Endothelial cells differentially sense laminar and disturbed flows by altering the lipid order of their plasma and mitochondrial membranes.

Endothelial cells (ECs) experience two different blood flow patterns: laminar and disturbed flow. Their responses to laminar flow contribute to vascular homeostasis, whereas their responses to disturbed flow result in EC dysfunction and vascular diseases. However, it remains unclear how ECs differentially sense laminar and disturbed flow and trigger signaling that elicits different responses. Here, we showed that ECs differentially sense laminar and disturbed flows by altering the lipid order of their plasma and mitochondrial membranes in opposite directions. This results in distinct changes in mitochondrial function, namely, increased adenosine triphosphate (ATP) production for laminar flow and increased hydrogen peroxide (H2O2) release for disturbed flow, leading to ATP- and H2O2-mediated signaling, respectively. When cultured human aortic ECs were subjected to laminar or disturbed flow in flow-loading devices, the lipid order of their plasma membranes immediately decreased in response to laminar flow and increased in response to disturbed flow. Laminar flow also decreased the lipid order of mitochondrial membranes and increased mitochondrial ATP production. In contrast, disturbed flow increased the lipid order of mitochondrial membranes and increased the release of H2O2 from the mitochondria. The addition of cholesterol to the cells increased the lipid order of both membranes and abrogated laminar flow-induced ATP production, while treatment of the cells with a cholesterol-depleting reagent, methyl-ß cyclodextrin, decreased the lipid order of both membranes and abolished disturbed flow-induced H2O2 release, indicating that changes in the membrane lipid order and/or cholesterol content are closely linked to flow-induced changes in mitochondrial functions.NEW & NOTEWORTHY How vascular endothelial cells (ECs) differentially sense laminar and disturbed flows and trigger intracellular signaling remains unclear. Here, we show that EC plasma membranes act as mechanosensors to discriminate between laminar and disturbed flows by undergoing opposite changes in their lipid order. Similar lipid order changes occur simultaneously in the mitochondrial membranes, which are linked to changes in mitochondrial function, that is, increased ATP production for laminar flow and increased H2O2 release for disturbed flow.

Hemodynamic Risk Factors for the Development of Carotid Stenosis in Patients with Unilateral Carotid Stenosis.

BACKGROUND: It is difficult to predict the development of carotid stenosis by means of the known risk factors. Using a computational fluid dynamics analysis, we examined the hemodynamic risks for carotid stenosis, focusing on wall shear stress (WSS) disturbances. METHODS: In 59 patients with unilateral carotid stenosis, the plaque was removed from the original three-dimensional computed tomography angiographic images, and the vessel shape before stenosis was artificially reproduced. A multivariate regression analysis was performed to determine the associations between the degree of area stenosis and hemodynamic and morphologic factors after adjustment for 6 known risk factors. RESULTS: Metrics for WSS disturbances were higher at and distal to a bifurcation in the carotid arteries after plaque removal compared with the normal carotid arteries, and metrics for WSS magnitudes were lower. In the plaque-removed arteries, the degree of stenosis was significantly negatively correlated with the ratio of stenotic to distal values of metrics for WSS disturbances and the diameter ratio of the external to common carotid artery, and positively correlated with the ratio of proximal to stenotic values of metrics for WSS magnitudes. CONCLUSIONS: Rapid increases in WSS from the common carotid artery toward the bifurcation, rapid decreases in WSS disturbance from the bifurcation toward the internal carotid artery, and lower diameter ratio of the external to common carotid artery are more likely than other risk factors to cause future severe stenosis. In patients with these hemodynamic risks, underlying diseases should be controlled more strictly, with imaging examinations at shorter intervals.

Bacterial detachment from a wall with a bump line.

The interactions of bacteria with surfaces have important implications in numerous areas of research, such as bioenergy, biofilm, biofouling, and infection. Recently, several experimental studies have reported that the adhesion of bacteria can be reduced considerably by microscale wall features. To clarify the effect of wall configurations, we numerically investigated the behavior of swimming bacteria near a flat wall with a bump line. The results showed that the effects of bump configuration are significant; a detachment time larger than several seconds can be achieved in certain parameter sets. These results illustrate that the number density of bacteria near the wall may be reduced by appropriately controlling the parameter sets. When background shear flow was imposed, the near-wall bacterium mainly moved towards the vorticity axis. The detachment time of cells increased significantly by adjusting the bump line to have 45^{∘} relative to the flow direction. The knowledge obtained in this study is fundamental for understanding the interactions between bacteria and surfaces according to more complex geometries, and is useful for reducing the adhesion of cells to walls.

