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Point-vortex dynamics in three-dimensional ageostrophic balanced flows
Geophysical turbulent flows, characterized by rapid rotation, quantified by small Rossby number, and stable stratification, often self-organize into a collection of coherent vortices, referred to as a vortex gas. The lowest-order asymptotic expansion in Rossby number is quasigeostrophy, which has purely horizontal velocities and cyclone–anticyclone antisymmetry. Ageostrophic effects are important components of many geophysical flows and, as such, these phenomena are not well modelled by quasigeostrophy. The next-order correction in Rossby number, which includes ageostrophic effects, is the so-called balanced dynamics. Balanced dynamics includes ageostrophic vertical velocity and breaks the geostrophic cyclone–anticyclone antisymmetry. Point-vortex solutions are well known in two-dimensional and quasigeostrophic dynamics and are useful for studying the vortex-gas regime of geophysical turbulence. Here, we find point-vortex solutions in fully three-dimensional continuously stratified QG$^{+1}$ dynamics, a particular formulation of balanced dynamics. Simulations of QG$^{+1}$ point vortices show several interesting features not captured by quasigeostrophic point vortices including significant vertical transport on long time scales. The ageostrophic component of QG$^{+1}$ point vortex point-vortex dynamics renders them useful in modelling flows where quasigeostrophy filters out important physical processes.
Journal Article
Extracellular Matrix Density Regulates the Rate of Neovessel Growth and Branching in Sprouting Angiogenesis
Angiogenesis is regulated by the local microenvironment, including the mechanical interactions between neovessel sprouts and the extracellular matrix (ECM). However, the mechanisms controlling the relationship of mechanical and biophysical properties of the ECM to neovessel growth during sprouting angiogenesis are just beginning to be understood. In this research, we characterized the relationship between matrix density and microvascular topology in an in vitro 3D organ culture model of sprouting angiogenesis. We used these results to design and calibrate a computational growth model to demonstrate how changes in individual neovessel behavior produce the changes in vascular topology that were observed experimentally. Vascularized gels with higher collagen densities produced neovasculatures with shorter vessel lengths, less branch points, and reduced network interconnectivity. The computational model was able to predict these experimental results by scaling the rates of neovessel growth and branching according to local matrix density. As a final demonstration of utility of the modeling framework, we used our growth model to predict several scenarios of practical interest that could not be investigated experimentally using the organ culture model. Increasing the density of the ECM significantly reduced angiogenesis and network formation within a 3D organ culture model of angiogenesis. Increasing the density of the matrix increases the stiffness of the ECM, changing how neovessels are able to deform and remodel their surroundings. The computational framework outlined in this study was capable of predicting this observed experimental behavior by adjusting neovessel growth rate and branching probability according to local ECM density, demonstrating that altering the stiffness of the ECM via increasing matrix density affects neovessel behavior, thereby regulated vascular topology during angiogenesis.
Journal Article
Molecular level detection and localization of mechanical damage in collagen enabled by collagen hybridizing peptides
Mechanical injury to connective tissue causes changes in collagen structure and material behaviour, but the role and mechanisms of molecular damage have not been established. In the case of mechanical subfailure damage, no apparent macroscale damage can be detected, yet this damage initiates and potentiates in pathological processes. Here, we utilize collagen hybridizing peptide (CHP), which binds unfolded collagen by triple helix formation, to detect molecular level subfailure damage to collagen in mechanically stretched rat tail tendon fascicle. Our results directly reveal that collagen triple helix unfolding occurs during tensile loading of collagenous tissues and thus is an important damage mechanism. Steered molecular dynamics simulations suggest that a likely mechanism for triple helix unfolding is intermolecular shearing of collagen α-chains. Our results elucidate a probable molecular failure mechanism associated with subfailure injuries, and demonstrate the potential of CHP targeting for diagnosis, treatment and monitoring of tissue disease and injury.
Collagen denaturation is thought to occur during tissue mechanical damage, but its role in damage initiation is still unclear. Here, the authors use a collagen hybridizing peptide to provide insights into the molecular mechanisms leading to collagen unfolding during tendon mechanical stretch.
Journal Article
On Kawara -- silence
\"This exhibition marks the first full museum overview of the work produced by On Kawara after 1963. It has been organized in close collaboration with the artist, who proposed most of the sections that comprise the final structure of the show...\"--Introduction, page 19.
