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Vortex dynamics in trabeculated embryonic ventricles

Proper heart morphogenesis requires a delicate balance between hemodynamic forces, myocardial activity, morphogen gradients, and epigenetic signaling, all of which are coupled with genetic regulatory networks. Recently both in vivo and in silico studies have tried to better understand hemodynamics at varying stages of vertebrate cardiogenesis. In particular, the intracardial hemodynamics during the onset of trabeculation is notably complex - the inertial and viscous fluid forces are approximately equal at this stage and small perturbations in morphology, scale, and steadiness of the flow can lead to significant changes in bulk flow structures, shear stress distributions, and chemical morphogen gradients. The immersed boundary method was used to solve the computational fluid dynamics problem involving fluid flow moving through the trabeculated ventricles of 72, 80, and 120 hours post fertilization wild type zebrafish embryos and ErbB2-inhibited embryos at 7 days post fertilization. An idealized trabeculated ventricular model was explored to map the bifurcations in flow structure that occur as a result of the unsteadiness of flow, trabeculae height, and fluid scale ($Re$). Vortex formation occurred in intertrabecular regions for biologically relevant parameter spaces, wherein flow velocities increased. This indicates that trabecular morphology may alter intracardial flow patterns and hence ventricular shear stresses and morphogen gradients. A potential implication of this work is that the onset of vortical (disturbed) flows can upregulate Notch1 expression in endothelial cells in vitro and hence impacts chamber morphogensis, valvulogenesis, and the formation of the trabeculae themselves.

q-bio.TO↗

Dynamics of Plant Growth; A Theory Based on Riemannian Geometry

In this work, a new model for macroscopic plant tissue growth based on dynamical Riemannian geometry is presented. We treat 1D and 2D tissues as continuous, deformable, growing geometries for sizes larger than 1mm. The dynamics of the growing tissue are described by a set of coupled tensor equations in non-Euclidean (curved) space. These coupled equations represent a novel feedback mechanism between growth and curvature dynamics. For 1D growth, numerical simulations are compared to two measures of root growth. First, modular growth along the simulated root shows an elongation zone common to many species of plant roots. Second, the relative elemental growth rate (REGR) calculated in silico exhibits temporal dynamics recently characterized in high-resolution root growth studies but which thus far lack a biological hypothesis to explain them. Namely, the REGR can evolve from a single peak localized near the root tip to a double-peak structure. In our model, this is a direct consequence of considering growth as both a geometric reaction-diffusion process and expansion due to a distributed source of new materials. In 2D, we study a circularly symmetric growing disk with emergent negative curvatures. These results are compared against thin disk experiments, which are a proxy model for plant leaves. These results also apply to the curvature evolution and the inhomogeneous growth pattern of the Acetabularia cap. Lastly, we extend the model to anisotropic disks and predict the growth dynamics for a 2D curved surface which develops an elongated shape with localized ruffling. Our model also provides several measures of the dynamics of tissue growth. These include the time evolution of the metric and velocity field, which are dynamical variables in the model, as well as expansion, shear and rotation which are deformation tensors characterizing the growth of the tissue.

q-bio.TO↗

Cancer and electromagnetic radiation therapy: Quo Vadis?

In oncology, treating cancer with a beam of photons is a well established therapeutic technique, developed over 100 years, and today over 50% of cancer patients will undergo traditional X-ray radiotherapy. However, ionizing radiation therapy is not the only option, as the high-energy photons delivering their cell-killing radiation energy into cancerous tumor can lead to significant damage to healthy tissues surrounding the tumor, located throughout the beam's path. Therefore, in nowadays, advances in ionizing radiation therapy are competitive to non-ionizing ones, as for example the laser light based therapy, resulting in a synergism that has revolutionized medicine. The use of non-invasive or minimally invasive (e.g. through flexible endoscopes) therapeutic procedures in the management of patients represents a very interesting treatment option. Moreover, as the major breakthrough in cancer management is the individualized patient treatment, new biophotonic techniques, e.g. photo-activated drug carriers, help the improvement of treatment efficacy and/or normal tissue toxicity. Additionally, recent studies support that laser technology progresses could revolutionize cancer proton therapy, by reducing the cost of the needed installations. The aim of this review is to present some laser-based future objectives for cancer radiation therapy, aiming to address the relevant advances in the ionizing and non-ionizing radiation therapy, i.e. protons and heavy ions therapy, as well as photodynamic targeted and molecular therapies.

