reached the Chiba Metropolitan Area on 15 March. We collected daily samples of air, fallout deposition, and tap water starting directly after the incident and measured their radioactivity. During the first two months maximum daily concentrations of airborne radionuclides observed at the Japan Chemical Analysis Center in the Chiba Metropolitan Area were as follows: 4.7 × 10 1 Bq m −3 of 131 I, 7.5 Bq m −3 of 137 Cs, and 6.1 Bq m −3 of 134 Cs. The ratio of gaseous iodine to total iodine ranged from 5.2 × 10 −1 to 7.1 × 10 −1 . Observed deposition rate maxima were as follows: 1.7 × 10 4 Bq m −2 d −1 of 131 I, 2.9 × 10 3 Bq m −2 d −1 of 137 Cs, and 2.9 × 10 3 Bq m −2 d −1 of 134 Cs. The deposition velocities (ratio of deposition rate to concentration) of cesium radionuclides and 131 I were detectably different. Radioactivity in tap water caused by the accident was detected several days after detection of radioactivity in fallout in the area. Radiation doses were estimated from external radiation and internal radiation by inhalation and ingestion of tap water for people living outdoor in the Chiba Metropolitan Area following the Fukushima accident.

A method of numerical simulation of cell division using phase fields is presented. The cell division plane is obtained as a result of the spindle position and orientation considered with the spatial distribution of the activated cortical force generators and the dividing cell shape. To exemplify the application of the proposed method, numerical simulations of the development of cysts and early embryos are performed. The numerical results demonstrate that the activated cortical force generators that are localized at the lateral cortices of the epithelial cells lead to the formation of a single central lumen. It is additionally shown that the linear distribution of the activated cortical force generators along the animal-vegetal axis of a spherical cell engenders a similar cell proliferation of the divided embryo generated by the 32 cell period in a sea cucumber.

Working memory (WM) is known to be associated with synchronization of the theta and alpha bands observed in electroencephalograms (EEGs). Although frontal-posterior global theta synchronization appears in modality-specific WM, local theta synchronization in frontal regions has been found in modality-independent WM. How frontal theta oscillations separately synchronize with task-relevant sensory brain areas remains an open question. Here, we focused on theta-alpha phase relationships in frontal areas using EEG, and then verified their functional roles with mathematical models. EEG data showed that the relationship between theta (6 Hz) and alpha (12 Hz) phases in the frontal areas was about 1:2 during both auditory and visual WM, and that the phase distributions between auditory and visual WM were different. Next, we used the differences in phase distributions to construct FitzHugh-Nagumo type mathematical models. The results replicated the modality-specific branching by orthogonally of the trigonometric functions for theta and alpha oscillations. Furthermore, mathematical and experimental results were consistent with regards to the phase relationships and amplitudes observed in frontal and sensory areas. These results indicate the important role that different phase distributions of theta and alpha oscillations have in modality-specific dissociation in the brain.

Inter- and intra-limb coordination for bipedal locomotion were numerically investigated using a “minimalist” bipedal robot model and an unconventional central pattern generator (CPG)-based control scheme that exploits local sensory feedback generated from the discrepancy between the control system, mechanical system, and environment. The simulation results showed that a bipedal robot controlled by the proposed controller exhibits walking and running gaits dependent only on one parameter: the angular velocity of the oscillators. Interestingly, spontaneous inter- and intra-limb coordination were found to be inherent to the proposed design scheme for stable bipedal locomotion. These findings are expected to lead to a useful methodology for robots to generate stable and adaptive locomotion.

This paper presents a two-dimensional simulation model of an amoeboid robot that exhibits locomotion in a decentralized manner. The significant feature to note is that the model does not control friction between parts of the robot and ground explicitly but exploits passive dynamics of the inner fluid of the robot, i.e., thixotropic flow, in order to generate locomotion. Thixotropy is a very interesting rheological property of a fluid to form a gelled structure over time when not subject to shearing and then to liquefy when agitated, which is observed in protoplasmic streaming of amoeba and plasmodium of true slime mold. Simulation results show that embedding this passive dynamics induces morphological positive feedback mechanism, leading to convection of the inner fluid, which in turn generates locomotion without relying on any hierarchical structure. The results obtained are expected to shed new light on revealing the secret of how decentralized control should be designed.

In the present paper, we propose a mathematical model of cleavage. Cleavage is a process during the early stages of development in which the fertile egg undergoes repeated division keeping the cluster size almost constant. During the cleavage process individual cells repeat cell division in an orderly manner to form a blastula, however, the mechanism which achieves such a coordination is still not very clear. In the present research, we took sea urchin as an example and focused on the diffusion of chemical substances from the animal and vegetal pole. By considering chemotactic motion of the centrosomes, we constructed a mathematical model that describes the processes in the early stages of cleavage.

On the 15 th of July 1888, a terrible eruption took place at the Bandai-san Volcano in northeastern Japan. Although many articles concerning that eruption were published during the last century, there are still some unsolved questions. The authors tried to solve some of them, including the uncertain situation of determining the beginning of that eruption. They found and examined some previously undiscovered data and the evidence of eyewitnesses. The results are as follows;1. Time: The eruption started at 7:45 a. m., 15th of July 1888 (Sekiya·Kikuchi 1890). But many eyewitnesses stated that it was between 8:00 and 8:10 or around 8:30. The disagreements in time are presumably caused by confusion on methods of hour system. The year 1888 fell into the transitional period between three kinds of hours or times: the temporal hour (-1872), the equinoctial hour with local time (1873-1887), and the equinoctial hour with Japanese Standard Time (1888-).2. Sites: The sites of the first explosions are inferred to be on the western foot of the peak of Kobandai and near Akanuma Pond, from photographs and sketches made by some residents at the foot of Bandai-san during the eruption.3. Height of eruption column: The height of eruption columns during the first explosion was estimated to be only 800m from the sketches and other evidence. This fact supports Moriya's opinion (1980) and Yonechi's hypothesis (1987) that the first explosion of Bandai-san had been not so big, but the following collapse (-s?) was (were?) much larger.

A new weighting method for CCD transversal filtering is proposed. This type of filtering or "input gate weighting method" is a novel design aspect of weighting and sampling by the input diodes and dual input gates. This method implies signal processing over the high frequency range and simple design of an on-a-chip CCD filter. Lowpass filters are fabricated on both of surface and buried channel structures. Experimental results indicate good agreement with theoretical calculations for both the surface and buried channel samples operated at a sample rate of up to 10 MHz.