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Previous article Next article. In collisions involving light systems, the low expected multiplicity of fragments increases the probability of achieving a quasi-complete reconstruction of the event. Moreover, a research campaign studying pre-equilibrium emission of light charged particles and cluster properties of light and medium-mass nuclei has been carried out. Data correspond to usage on the plateform after The current usage metrics is available hours after online publication and is updated daily on week days.

Open Access. As the MCAs grow in size, the average nuclear size decreases with a commensurate increase in average pressure.

Clusters in Nuclei

This figure presents the volume of the nuclei as a function of position in the MCA; volume of the nuclei in the: spherical red stars MCAs, elliptical MCAs from the center along the major axis blue circles , elliptical MCAs from the center along the minor axis black squares. As the MCAs grow, they compress their microenvironment; these forces also compress the MCAs, the individual cells, and their organelles as well. The corresponding pressure for each nucleus calculated based on volume-pressure relationship in Fig 1B shows around 1 MPa difference all over the MCA, however, it is not strongly position dependent, as shown in Fig 4C.

We also measured the deformation of nuclei in the direction major and minor axes, which shows nuclei are more compressed in the major axes shown in Fig 4E and 4F. This suggests that the pressure is rather evenly distributed in the investigated MCAs when they have spherical morphologies. In stiffer alginate environments, MCAs tends to grow elliptically asymmetrically [ 28 ].

Clusters in nuclei - Scholarpedia

Nuclei oriented along the minor axis sides are more elongated and have smaller volumes while those in the center are larger Fig 3B and morphologically closer to spheres. Fig 5C shows that the pressure is also higher at the minor axis and decreases towards the center of the MCA.

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These measurements are consistent with previous findings which also observed that the local external stress field is higher at the minor axis side of the elliptical MCAs using embedded tracer particles in the gel [ 34 ]. B Confocal microscopy determined nuclear volumes throughout the MCA, C Calculated pressures of individual nuclei in the MCA, D aspect ratios of individual compressed nuclei, E nuclear strains in the direction of minor axis of each nucleus, F nuclear strains in the direction of major axis of the nuclei.

Here we have shown that nuclei volumes imaged with confocal microscopy may be used as pressure sensors within multicellular aggregates, enabling previously inaccessible regions of multicellular structures or tissues to be measured without the introduction of an exogenous mechanical probe. We have shown that using PEG we can apply a precise osmotic pressure to produce a reversible and predictable compression of the nucleus.

Osmotic pressures from PEG were verified through direct measurement and found to be consistent with literature values. We employed osmotic pressure to measure the pressure-volume PV curve of nuclei in isolated cells, where cells are not under compression from neighbors or from substrate-based contraction.

The measurement of bulk moduli for cells from osmotic compression is an established technique. It is important to note that unlike physiological salts, there are no pumps for PEG, it does not pass through the membrane, and cells are unable to adapt osmotically; thus, using osmotic stress from a salt-based source would be inaccurate, however, PEG-based osmotic stress is accurate in calculating bulk moduli.

We evaluated the validity of this approach by applying prolonged various pressures to cells, and quantifying their mechanical responses.

Segmentation of confocal microscope images of cell nuclei in thick tissue sections

This demonstrates that these nuclei do not mechanically adapt to these pressures, validating their use as calibrated pressure probes. While these data demonstrate that this approach is robust for measuring these cells and employing them as pressure sensors, this may not always be the case; during early development, differentiation, and disease progression nuclear mechanics may be variable as cells change expression of proteins such as lamins [ 35 — 38 ].

Other conditions such as biochemical, nutrient, or oxygen deprivation may influence bulk moduli.

Clusters in Nuclei

Such mechanical variability of nuclei could hinder or invalidate this methodology. Having established and validated these PV curves, we then calculate the equivalent total pressure in the multi-cellular aggregate from the confocal microscopy measured volumes. Our study reveals that these compressive stresses acting on nuclei are in the MPa range, which appears quite large when considering the typical stress regimes of kPa that are reported for cell stresses.

