Flow in temporally and spatially varying porous media: a model for transport of interstitial fluid in the brain.

Flow in a porous medium can be driven by the deformations of the boundaries of the porous domain. Such boundary deformations locally change the volume fraction accessible by the fluid, creating non-uniform porosity and permeability throughout the medium. In this work, we construct a deformation-driven porous medium transport model with spatially and temporally varying porosity and permeability that are dependent on the boundary deformations imposed on the medium. We use this model to study the transport of interstitial fluid along the basement membranes in the arterial walls of the brain. The basement membrane is modeled as a deforming annular porous channel with the compressible pore space filled with an incompressible, Newtonian fluid. The role of a forward propagating peristaltic heart pulse wave and a reverse smooth muscle contraction wave on the flow within the basement membranes is investigated. Our results identify combinations of wave amplitudes that can induce either forward or reverse transport along these transport pathways in the brain. The magnitude and direction of fluid transport predicted by our model can help in understanding the clearance of fluids and solutes along the Intramural Periarterial Drainage route and the pathology of cerebral amyloid angiopathy.

International collaboration between low-middle-income and high-income institutions to improve radiation therapy care delivery.

INTRODUCTION: The Philippines is a lower-middle-income island country with over 153 000 new cancer diagnosis each year. Despite many patients needing radiotherapy as part of disease management, there remains limitations to access. Currently, the Philippines has 50 linear accelerator facilities serving a population of 110 million. However, given the recommendation of 1 linear accelerator for every 250 thousand people, it is evident that the demand for accessible radiotherapy resources is significantly underserved in the country. This paper outlines the collaboration between GenesisCare Solutions (GCS) and Fairview Cancer Center (FCC) to address efficiency and access within the radiotherapy department at FCC. METHODS: Through international collaboration between GCS and FCC, areas for improvement were identified and categorized into four domains: Dosimetry quality, Patient workflow, Data & Reporting, and Information Technology (IT) Infrastructure. Action plans were developed then implemented. A baseline measurement was obtained for each domain, and post-implementation evaluation undertaken at 3 months, 6 months, and 12 months. Data captured within the electronic medical record system was extrapolated, and average treatment times were established for pre- and post-engagement. A paired, 2-tailed t-test was used for statistical analysis of outcome parameters using IBM SPSS version 23 for all statistics. RESULTS: Twelve months post-initial engagement, all four domains saw positive outcomes. Improved plan quality linked to Intensity Modulated Radiotherapy (IMRT) utilization rates saw an increase from 20% to 54%. A significant reduction in patient average wait times was also observed, from 27 to 17 min (p ≤ 0.001). Prior to engagement, tracking patient demographics and diagnosis was not prioritized, post engagement an average of 92% diagnosis entry compliance was achieved. CONCLUSION: Through the collaboration of GCS and FCC, objectives in all action plan domains were achieved, highlighting the benefits of collaboration between low-middle-income and high-income institutions.

Multiscale computational modeling of aortic valve calcification.

Calcific aortic valve disease (CAVD) is a common cardiovascular disease that affects millions of people worldwide. The disease is characterized by the formation of calcium nodules on the aortic valve leaflets, which can lead to stenosis and heart failure if left untreated. The pathogenesis of CAVD is still not well understood, but involves several signaling pathways, including the transforming growth factor beta (TGF ß ) pathway. In this study, we developed a multiscale computational model for TGF ß -stimulated CAVD. The model framework comprises cellular behavior dynamics, subcellular signaling pathways, and tissue-level diffusion fields of pertinent chemical species, where information is shared among different scales. Processes such as endothelial to mesenchymal transition (EndMT), fibrosis, and calcification are incorporated. The results indicate that the majority of myofibroblasts and osteoblast-like cells ultimately die due to lack of nutrients as they become trapped in areas with higher levels of fibrosis or calcification, and they subsequently act as sources for calcium nodules, which contribute to a polydispersed nodule size distribution. Additionally, fibrosis and calcification processes occur more frequently in regions closer to the endothelial layer where the cell activity is higher. Our results provide insights into the mechanisms of CAVD and TGF ß signaling and could aid in the development of novel therapeutic approaches for CAVD and other related diseases such as cancer. More broadly, this type of modeling framework can pave the way for unraveling the complexity of biological systems by incorporating several signaling pathways in subcellular models to simulate tissue remodeling in diseases involving cellular mechanobiology.