physics.med-ph↗

Are leaves optimally designed for self-support? An investigation on giant monocots

Leaves are the organs that intercept light and create photosynthesis. Efficient light interception is provided by leaves oriented orthogonal to most of the sun rays. Except in the polar regions, this means orthogonal to the direction of acceleration due to gravity, or simply horizontal. The leaves of almost all terrestrial plants grow in a gravity field that tends to bend them downward and therefore may counteract light interception. Plants thus allocate biomass for self-support in order to maintain their leaves horizontal. To compete with other species (inter-species competition), as well as other individuals within the same species (intra-species competition), self-support must be achieved with the least biomass produced. This study examines to what extent leaves are designed to self-support. We show here that a basic mechanical model provides the optimal dimensions of a leaf for light interception and self-support. These results are compared to measurements made on leaves of various giant monocot species,especially palm trees and banana trees. The comparison between experiments and model predictions shows that the longer palms are optimally designed for self-support whereas shorter leaves are shaped predominantly by other parameters of selection.

cond-mat.soft↗

Special Operations Forces: A Global Immune System?

The use of special operations forces (SOF) in war fighting and peace keeping efforts has increased dramatically in recent decades. A scientific understanding of the reason for this increase would provide guidance as to the contexts in which SOF can be used to their best effect. Ashby's law of requisite variety provides a scientific framework for understanding and analyzing a system's ability to survive and prosper in the face of environmental challenges. We have developed a generalization of this law to extend the analysis to systems that must respond to disturbances at multiple scales. This analysis identifies a necessary tradeoff between scale and complexity in a multiscale control system. As with Ashby's law, the framework applies to the characterization of successful biological and social systems in the context of complex environmental challenges. Here we apply this multiscale framework to provide a control theoretic understanding of the historical and increasing need for SOF, as well as conventional military forces. We propose that the essential role distinction is in the separation between high complexity fine scale challenges as opposed to large scale challenges. This leads to a correspondence between the role SOF can best serve and that of the immune system in complex organisms--namely, the ability to respond to fine-grained, high-complexity disruptors and preserve tissue health. Much like a multicellular organism, human civilization is composed of a set of distinct and heterogeneous social tissues. Responding to disruption and restoring health in a system with highly diverse local social conditions is an essentially complex task. SOF have the potential to mitigate against harm without disrupting normal social tissue behavior. This analysis suggests how SOF might be leveraged to support global stability and mitigate against cascading crises.

physics.soc-ph↗

HIV, Cardiovascular Diseases, and Chronic Arsenic Exposure co-exist in a Positive Synergy

Recent epidemiological evidences indicate that arsenic exposure increases risk of atherosclerosis, cardiovascular diseases and microangiopathies in addition to the serious global health concern related to its carcinogenic effects. In experiments on animals, acute and chronic exposure to arsenic directly correlates cardiac tachyarrhythmia, and atherogenesis in a concentration and duration dependent manner. Moreover, the other effects of long-term arsenic exposure include induction of non-insulin dependent diabetes by mechanisms yet to be understood. On the other hand, there are controversial issues, gaps in knowledge, and future research priorities of accelerated incidences of CVD and mortalities in patients with HIV who are under long-term anti-retroviral therapy (ART). Although, both HIV infection itself and various components of ART initiate significant pathological alterations in the myocardium and the vasculature, simultaneous environmental exposure to arsenic which is more convincingly being recognized as a facilitator of HIV viral cycling in the infected immune cells, may contribute an additional layer of adversity in these patients. In this mini-review which have been fortified with our own preliminary data, we will discuss some of the key current understating of chronic arsenic exposure, and its possible impact on the accelerated HIV/ART induced CVD. The review will conclude with notes on recent developments in mathematical modeling in this field that probabilistically forecast incidence prevalence as functions of aging and life style parameters, most of which vary with time themselves; this interdisciplinary approach provides a complementary kernel to conventional biology.