Real-World Variability in the Prediction of Intracranial Aneurysm Wall Shear Stress: The 2015 International Aneurysm CFD Challenge.

PURPOSE: Image-based computational fluid dynamics (CFD) is widely used to predict intracranial aneurysm wall shear stress (WSS), particularly with the goal of improving rupture risk assessment. Nevertheless, concern has been expressed over the variability of predicted WSS and inconsistent associations with rupture. Previous challenges, and studies from individual groups, have focused on individual aspects of the image-based CFD pipeline. The aim of this Challenge was to quantify the total variability of the whole pipeline. METHODS: 3D rotational angiography image volumes of five middle cerebral artery aneurysms were provided to participants, who were free to choose their segmentation methods, boundary conditions, and CFD solver and settings. Participants were asked to fill out a questionnaire about their solution strategies and experience with aneurysm CFD, and provide surface distributions of WSS magnitude, from which we objectively derived a variety of hemodynamic parameters. RESULTS: A total of 28 datasets were submitted, from 26 teams with varying levels of self-assessed experience. Wide variability of segmentations, CFD model extents, and inflow rates resulted in interquartile ranges of sac average WSS up to 56%, which reduced to < 30% after normalizing by parent artery WSS. Sac-maximum WSS and low shear area were more variable, while rank-ordering of cases by low or high shear showed only modest consensus among teams. Experience was not a significant predictor of variability. CONCLUSIONS: Wide variability exists in the prediction of intracranial aneurysm WSS. While segmentation and CFD solver techniques may be difficult to standardize across groups, our findings suggest that some of the variability in image-based CFD could be reduced by establishing guidelines for model extents, inflow rates, and blood properties, and by encouraging the reporting of normalized hemodynamic parameters.

What causes the spatial heterogeneity of bacterial flora in the intestine of zebrafish larvae?

Microbial flora in the intestine has been thoroughly investigated, as it plays an important role in the health of the host. Jemielita et al. (2014) showed experimentally that Aeromonas bacteria in the intestine of zebrafish larvae have a heterogeneous spatial distribution. Although bacterial aggregation is important biologically and clinically, there is no mathematical model describing the phenomenon and its mechanism remains largely unknown. In this study, we developed a computational model to describe the heterogeneous distribution of bacteria in the intestine of zebrafish larvae. The results showed that biological taxis could cause the bacterial aggregation. Intestinal peristalsis had the effect of reducing bacterial aggregation through mixing function. Using a scaling argument, we showed that the taxis velocity of bacteria must be larger than the sum of the diffusive velocity and background bulk flow velocity to induce bacterial aggregation. Our model and findings will be useful to further the scientific understanding of intestinal microbial flora.

Mixing and pumping functions of the intestine of zebrafish larvae.

Due to its transparency, the intestine of zebrafish larvae has been widely used in studies of gastrointestinal diseases and the microbial flora of the gut. However, transport phenomena in the intestine of zebrafish larvae have not been fully clarified. In this study, therefore, transport caused by peristaltic motion in the intestine of zebrafish larvae was investigated by numerical simulation. An anatomically realistic three-dimensional geometric model of the intestine at various times after feeding was constructed based on the experimental data of Field et al. (2009). The flow of digested chyme was analyzed using the governing equations of fluid mechanics, together with peristaltic motion and long-term contraction of the intestinal wall. The results showed that retrograde peristaltic motion was the main contributor to the mixing function. The dispersion caused by peristalsis over 30min was in the order of 10-12m2/s, which is greater than the Brownian diffusion of a sphere of 0.4µm diameter. In contrast, anterograde peristaltic motion contributed mainly to the pumping function. The pressure decrease due to peristalsis was in the order of millipascals, which may reduce the activation and maintenance heat of intestinal muscle. These findings enhance our understanding of the mixing and pumping functions of the intestine of zebrafish larvae.

Sustained expression of MCP-1 by low wall shear stress loading concomitant with turbulent flow on endothelial cells of intracranial aneurysm.

