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Abstract As a blood clot forms, grows, deforms, and embolizes following a vascular injury, local clot-flow interactions lead to a highly dynamic flow environment. The local flow influences transport of biochemical species relevant for clotting, and determines the forces on the clot that in turn lead to clot deformation and embolization. Despite this central role, quantitative characterization of this dynamic clot-flow interaction and flow environment in the clot neighborhood remains a major challenge. Here, we propose an approach that integrates dynamic intravital imaging with computer geometric modeling and computational flow and transport modeling to develop a unified in silico framework to quantify the dynamic clot-flow interactions. We outline the development of the methodology referred to as Intravital Integrated In Silico Modeling or IVISim, and then demonstrate the method on a sample set of simulations comprising clot formation following laser injury in two mouse cremaster arteriole injury model data: one wild-type mouse case, and one diYF knockout mouse case. Simulation predictions are verified against experimental observations of transport of caged fluorescent Albumin (cAlb) in both models. Through these simulations, we illustrate how the IVISim methodology can provide insights into hemostatic processes, the role of flow and clot-flow interactions, and enable further investigations comparing and contrasting different biological model scenarios and parameter variations.

Background Disambiguation of embolus pathogenesis in embolic strokes is often a clinical challenge. One common source of embolic stroke is the carotid arteries, with emboli originating due to plaque buildup or perioperatively during revascularization procedures. Although it is commonly thought that thromboemboli from carotid sources travel to cerebral arteries ipsilaterally, there are existing reports of contralateral embolic events that complicate embolus source destination relationship for carotid sources. Here, we hypothesize that emboli from carotid sources can travel to contralateral hemispheres and that embolus interactions with collateral hemodynamics in the circle of Willis influence this process. Methods and Results We use a patient‐specific computational embolus‐hemodynamics interaction model developed in prior works to conduct an in silico experiment spanning 4 patient vascular models, 6 circle of Willis anastomosis variants, and 3 different thromboembolus sizes released from left and right carotid artery sites. This led to a total of 144 different experiments, estimating trajectories and distribution of approximately 1.728 million embolus samples. Across all cases considered, emboli from left and right carotid sources showed nonzero contralateral transport (P value

We investigated differences in haemodynamic forces between carotid arteries that underwent primary closure (PC) or patch angioplasty (PA) using computational fluid dynamics (CFD). A total of 30 subjects were enrolled in this study, consisting of 10 subjects who underwent PC, 10 who underwent PA and 10 healthy subjects. Three-dimensional models of carotid arteries were reconstructed using patient-specific computed tomography angiography images. The conventional Navier-Stokes, continuity equation and constitutive stress-strain law with a stabilized Petrov-Galerkin scheme were solved with Newtonian and incompressible assumptions. The boundary conditions employed patient-specific velocity profiles as the inflow and lumped parameters of the three-element Windkessel model as the outflow with a rigid wall assumption. Thus, the CFD results exhibited good agreement with measurements from the subjects (r = .78). The carotid arteries of the PC group were exposed to abnormal haemodynamic forces related to building atherosclerosis in a smaller (p .05) to healthy arteries. The morphological characteristics of the carotid artery were significantly associated with the area exposed to abnormal haemodynamic forces. We identified that abnormal haemodynamic forces could be avoided by selecting appropriate surgical techniques that produce less bifurcation expansion.

Here we describe a systematic approach towards creating effective screencast based modules for teaching computational techniques in remote and online modalities. We adopted a multi-stage approach to create screencast videos that replaced in-person demos and active learning content in a finite element analysis based class. The stages include systematic preparation of video data and script; production stage, for recording and editing of captured video and audio; and post-production stage, for uploading generated media files into our learning management system. Modules were paired with assignments, thereby enhancing student learning and enabling assessment of module content efficacy. Our approach and technology received highly positive reception from students. Students also successfully navigated all associated assignments and final course project, which builds upon the content addressed in the modules. We identified several avenues for improvement in continued future offerings of such modules. We have outlined our design experience and student reception of screencast based modules for creating engaging learning content in remote teaching modalities. The description has been presented in form of teaching tips for other educators to adopt for their teaching needs.

The reasons why malaria manifests with a variety of well-recognized clinical phenotypes remain poorly understood. Here, using distinct rodent models, the authors reveal that the microbiota colonizing the lung promotes respiratory distress syndrome and mortality during malaria infections.

Haemodynamic correlations among the pulsatility index (PI), resistive index (RI), time to peak velocity (TPV), and mean Reynolds number (ReMean) were numerically investigated during the progression of carotid stenosis (CS), a highly prevalent condition. Fifteen patient-specific CS cases were modeled in the package, SimVascular, by using computed tomography angiography data for the aortic-cerebral vasculature. Computational fluid domains were solved with a stabilized Petrov–Galerkin scheme under Newtonian and incompressible assumptions. A rigid vessel wall was assumed, and the boundary conditions were pulsatile inflow and three-element lumped Windkessel outlets. During the progression, the increase in the TPV resembled that during aortic stenosis, and the parameter was negatively correlated with PI, RI, and ReMean in the ipsilateral cerebral region. The ReMean was inversely related to PI and RI on the contralateral side. In particular, PI and RI in cerebral arteries showed three second-order regression patterns: ‘constant (Group A)’, ‘moderately decreasing (Group B)’, and ‘decreasing (Group C)’. The patterns were defined using a new parameter, mean ratio (lowest mean index/mean index at 0% CS). This parameter could effectively indicate stenosis-driven tendencies in local haemodynamics. Overall, the haemodynamic indices changed drastically during severe unilateral CS, and they reflected both regional and aortic-cerebral flow characteristics.