EigenFold: Generative Protein Structure Prediction with Diffusion Models.

Protein structure prediction has reached revolutionary levels of accuracy on single structures, yet distributional modeling paradigms are needed to capture the conformational ensembles and flexibility that underlie biological function. Towards this goal, we develop EigenFold, a diffusion generative modeling framework for sampling a distribution of structures from a given protein sequence. We define a diffusion process that models the structure as a system of harmonic oscillators and which naturally induces a cascading-resolution generative process along the eigenmodes of the system. On recent CAMEO targets, EigenFold achieves a median TMScore of 0.84, while providing a more comprehensive picture of model uncertainty via the ensemble of sampled structures relative to existing methods. We then assess EigenFold's ability to model and predict conformational heterogeneity for fold-switching proteins and ligand-induced conformational change. Code is available at https://github.com/bjing2016/EigenFold.

Probing Colloidal Assembly on Non-Axisymmetric Droplet Surfaces via Electrospray.

Microparticles trapped on the surface of a sessile droplet interact via electrostatic and capillary forces. The assembly of colloids at a fluid-fluid interface is governed by particle size, surface chemistry, and contact line roughness. We created nonspherical droplets using surface energy patterning and delivered microparticles to the liquid-air interface with electrospray atomization. Using a water droplet as the target, the particle assembly was observed over time. We found that the underlying surface energy pattern significantly influenced the colloidal assembly and drove particles toward the center of the droplet. The particles were arranged into a single, non-close-packed cluster with local hexagonal ordering but left a clear region with very few particles near the contact line. This depletion region is attributed to long-range electrostatic repulsion from the photoresist used to create the surface energy pattern, which retained electric charge from the electrospray. To understand the effect of electrostatic interactions, we explored target droplets with dissimilar dielectric properties. Using patterned substrates and electrospray for particle deposition, we can harness the assembly of colloids at a fluid interface to build repeatable monolayer patterns.

Efficacy evaluation of True Lift®, a nonsurgical facial ligament retightening injection technique: Two case reports.

BACKGROUND: With aging, four major facial retaining ligaments become elongated, leading to facial sagging and wrinkling. Even though synthetic fillers are popular, however, it cannot address the problems of soft tissue descent alone, and injection of these fillers requires knowledge of the injection technique including the selection of injection sites, the amount of filler, and the dosage used per injection site. CASE SUMMARY: This report aimed to assess the safety and efficacy of a nonsurgical retightening technique to lift and tighten the true ligaments of the face, to improve age-related skin sagging and wrinkling. We objectively quantified the aesthetic lifting effect of a nonsurgical facial retightening procedure that strategically injected high G' fillers into the base of the true retaining ligaments of the face in two female patients. Facial images were recorded with a three-dimensional facial imaging system for comparison of the clinical outcome. The primary efficacy outcome was the change in facial anthropometric measurements obtained prior to and after injection. The patients were followed for 6 mo after the procedure. Skin retightening was observed, with an evident lift in the orbital, zygomatic, and mandibular regions, and the lifting effect was still observable at the 6-mo follow-up. Few mild adverse events, such as mild-to-moderate pain, tenderness, and itching, occurred during the 1st week after the procedure. No adverse events were reported 1 mo post-procedure. CONCLUSION: The results of this study demonstrated that our nonsurgical retightening procedure with strategically placed high G' fillers achieved quantifiable aesthetic improvements in the orbital, zygomatic, and mandibular regions of two patients. Future research with a larger sample could provide a more in-depth evaluation and validation of the aesthetic improvements observed in this study.

Glycosaminoglycans affect endothelial to mesenchymal transformation, proliferation, and calcification in a 3D model of aortic valve disease.

