3D mesh processing using GAMer 2 to enable reaction-diffusion simulations in realistic cellular geometries

Recent advances in electron microscopy have enabled the imaging of single cells in 3D at nanometer length scale resolutions. An uncharted frontier for in silico biology is the ability to simulate cellular processes using these observed geometries. Enabling such simulations requires watertight meshing of electron micrograph images into 3D volume meshes, which can then form the basis of computer simulations of such processes using numerical techniques such as the Finite Element Method. In this paper, we describe the use of our recently rewritten mesh processing software, GAMer 2, to bridge the gap between poorly conditioned meshes generated from segmented micrographs and boundary marked tetrahedral meshes which are compatible with simulation. We demonstrate the application of a workflow using GAMer 2 to a series of electron micrographs of neuronal dendrite morphology explored at three different length scales and show that the resulting meshes are suitable for finite element simulations. This work is an important step towards making physical simulations of biological processes in realistic geometries routine. Innovations in algorithms to reconstruct and simulate cellular length scale phenomena based on emerging structural data will enable realistic physical models and advance discovery at the interface of geometry and cellular processes. We posit that a new frontier at the intersection of computational technologies and single cell biology is now open.Comment: 39 pages, 14 figures. High resolution figures and supplemental movies available upon reques

Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights

There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve functional tumour-associated blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation medi- ated by vascular targeting agents that induce occlusion/collapse of tumour blood vessels. In contrast, the therapeutic intention of normalising the abnormal structure and function of tumour vascular net- works, e.g. via alleviating stress-induced vaso-occlusion, is to improve chemo-, immuno- and radiation therapy efficacy. Although both strategies have shown therapeutic potential, it remains unclear why they often fail to control glioma invasion into the surrounding healthy brain tissue. To shed light on this issue, we propose a mathematical model of glioma invasion focusing on the interplay between the mi- gration/proliferation dichotomy (Go-or-Grow) of glioma cells and modulations of the functional tumour vasculature. Vaso-modulatory interventions are modelled by varying the degree of vaso-occlusion. We discovered the existence of a critical cell proliferation/diffusion ratio that separates glioma invasion re- sponses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the tumour front speed and increase the infiltration width, for those in the other regime the invasion speed increases and infiltration width decreases. We show how these in silico findings can be used to guide individualised approaches of vaso-modulatory treatment strategies and thereby improve success rates

Complexity in city systems: Understanding, evolution, and design

6.4 Exemplars of complex systems There are many signatures of complexity revealed in the space-time patterning of cities (Batty, 2005) and here we will indicate three rather different but nevertheless linked exemplars. Our first deals with ..

The role of dopaminergic and cholinergic modulation on the striatal network : a computational investigation

The famous words from the French philosopher René Descartes (1596-1650), “I think therefore I am”, proclaims that since we are thinking we must also exist. At the time when this was stated, very little was known about the main organ involved in thinking, the nervous system. Today we know that the nervous system consists of interconnected cells, so called neurons that communicate with each other through electro-chemical signals. This has been known for little over a century and during this time we have gathered an impressive amount of detailed data on neurons and the circuits they make up. Despite this, we still don’t have a detailed description of the overall computing mechanism of the central nervous system, the brain, or even single nuclei within the brain. One reason for this is the transient nature of the brain, continuously going in and out of operational modes, or so called brain states. The state of the brain is heavily influenced by neuromodulators – molecules changing the properties of neurons and the connections between them. One area strongly affected by neuromodulators is the striatum, the main input structure of the basal ganglia. The basal ganglia are an evolutionary conserved set of interconnected nuclei tightly connected to the cerebral cortex and thalamus, with which they form a loop. From pathological states like Parkinson’s disease we know that the basal ganglia are involved in motor control. More specifically they have been proposed to drive formation and control of automatic motor response sequences (including habits), but like in the rest of the brain, the modus operandi of the basal ganglia is not known. To bridge the gap between data and function we therefore need models and testable theories. In this thesis I have studied the role of neuromodulation in the striatal microcircuit, with the aim of understanding how subcellular changes affect cellular behavior. The technique used is biophysically detailed computational modelling. The essence of these models tries to mimic the electro-chemical signals within and between neurons using as detailed a description of individual neurons as possible. From this standpoint a good model minimizes the number of assumptions used in construction, by restricting the model to experimentally measured entities. Simulations of the striatal projection neurons in such models show that complex spikes – a particular type of neuronal signal associated with learning in other brain regions – may be triggered following manipulation of certain conductances in the cell membrane. In our simulations, the complex spikes were associated with large calcium signals in the dendrites, indicating a more robust form of crosstalk in the soma-to-dendrites direction than following regular action potentials. Together these simulations extend the theory of striatal function and learning

State of the Art of Laser Hardening and Cladding

In this paper an overview is given about laser surface modification processes, which are developed especially with the aim of hardness improvement for an enhanced fatigue and wear behaviour. The processes can be divided into such with and without filler material and in solid-state and melting processes. Actual work on shock hardening, transformation hardening, remelting, alloying and cladding is reviewed, where the main focus was on scientific work from the 21st century