This is due to much larger forces being required to compress hydrogels and expel water, than to shear and deform them with no change in volume. As bulk moduli are so large, even small changes in volume represent large compressive stresses on the order of MPa. The pressures measured here are the sums of all forces compressing the nuclei; these include compressive-stresses, as well as any osmotic pressures from diffusive gradients. We are unable to differentiate between these; as such, we report these as cumulative pressures contributing to nuclear compression.

formation of nuclear clusters in heavy-ion collisions in vaporization

Nevertheless, previous work has shown that compression stresses applied to cells such as through contractility and osmotic pressures applied through diffusive factors such as PEG provoke identical physical and biochemical responses from cells, suggesting that total pressure is a metric mechanosensed by the cell and that compression from any source was sufficient to regulate stem cell differentiation[ 31 ]. This highlights the importance of this type of data. To our knowledge, these data represent the first measurements of intracellular compressive forces. Given the importance of nuclear compression in determining cell function and fate, we believe it is of value to the community.

Using these nuclear sensors, we find that stresses compressing nuclei are extremely cell cluster size dependent. Nuclei are more compressed in larger MCAs, suggesting that cell density and MCA volume affect nuclei deformation and compression. As cells proliferate and MCAs grow, the cells compress each other and their microenvironment; higher numbers of cells apply larger stress in the larger MCAs, therefore cells are more deformed and compressed.


Our observation is consistent with the work of Nia et al. The nuclear stresses are also dependent on MCA geometry, with spherical cell clusters displaying very uniform stresses of approximately 3 MPa throughout the cluster. In stark contrast, elliptical MCAs have highly non-uniform nuclear stress-distributions, with nuclei along the outer major axis bearing roughly twice the pressure 5—6 MPa of cells in the interior, or at the distal tips of the MCA.

Previous work has shown that the MCAs tend to grow in the regions of lower stress[ 28 , 41 ], suggesting that the lower pressure at the curvature than the sides may be a reason for MCAs to grow elliptically. The nuclei along the sides of the MCAs are deformed in the minor axes much more than the major axis, again mirroring the overall MCA shape. Differential pressures such as these may play a key role in mechanically regulating cell growth and proliferation in a variety of contexts from development to pathology, as nuclear deformation leads to changes in genes expression and cell function [ 42 ], making the nucleus a central mechanosensor for the cell [ 43 ].

We hope that this simple technique will enable future work to examine not only how growth changes these pressures, but how these pressures regulate multi-cellular structure and mechanotransduction. The osmotic pressure in column 2 corresponds to each PEG concentration based on the literature [ 1 ]. The osmolality of different PEG concentration column 3 was measured by a freezing point depression osmometer, and their corresponding calculated osmotic pressures column 4 is consistent with values previously reported in the literature.

A Volume of the nuclei measured after culturing cells under an osmotic pressure of 0. Nuclei that have been exposed to higher pressures show similar volumes as control. B Volume of nuclei measured after 38 hours under each given pressure, and then 18 hours of recovery. The pressure of 0. Nuclei that have been exposed to higher pressures and then allowed to recover exhibit the same volume as control, indicating that no permanent size alterations have occurred during osmotic compression.

The volumetric ratio is approximately 1 ranging from 0. This quantification demonstrates that the volumetric measurements in z using a 5 micron step are accurate. A fluorescence image of nuclei in spherical MCAs, B their measured volume, and C their calculated pressure, of the nuclei relative to their position in the MCA in a 3D projection.

As the MCA size increases in the fluorescence images shown in panel A, the nuclei volumes decrease in the plots in panel B, however no spatial pattern of volumes is visible, nor is there a clear pattern in the distribution of pressures in panel C. These data suggest that the volumes and pressures throughout spherical MCAs are similar, and that there is not a gradient from center to edge. The perspectives in B and C are rotated to give a better visualisation of the 3D reconstruction of each MCA, and spatial dimensions are given in microns.

A fluorescence image of nuclei in elliptical MCAs, B their measured volume, and C their calculated pressure, of the nuclei relative to their position in the MCA in a 3D projection. As the MCA size increases in the fluorescence images shown in panel A, the nuclei volumes decrease in the plots in panel B, and they appear more compressed near the edges of the elliptical MCAs. Their calculated pressures thus also suggested that nuclei at the periphery of the MCAs are under higher stresses, as shown in panel C.

These data suggest that the volumes and pressures throughout spherical MCAs are different, with a gradient of increasing stress from center to edge. The authors thank D. Weitz for confocal microscope usage in Leica SP5 experiments, and C. Moraes for helpful discussions. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Measuring pressures within complex multi-cellular environments is critical for studying mechanobiology as these forces trigger diverse biological responses, however, these studies are difficult as a deeply embedded yet well-calibrated probe is required.

Introduction Cells are exposed to diverse forces in vivo , including compression, tension, fluid shear. Calibration of nuclear volume -pressure Osmotic pressure. Download: PPT. Fig 1.