We investigated the effects of atherosclerosis in the carotid region on cerebral haemodynamics. A total of 15 stenosis cases following NASCET criteria were modelled using patient-specific medical image data and an open-source package, SimVascular. The formulation adopted the stabilised Petrov–Galerkin scheme with Newtonian and incompressible assumptions. The boundary conditions employed pulsatile inflow and three-element lumped Windkessel outlet conditions with a rigid wall assumption. We present transitions in the represented CoW during stenosis progression using three-dimensional aortic-cerebral vasculature for the first time. This was driven by the conserved total cerebral blood flow to 50% carotid stenosis (CS) (P-value, P > 0.05), which deteriorated during subsequent stages of CS (P < 0.01), and the effective collateral capability of the communicating arteries (CoAs) activated from a degree of 75% and above (P < 0.0001). The prevalence of ‘complete’ CoW peaked at 50% CS and then declined. Despite the collateral flow, the ipsilateral hemispheric perfusion was moderately reduced (P < 0.01), and the contralateral perfusion was conserved (P > 0.05), revealing the ineffectiveness of collateral capability of CoW at the extreme stages of CS. We identified bulk cerebral auto-regulation effects of the conventional Windkessel model, demonstrating accurate flow reduction in the stenosed artery.

Summary: Despite decades of studies suggesting that the in vivo adipocyte progenitor resides within the vascular niche, the exact nature of this progenitor remains controversial because distinct studies have attributed adipogenic properties to multiple vascular cell types. Using Cre recombinases labeling distinct vascular lineages, we conduct parallel lineage tracing experiments to assess their degree of contribution to de novo adipogenesis. Although we detect occasional adipocytes that were lineage traced by endothelial or mural recombinases, these are rare events. On the other hand, platelet-derived growth factor receptor alpha (PDGFRα)-expressing adventitial or capsular fibroblasts make a significant contribution to adipocytes in all depots and experimental settings tested. Our data also suggest that fibroblasts transition to an intermediate beige adipocyte phenotype prior to differentiating to a mature white adipocyte. These observations, together with histological analyses revealing that adipose tissue fibroblasts express the mural cell marker PDGFRβ, harmonize a highly controversial field with implications for multiple human diseases, including the pandemic of obesity. : Cattaneo et al. used genetic fate mapping in murine models to test the adipogenic potential of distinct cell types of the vascular wall. These parallel lineage-tracing experiments reveal that fibroblasts are the sole vascular cell type with significant adipocyte progenitor activity, giving rise to brown, beige, and white adipocytes. Keywords: adipogenesis, obesity, vascular wall, lineage tracing, endothelium, mural cells, fibroblasts

Plasmodium falciparum enolase (Pfeno) is a dimeric enzyme with multiple moonlighting functions. This enzyme is thus a potential target for anti‐malarial treatments. A unique feature of Pfeno is the presence of a pentapeptide insert 104EWGWS108. The functional role of tryptophan residues in this insert was investigated using site‐directed mutagenesis. Replacement of these two Trp residues with alanines (or lysines) resulted in a near complete loss of enolase activity and dissociation of the normal dimeric form into monomers. Molecular modeling indicated that 340R forms π‐cation bonds with the aromatic rings of 105W and 46Y. Mutation induced changes in the interactions among these three residues were presumably relayed to the inter‐subunit interface via a coil formed by 46Y : 59Y, resulting in the disruption of a salt bridge between 11R : 425E and a π‐cation interaction between 11R : 59Y. This led to a drop of ~ 4 kcal·mole−1 in the inter‐subunit docking energy in the mutant, causing a ~ 103 fold decrease in affinity. Partial restoration of the inter‐subunit interactions led to reformation of dimers and also restored a significant fraction of the lost enzyme activity. These results suggested that the perturbations in the conformation of the surface loop containing the insert sequence were relayed to the interface region, causing dimer dissociation that, in turn, disrupted the enzyme's active site. Since Plasmodium enolase is a moonlighting protein with multiple parasite‐specific functions, it is likely that these functions may map on to the highly conserved unique insert region of this protein. Enzymes Enolase(EC4.2.1.11).

Abstract Despite our increasing understanding of zebrafish heart development and regeneration, there is limited information about the distribution of endothelial cells (ECs) in the adult zebrafish heart. Here, we investigate and compare the distribution of cardiac ECs (cECs) in adult mouse and zebrafish ventricles. Surprisingly, we find that (i) active coronary vessel growth is present in adult zebrafish, (ii) ~37 and ~39% of cells in the zebrafish heart are ECs and cardiomyocytes, respectively, a composition similar to that seen in mouse. However, we find that in zebrafish, ~36% of the ventricular tissue is covered with ECs, i.e., a substantially larger proportion than in mouse. Capitalising on the high abundance of cECs in zebrafish, we established a protocol to isolate them with high purity using fluorescent transgenic lines. Our approach eliminates side-effects due to antibody utilisation. Moreover, the isolated cECs maintained a high proliferation index even after three passages and were amenable to pharmacological treatments to study cEC migration in vitro. Such primary cultures will be a useful tool for supplementary in vitro studies on the accumulating zebrafish mutant lines as well as the screening of small molecule libraries on cardiac specific endothelial cells.