q-bio.TO↗

Mathematical control theory, the immune system, and cancer

Simple ideas, endowed from the mathematical theory of control, are used in order to analyze in general grounds the human immune system. The general principles are minimization of the pathogen load and economy of resources. They should constrain the parameters describing the immune system. In the simplest linear model, for example, where the response is proportional to the load, the annihilation rate of pathogens in any tissue should be greater than the pathogen's average rate of growth. When nonlinearities are added, a reference value for the number of pathogens is set, and a stability condition emerges, which relates strength of regular threats, barrier height and annihilation rate. The stability condition allows a qualitative comparison between tissues. On the other hand, in cancer immunity, the linear model leads to an expression for the lifetime risk, which accounts for both the effects of carcinogens (endogenous or external) and the immune response.

q-bio.TO↗

A Cancer Biotherapy Resource

Cancer Biotherapy (CB), as opposed to cancer chemotherapy, is the use of macromolecular, biological agents instead of organic chemicals or drugs to treat cancer. Biological agents usually have higher selectivity and have less toxic side effects than chemical agents. The I.S.B.T.C., being the only major information database for CB, seems lacking in some crucial information on various cancer biotherapy regimens. It is thus necessary to have a comprehensive curated CB database. The database accessible to cancer patients and also should be a sounding board for scientific ideas by cancer researchers. The database/web server has information about main families of cancer biotherapy regimens to date, namely, Protein Kinase Inhibitors, Ras Pathway Inhibitors, Cell-Cycle Active Agents, MAbs (monoclonal antibodies), ADEPT (Antibody-Directed Enzyme Pro-Drug Therapy), Cytokines, Anti-Angiogenesis Agents, Cancer Vaccines, Cell-based Immunotherapeutics, Gene Therapy, Hematopoietic Growth Factors, Retinoids, and CAAT. For each biotherapy regimen, we will extract the following attributes in populating the database: Cancer type, Gene/s and gene product/s involved, Gene sequence, Organs affected, Reference papers, Clinical phase/stage, Survival rate, Clinical test center locations, Cost, Patient blogs, Researcher blogs, and Future work. The database will be accessible to public through a website and had FAQs for making it understandable to the laymen and discussion page for researchers to express their views and ideas. In addition to information about the biotherapy regimens, the website will link to other biologically significant databases like structural proteomics, metabolomics, glycomics, and lipidomics databases, as well as to news around the world regarding cancer therapy results. The database attributes would be regularly updated for novel attributes as discoveries are made.

q-bio.BM↗

Optimizing chemoradiotherapy to target multi-site metastatic disease and tumor growth

The majority of cancer-related fatalities are due to metastatic disease. In chemoradiotherapy, chemotherapeutic agents are administered along with radiation to increase damage to the primary tumor and control systemic disease such as metastasis. This work introduces a mathematical model to obtain optimal drug and radiation protocols in a chemoradiotherapy scheduling problem with the objective of minimizing metastatic cancer cell populations at multiple potential sites while maintaining a minimum level of damage to the primary tumor site. We derive closed-form expressions for an optimal chemotherapy fractionation regimen. A dynamic programming framework is used to determine the optimal radiotherapy fractionation regimen. Results show that chemotherapeutic agents do not change the optimal radiation fractionation regimens, and vice-versa. Interestingly, we observe that regardless of radio-sensitivity parameters, hypo-fractionated schedules are optimal solutions for the radiotherapy fractionation problem. Furthermore, it is optimal to immediately start radiotherapy. However, for chemotherapy, we find that the structure of the optimal schedule depends on model parameters such as chemotherapy-induced cell-kill at primary and metastatic sites, as well as the ability of primary tumor cells to initiate successful metastasis at different body sites. We quantify the trade-off between the new and traditional objectives of minimizing the metastatic population size and maximizing the tumor control probability, respectively, for a cervical cancer case. The trade-off information indicates the potential for significant reduction in the metastatic population with minimal loss in primary tumor control.

math.OC↗

Radon induced hyperplasia: effective adaptation reducing the local doses in the bronchial epithelium