Book
Spatial Configurations of 3D Extracellular Matrix Collagen Density and Anisotropy Simultaneously Guide Angiogenesis
Extracellular matrix (ECM) collagen density and fibril anisotropy are thought to affect the development of new vasculatures during pathologic and homeostatic angiogenesis. Computational simulation is emerging as a tool to investigate the role of matrix structural configurations on cell guidance. However, prior computational models have only considered the orientation of collagen as a model input. Recent experimental evidence indicates that cell guidance is simultaneously influenced by the direction and intensity of alignment (i.e., degree of anisotropy) as well as the local collagen density. The objective of this study was to explore the role of ECM collagen anisotropy and density during sprouting angiogenesis through simulation in the AngioFE and FEBio modeling frameworks. AngioFE is a plugin for FEBio (Finite Elements for Biomechanics) that simulates cell-matrix interactions during sprouting angiogenesis. We extended AngioFE to represent ECM collagen as deformable 3D ellipsoidal fibril distributions (EFDs). The rate and direction of microvessel growth were modified to depend simultaneously on the ECM collagen anisotropy (orientation and degree of anisotropy) and density. The sensitivity of growing neovessels to these stimuli was adjusted so that AngioFE could reproduce the growth and guidance observed in experiments where microvessels were cultured in collagen gels of varying anisotropy and density. We then compared outcomes from simulations using EFDs to simulations that used AngioFE’s prior vector field representation of collagen anisotropy. We found that EFD simulations were more accurate than vector field simulations in predicting experimentally observed microvessel guidance. Predictive simulations demonstrated the ability of anisotropy gradients to recruit microvessels across short and long distances relevant to wound healing. Further, simulations predicted that collagen alignment could enable microvessels to overcome dense tissue interfaces such as tumor-associated collagen structures (TACS) found in desmoplasia and tumor-stroma interfaces. This approach can be generalized to other mechanobiological relationships during cell guidance phenomena in computational settings.
Journal Article
Mechanics of lung cancer: A finite element model shows strain amplification during early tumorigenesis
Early lung cancer lesions develop within a unique microenvironment that undergoes constant cyclic stretch from respiration. While tumor stiffening is an established driver of tumor progression, the contribution of stress and strain to lung cancer is unknown. We developed tissue scale finite element models of lung tissue to test how early lesions alter respiration-induced strain. We found that an early tumor, represented as alveolar filling, amplified the strain experienced in the adjacent alveolar walls. Tumor stiffening further increased the amplitude of the strain in the adjacent alveolar walls and extended the strain amplification deeper into the normal lung. In contrast, the strain experienced in the tumor proper was less than the applied strain, although regions of amplification appeared at the tumor edge. Measurements of the alveolar wall thickness in clinical and mouse model samples of lung adenocarcinoma (LUAD) showed wall thickening adjacent to the tumors, consistent with cellular response to strain. Modeling alveolar wall thickening by encircling the tumor with thickened walls moved the strain amplification radially outward, to the next adjacent alveolus. Simulating iterative thickening in response to amplified strain produced tracks of thickened walls. We observed such tracks in early-stage clinical samples. The tracks were populated with invading tumor cells, suggesting that strain amplification in very early lung lesions could guide pro-invasive remodeling of the tumor microenvironment. The simulation results and tumor measurements suggest that cells at the edge of a lung tumor and in surrounding alveolar walls experience increased strain during respiration that could promote tumor progression.
Journal Article
Nocturia: aetiology and treatment in adults
Key Points
Nocturia remains underreported and undertreated, despite its prevalence and association with significant morbidity and mortality
Nocturia has multiple aetiologies, including overproduction of urine (global polyuria and nocturnal polyuria), reduced bladder storage capacity, sleep disorders and a combination of these conditions
The frequency volume chart, Nocturia Quality of Life questionnaire and the duration of the first uninterrupted sleep period should be used in the assessment and follow-up monitoring of each patient
Management strategies should be targeted to each patient's specific aetiology of nocturia; some patients might require multicomponent therapies
Nocturia is a very common condition with major sequelae for affected patients. It leads to impaired quality of life and is associated with numerous morbidities including diabetes, coronary artery disease, obstructive sleep apnoea, obesity, metabolic syndrome, and depression. In this Review, the authors discuss the clinical relevance of nocturia and the need for treatment. They describe the various aetiologies of the condition and discuss a contemporary approach to its treatment and management, including methods to tailor treatment strategies to individual patients.
Nocturia is an extremely common condition that has major sequelae for affected patients. Through disruption of sleep, nocturia impairs quality of life and worsens health outcomes, and is associated with a variety of morbidities including diabetes, coronary artery disease, obstructive sleep apnoea, obesity, metabolic syndrome, and depression. Unsurprisingly, several studies have also linked nocturia with reduced survival. Nocturia is not simply a consequence of lower urinary tract disease; rather, it is a multifactorial disorder that is often a manifestation of an underlying renal or systemic disease. Through the use of the frequency volume chart, clinicians can accurately quantify nocturia and determine its aetiology. Evaluation of quality of life and sleep using simple measures is essential in order to assess the impact of nocturia on a patient. Numerous treatment options for nocturia exist, but most are associated with minor benefit or lack sufficient evidence supporting their use. By systematically analysing an individual's causes of nocturia, clinicians can design appropriate treatment strategies to most effectively treat this condition.
Journal Article