Electrospray deposition: a breakthrough technique for proton exchange membrane fuel cell catalyst layer fabrication

This Spotlight article presents the state-of-the-art of electrospray deposition technique applied to the fabrication of proton exchange membrane fuel cell (PEMFC) components, mainly focusing on catalyst layers in gas diffusion electrodes. The atomization of a suspension of particles over a substrate under the influence of a strong electric field results in the growth of a film with macroporous morphology and many interesting properties. This so-called electrospray deposition has reported many noteworthy beneficial effects for the fabrication of the catalyst layers of gas diffusion electrodes of PEMFCs. The electrosprayed catalyst layers prepared from suspensions of catalyst particles and ionomers present a dendritic macroporous morphology with superhydrophobic character that improves the water management inside the cell and increases the performance by ∼20% with respect to standard electrodes prepared by airbrushing. Other interesting effects observed with electrosprayed catalyst layers are increased catalyst utilization and water absorption capabilities of the ionomer, improved performance under nonhumidified conditions, and a reduction in catalyst degradation. In addition, the electrospray deposition decreases platinum losses during fabrication thanks to the attractive electrostatic forces between the ion mist and the substrate compared with regular ink-based spray methodsThe work is partially financed by the ELHYPORT project (PID2019–110896RB-I00), Spanish Ministry of Science and InnovationS

Image morphology: from perception to rendering

Complete image ontology can be obtained by formalising a top-down meta-language wich must address all possibilities, from global message and composition to objects and local surface properties

Study of the role of skin lymphatics in electrolyte and blood pressure regulation

Cardiovascular diseases are the major cause of death worldwide and represent a dramatic socio-economic challenge. Hypertension accounts for 18% of cardiovascular disease deaths in the Western countries, and is a major risk factor for stroke, coronary heart disease and heart failure. Excessive dietary salt intake is known to be a risk factor for developing hypertension, but the pathophysiology of salt sensitive hypertension is poorly understood. The kidneys are the main regulators of Na+ and water in the body. Salt sensitive hypertension has traditionally been explained by an impaired capacity of the kidneys to excrete Na+, resulting in water retention and thereby a progressive alteration in the filling of the vasculature, resulting in increased blood pressure. Recent studies have suggested that Na+ can be retained or removed from the body without commensurate water, and that the skin may function as sodium reservoir. It has been shown that the Na+ accumulation is controlled by immune cells and involves modification of the extracellular matrix and lymphangiogenesis in the skin. In this thesis we therefore addressed three major questions to clarify aspects of the new hypothesis proposing the skin as a contributor to Na+ and blood pressure homeostasis; 1) What are the microcirculatory effects of increased lymphatic vasculature in the skin, 2) are new lymph vessels induced by Na+ retention functional, and 3) does lymphatic vasculature in the skin affect Na+ accumulation and blood pressure homeostasis. To study the microcirculatory effects of a chronically expanded lymphatic vasculature in the skin we used K14-VEGF-C mice overexpressing vascular endothelial growth factor-C (VEGF-C), resulting in an expanded lymphatic network in skin. Acute and chronic inflammation resulted in increased interstitial fluid pressure and reduced lymph flow, but to the same extent in transgenic mice and WT controls. However, after local overhydration in the skin we observed increased lymph flow and fluid transport in the transgenic mice. Despite increased production of the immune cell chemoattractant CCL21 in K14-VEGF-C mice, local inflammation did not result in an increased number of migrating immune cells from the skin to the draining lymph node. We concluded that lymphangiogenesis might enhance clearance of fluid in situations with increased fluid filtration. Sodium accumulation in the skin is suggested to be regulated by macrophages that secrete VEGF-C in response to a hyperosmotic microenvironment thereby stimulating lymphangiogenesis. An important question is whether these newly formed vessels are functional. After salt loading in rats we measured lymph flow in skin and muscle with optical imaging and a newly developed PET-CT method. Increased lymph flow was observed in skin as well as muscle. A reduction of lymph flow was observed after macrophage depletion in the skin. Our findings suggest that newly formed lymphatic vessels are functional, and that macrophages may be involved in the regulation of lymph flow and thereby clearance of Na+ from tissues. Previous studies have shown that mice lacking lymphatics in the skin develop higher blood pressure after salt loading. To address the question whether lymphatic vasculature in skin is important for Na+ accumulation and blood pressure homeostasis, we used genetically engineered mice with either increased or reduced lymphatic vasculature in the skin. Blood pressure was measured with telemetric recording before salt loading and at the termination of the experiment. Tissue samples from skin and muscle were harvested for analysis of Na+ and K+ concentration. We found no differences in Na+ accumulation or blood pressure response between genetically engineered mice and normal controls. Our results suggest that lymphatic vasculature in skin does not have an important role in electrolyte and blood pressure homeostasis in mice