There is experimental and histological evidence that chronic irritation and cell death may cause hyperplasia in the exposed tissue. As the heterogeneous deposition of inhaled radon progeny results in high local doses at the peak of the bronchial bifurcations, it was proposed earlier that hyperplasia occurs in these deposition hot spots upon chronic radon exposure. The objective of the present study is to quantify how the induction of basal cell hyperplasia modulates the microdosimetric consequences of a given radon exposure. For this purpose, numerical epithelium models were generated with spherical cell nuclei of six different cell types based on histological data. Basal cell hyperplasia was modelled by epithelium models with additional basal cells and increased epithelium thickness. Microdosimetry for alpha-particles was performed by an own-developed Monte-Carlo code. Results show that the average tissue dose, and the average hit number and dose of basal cells decrease by the increase of the measure of hyperplasia. Hit and dose distribution reveal that the induction of hyperplasia may result in a basal cell pool which is shielded from alpha radiation. It highlights that the exposure history affects the microdosimetric consequences of a present exposure, while the biological and health effects may also depend on previous exposures. The induction of hyperplasia can be considered as a radioadaptive response at the tissue level. Such an adaptation of the tissue challenges the validity of the application of the dose dose rate effectiveness factor from a mechanistic point of view. As the location of radiosensitive target cells may change due to previous exposures, dosimetry models considering the tissue geometry characteristic of normal conditions may be inappropriate for dose estimation in case of protracted exposures. As internal exposures are frequently chronic, such changes in tissue...

q-bio.TO↗

Adjoint Multi-Start Based Estimation of Cardiac Hyperelastic Material Parameters using Shear Data

Cardiac muscle tissue during relaxation is commonly modelled as a hyperelastic material with strongly nonlinear and anisotropic stress response. Adapting the behavior of such a model to experimental or patient data gives rise to a parameter estimation problem which involves a significant number of parameters. Gradient-based optimization algorithms provide a way to solve such nonlinear parameter estimation problems with relatively few iterations, but require the gradient of the objective functional with respect to the model parameters. This gradient has traditionally been obtained using finite differences, the calculation of which scales linearly with the number of model parameters, and introduces a differencing error. By using an automatically derived adjoint equation, we are able to calculate this gradient more efficiently, and with minimal implementation effort. We test this adjoint framework on a least squares fitting problem involving data from simple shear tests on cardiac tissue samples. A second challenge which arises in gradient-based optimization is the dependency of the algorithm on a suitable initial guess. We show how a multi-start procedure can alleviate this dependency. Finally, we provide estimates for the material parameters of the Holzapfel and Ogden strain energy law using finite element models together with experimental shear data.

q-bio.TO↗

Towards the Emulation of the Cardiac Conduction System for Pacemaker Testing

The heart is a vital organ that relies on the orchestrated propagation of electrical stimuli to coordinate each heart beat. Abnormalities in the heart's electrical behaviour can be managed with a cardiac pacemaker. Recently, the closed-loop testing of pacemakers with an emulation (real-time simulation) of the heart has been proposed. An emulated heart would provide realistic reactions to the pacemaker as if it were a real heart. This enables developers to interrogate their pacemaker design without having to engage in costly or lengthy clinical trials. Many high-fidelity heart models have been developed, but are too computationally intensive to be simulated in real-time. Heart models, designed specifically for the closed-loop testing of pacemakers, are too abstract to be useful in the testing of physical pacemakers. In the context of pacemaker testing, this paper presents a more computationally efficient heart model that generates realistic continuous-time electrical signals. The heart model is composed of cardiac cells that are connected by paths. Significant improvements were made to an existing cardiac cell model to stabilise its activation behaviour and to an existing path model to capture the behaviour of continuous electrical propagation. We provide simulation results that show our ability to faithfully model complex re-entrant circuits (that cause arrhythmia) that existing heart models can not.

eess.SY↗

Mathematical modeling of T-cells activation dynamics for CD3 molecules recycling process

The down regulation of CD3 protein present on the surface of a T-cell triggers the process of activation. A rapid decrease of CD3 from the surface is required to reach the threshold that is necessary for the continuation of the activation process. By flow cytometry technique, it is well established that an amount of down regulated CD3 proteins recycle and may come on the surface of T-cell. This article is dedicated to study the impact of recycled CD3 protein that is recruited into the immune synapse at different rates. The population density of T-cells is distributed over surface protein (CD3) concentration under the framework of population balance models by using coupled system of PDEs. Such problems need non-conventional population balance modeling so that classical numerical technique can be applied. A recently developed efficient numerical method is validated against the analytical and numerical solutions.