INTRODUCTION: Enlargement of a pre-existing intracranial aneurysm is a well-established risk factor of rupture. Excessive low wall shear stress concomitant with turbulent flow in the dome of an aneurysm may contribute to progression and rupture. However, how stress conditions regulate enlargement of a pre-existing aneurysm remains to be elucidated. RESULTS: Wall shear stress was calculated with 3D-computational fluid dynamics simulation using three cases of unruptured intracranial aneurysm. The resulting value, 0.017 Pa at the dome, was much lower than that in the parent artery. We loaded wall shear stress corresponding to the value and also turbulent flow to the primary culture of endothelial cells. We then obtained gene expression profiles by RNA sequence analysis. RNA sequence analysis detected hundreds of differentially expressed genes among groups. Gene ontology and pathway analysis identified signaling related with cell division/proliferation as overrepresented in the low wall shear stress-loaded group, which was further augmented by the addition of turbulent flow. Moreover, expression of some chemoattractants for inflammatory cells, including MCP-1, was upregulated under low wall shear stress with concomitant turbulent flow. We further examined the temporal sequence of expressions of factors identified in an in vitro study using a rat model. No proliferative cells were detected, but MCP-1 expression was induced and sustained in the endothelial cell layer. CONCLUSIONS: Low wall shear stress concomitant with turbulent flow contributes to sustained expression of MCP-1 in endothelial cells and presumably plays a role in facilitating macrophage infiltration and exacerbating inflammation, which leads to enlargement or rupture.

Numerical methods for simulating blood flow at macro, micro, and multi scales.

In the past decade, numerical methods for the computational biomechanics of blood flow have progressed to overcome difficulties in diverse applications from cellular to organ scales. Such numerical methods may be classified by the type of computational mesh used for the fluid domain, into fixed mesh methods, moving mesh (boundary-fitted mesh) methods, and mesh-free methods. The type of computational mesh used is closely related to the characteristics of each method. We herein provide an overview of numerical methods recently used to simulate blood flow at macro and micro scales, with a focus on computational meshes. We also discuss recent progress in the multi-scale modeling of blood flow.

Torque-induced precession of bacterial flagella.

The bacterial flagellar motor is an ion-driven rotary machine in the cell envelope of bacteria. Using a gold nanoparticle as a probe, we observed the precession of flagella during rotation. Since the mechanism of flagella precession was unknown, we investigated it using a combination of full simulations, theory, and experiments. The results show that the mechanism can be well explained by fluid mechanics. The validity of our theory was confirmed by our full simulation, which was utilized to predict both the filament tilt angle and motor torque from experimental flagellar precession data. The knowledge obtained is important in understanding mechanical properties of the bacterial motor and hook.

Sensitivity of the gradient oscillatory number to flow input waveform shapes.

The sensitivity of the gradient oscillatory number (GON), which is a potential hemodynamic indicator for cerebral aneurysm initiation, to flow input waveform shapes was examined by performing computational fluid dynamics (CFD) simulations of an anatomical model of a human internal carotid artery under three different waveform shape conditions. The local absolute variation (standard deviation) and relative variation (coefficient of variation) of the GON calculations for three waveform shapes were computed to quantify the variation in GON due to waveform shape changes. For all waveform shapes, an elevated GON was evident at a known aneurysm site, albeit occurring at additional sites. No significant differences were observed among the qualitative GON distributions derived using the three different waveform shapes. These results suggest that the GON is largely insensitive to the variability in flow input waveform shapes. The quantitative analysis revealed that GON displays an improved relative variation over a relatively high GON range. We therefore conclude that it is reasonable to use assumed flow input waveform shapes as a substitute for individual real waveform shapes for the detection of possible GON elevations of individual clinical cases in large-scale studies, where the higher values of GON are of primary interest.

Can temporal fluctuation in spatial wall shear stress gradient initiate a cerebral aneurysm? A proposed novel hemodynamic index, the gradient oscillatory number (GON).

We propose a new hemodynamic index for the initiation of a cerebral aneurysm, defined by the temporal fluctuations of tension/compression forces acting on endothelial cells. We employed a patient-specific geometry of a human internal carotid artery (ICA) with an aneurysm, and reconstructed the geometry of the ICA before aneurysm formation by artificially removing the aneurysm. We calculated the proposed hemodynamic index and five other hemodynamic indices (wall shear stress (WSS) at peak systole, time-averaged WSS, time-averaged spatial WSS gradient, oscillatory shear index (OSI), and potential aneurysm formation indicator (AFI)) for the geometry before aneurysm formation using a computational fluid dynamics technique. By comparing the distribution of each index at the location of aneurysm formation, we discussed the validity of each. The results showed that only the proposed hemodynamic index had a significant correlation with the location of aneurysm formation. Our findings suggest that the proposed index may be useful as a hemodynamic index for the initiation of cerebral aneurysms.