Calcific nodules form in the fibrosa layer of the aortic valve in calcific aortic valve disease (CAVD). Glycosaminoglycans (GAGs), which are normally found in the valve spongiosa, are located local to calcific nodules. Previous work suggests that GAGs induce endothelial to mesenchymal transformation (EndMT), a phenomenon described by endothelial cells' loss of the endothelial markers, gaining of migratory properties, and expression of mesenchymal markers such as alpha smooth muscle actin (α-SMA). EndMT is known to play roles in valvulogenesis and may provide a source of activated fibroblast with a potential role in CAVD progression. In this study, a 3D collagen hydrogel co-culture model of the aortic valve fibrosa was created to study the role of EndMT-derived activated valvular interstitial cell behavior in CAVD progression. Porcine aortic valve interstitial cells (PAVIC) and porcine aortic valve endothelial cells (PAVEC) were cultured within collagen I hydrogels containing the GAGs chondroitin sulfate (CS) or hyaluronic acid (HA). The model was used to study alkaline phosphatase (ALP) enzyme activity, cellular proliferation and matrix invasion, protein expression, and calcific nodule formation of the resident cell populations. CS and HA were found to alter ALP activity and increase cell proliferation. CS increased the formation of calcified nodules without the addition of osteogenic culture medium. This model has applications in the improvement of bioprosthetic valves by making replacements more micro-compositionally dynamic, as well as providing a platform for testing new pharmaceutical treatments of CAVD.

Shear and endothelial induced late-stage calcific aortic valve disease-on-a-chip develops calcium phosphate mineralizations.

Calcific aortic valve disease (CAVD) is an active pathobiological process leading to severe aortic stenosis, where the only treatment is valve replacement. Late-stage CAVD is characterized by calcification, disorganization of collagen, and deposition of glycosaminoglycans, such as chondroitin sulfate (CS), in the fibrosa. We developed a three-dimensional microfluidic device of the aortic valve fibrosa to study the effects of shear stress (1 or 20 dyne per cm2), CS (1 or 20 mg mL-1), and endothelial cell presence on calcification. CAVD chips consisted of a collagen I hydrogel, where porcine aortic valve interstitial cells were embedded within and porcine aortic valve endothelial cells were seeded on top of the matrix for up to 21 days. Here, we show that this CAVD-on-a-chip is the first to develop human-like calcified nodules varying in calcium phosphate mineralization maturity resulting from high shear and endothelial cells, specifically di- and octa-calcium phosphates. Long-term co-culture microfluidic studies confirmed cell viability and calcium phosphate formations throughout 21 days. Given that CAVD has no targeted therapies, the creation of a physiologically relevant test-bed of the aortic valve could lead to advances in preclinical studies.

Chondroitin Sulfate Promotes Interstitial Cell Activation and Calcification in an In Vitro Model of the Aortic Valve.

PURPOSE: Calcific aortic valve disease (CAVD), has been characterized as a cascade of cellular changes leading to leaflet thickening and valvular calcification. In diseased aortic valves, glycosaminoglycans (GAGs) normally found in the valve spongiosa migrate to the collagen I-rich fibrosa layer near calcified nodules. Current treatments for CAVD are limited to valve replacement or drugs tailored to other cardiovascular diseases. METHODS: Porcine aortic valve interstitial cells and porcine aortic valve endothelial cells were seeded into collagen I hydrogels of varying initial stiffness or initial stiffness-matched collagen I hydrogels containing the glycosaminoglycans chondroitin sulfate (CS), hyaluronic acid (HA), or dermatan sulfate (DS). Assays were performed after 2 weeks in culture to determine cell gene expression, protein expression, protein secretion, and calcification. Multiple regression analyses were performed to determine the importance of initial hydrogel stiffness, GAGs, and the presence of endothelial cells on calcification, both with and without osteogenic medium. RESULTS: High initial stiffness hydrogels and osteogenic medium promoted calcification, while for DS or HA the presence of endothelial cells prevented calcification. CS was found to increase the expression of pro-calcific genes, increase activated myofibroblast protein expression, induce the secretion of collagen I by activated interstitial cells, and increase calcified nodule formation. CONCLUSION: This study demonstrates a more complete model of aortic valve disease, including endothelial cells, interstitial cells, and a stiff and disease-like ECM. In vitro models of both healthy and diseased valves can be useful for understanding the mechanisms of CAVD pathogenesis and provide a model for testing novel therapeutics.