q-bio.TO↗

A multiscale mathematical model of tumour invasive growth

Known as one of the hallmarks of cancer [30], cancer cell invasion of human body tissue is a complicated spatio-temporal multiscale process which enables a localised solid tumour to transform into a systemic, metastatic and fatal disease. This process explores and takes advantage of the reciprocal relation that solid tumours establish with the extracellular matrix (ECM) components and other multiple distinct cell types from the surrounding microenvironment. Through the secretion of various proteolytic enzymes such as matrix metalloproteinases (MMP) or the urokinase plasminogen activator (uPA), the cancer cell population alters the configuration of the surrounding ECM composition and overcomes the physical barriers to ultimately achieve local cancer spread into the surrounding tissue. The active interplay between the tissue-scale tumour dynamics and the molecular mechanics of the involved proteolytic enzymes at the cell-scale underlines the biologically multiscale character of invasion, and raises the challenge of modelling this process with an appropriate multiscale approach. In this paper, we present a new two-scale moving boundary model of cancer invasion that explores the tissue scale tumour dynamics in conjunction with the molecular dynamics of the urokinase plasminogen activation system. Building on the multiscale moving boundary method proposed in [58], the modelling that we propose here allows us to study the changes in tissue scale tumour morphology caused by the cell-scale uPA micro-dynamics occurring along the invasive edge of the tumour. Our computational simulation results demonstrate a range of heterogeneous dynamics which are qualitatively similar to the invasive growth patterns observed in a number of different types of cancer, such as the tumour infiltrative growth patterns discussed in [33].

math.DS↗

Estimating the number of tissue resident macrophages

I provide a simple estimation for the number of macrophages in a tissue, arising from the hypothesis that they should keep infections below a certain threshold, above which neutrophils are recruited from blood circulation. The estimation reads Nm=a Ncel^α/Nmax, where a is a numerical coefficient, the exponent α is near 2/3, and Nmax is the maximal number of pathogens a macrophage may engulf in the time interval, tr, between pathogen replications.

q-bio.TO↗

Analysis of a Cahn--Hilliard system with non-zero Dirichlet conditions modeling tumor growth with chemotaxis

We consider a diffuse interface model for tumor growth consisting of a Cahn--Hilliard equation with source terms coupled to a reaction-diffusion equation, which models a tumor growing in the presence of a nutrient species and surrounded by healthy tissue. The well-posedness of the system equipped with Neumann boundary conditions was found to require regular potentials with quadratic growth. In this work, Dirichlet boundary conditions are considered, and we establish the well-posedness of the system for regular potentials with higher polynomial growth and also for singular potentials. New difficulties are encountered due to the higher polynomial growth, but for regular potentials, we retain the continuous dependence on initial and boundary data for the chemical potential and for the order parameter in strong norms as established in the previous work. Furthermore, we deduce the well-posedness of a variant of the model with quasi-static nutrient by rigorously passing to the limit where the ratio of the nutrient diffusion time-scale to the tumor doubling time-scale is small.

math.AP↗

A Possible Link Between Pyriproxyfen and Microcephaly

The Zika virus is the primary suspect in the large increase in microcephaly cases in 2015-6 in Brazil, however its role is unconfirmed despite individual cases of viral infections found in neural tissue. Here we consider the alternative that the insecticide pyriproxyfen, used in Brazilian drinking water for mosquito control, may actually be the cause. Pyriproxifen is an analog of juvenile hormone, which corresponds in mammals to regulatory molecules including retinoic acid, a vitamin A metabolite, with which it has cross-reactivity and whose application during development causes microcephaly. Methoprene, another juvenile hormone analog approved as an insecticide has metabolites that bind to the retinoid X receptor, and causes developmental disorders in mammals. Isotretinoin is another example of a retinoid causing microcephaly in human babies via activation of the retinoid X receptor. Moreover, tests of pyriproxyfen by the manufacturer, Sumitomo, widely quoted as giving no evidence for developmental toxicity, actually found some evidence for such an effect, including low brain mass and arhinencephaly--incomplete formation of the anterior cerebral hemispheres--in rat pups. Finally, the pyriproxyfen use in Brazil is unprecedented--it has never before been applied to a water supply on such a scale. Claims that it is not being used in Recife, the epicenter of microcephaly cases, do not distinguish the metropolitan area of Recife, where it is widely used, and the municipality, where it is not. Given this combination of information we strongly recommend that the use of pyriproxyfen in Brazil be suspended pending further investigation.

q-bio.QM↗

Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.

q-bio.TO↗