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arXiv2017

Mechanics and Variability of Cell Sheet Folding in the Embryonic Inversion of $Volvox$

Many embryonic deformations during development are the global result of local cell shape changes and other local active cell sheet deformations. Morphogenesis does not only therefore rely on the ability of the tissue to produce these active deformations, but also on the ability to regulate them in such a way as to overcome the intrinsic variability of and geometric constraints on the tissue. Here, we explore the interplay of regulation and variability in the green alga $Volvox$, whose spherical embryos turn themselves inside out to enable motility. Through a combination of light sheet microscopy and theoretical analysis, we quantify the variability of this inversion and analyse its mechanics in detail to show how shape variability arises from a combination of geometry, mechanics, and active regulation.

cond-mat.soft↗
arXiv2017

Quantifying and Visualizing Hidden Preferential Aggregations Amid Heterogeneity

Biological systems often exhibit a heterogeneous arrangement of objects, such as assorted nuclear chromatin patterns in a tumor, assorted species of bacteria in biofilms, or assorted aggregates of subcellular particles. Principle Component Analysis (PCA) and Multiple Component Analysis (MCA) provide information about which features in multidimensional data aggregate, but do not provide in situ spatial information about these aggregations. This paper outlines the Numericized Histogram Score (NHS) algorithm, which converts the histogram distribution of shortest distances between objects into a continuous variable that can be represented as a spatial heatmap. A histogram can be transformed into an intensity value by assigning a weighting factor to each sequential bin. Each object in an image can be replaced by its NHS value, which when calibrated to a color scale results in a heatmap. These spatial heatmaps reveal regions of aggregation amid heterogeneity that would otherwise mask loco-regional spatial associations, which will be especially useful in the field of digital pathology. In addition to visualizing aggregations as heatmaps, the ability to calculate degrees of recurring patterns of aggregation allows investigators to stratify samples for further insights into clinical outcome, response to treatment, or omic subtypes (genomic, transcriptomic, proteomic, metabolomic, etc.).

q-bio.QM↗
arXiv2017

Spontaneous Chiral Symmetry Breaking in Planar Polarized Epithelia

Most animal body plans have some degree of left-right asymmetry. This chirality at the tissue and organ level is often assumed to originate from the intrinsic handedness of biological molecules. How this handedness might be transferred from molecules to tissues during development, however, is not well understood. Here we explore an alternative paradigm where tissue chirality results from spontaneous symmetry breaking at the cellular scale, with molecular chirality acting only as a weak bias that ensures that one handedness predominates over the other. Specifically, we show that systems capable of generating planar polarity, found in many epithelial tissues, can also generically break left-right symmetry, and we identify the key interaction parameters that must be varied to access the chiral phase. In addition to a chiral polar phase corresponding to one found in liquid crystal films, a two-dimensional chiral nematic phase with no liquid crystal analog is also possible. Our results have clear implications for the interpretation of mutant phenotypes, especially in certain Drosophila epithelia.

q-bio.TO↗
arXiv2017

Targeted and Imaging-guided In Vivo Photodynamic Therapy of Tumors Using Dual-functional, Aggregation-induced Emission Nanoparticles

Dual-functional nanoparticles, with the property of aggregation-induced emission and the capability of reactive oxygen species, were used to achieve passive/active targeting of tumor. Good contrast in in vivo imaging and obvious therapeutic efficiency were realized with a low dose of AIE nanoparticles as well as a low power density of light, resulting in negligible side effects.

q-bio.TO↗
arXiv2019

Estimating Cost Savings from Early Cancer Diagnosis

We estimate treatment cost-savings from early cancer diagnosis. For breast, lung, prostate and colorectal cancers and melanoma, which account for more than 50% of new incidences projected in 2017, we combine published cancer treatment cost estimates by stage with incidence rates by stage at diagnosis. We extrapolate to other cancer sites by using estimated national expenditures and incidence rates. A rough estimate for the U.S. national annual treatment cost-savings from early cancer diagnosis is in 11 digits. Using this estimate and cost-neutrality, we also estimate a rough upper bound on the cost of a routine early cancer screening test.

q-bio.TO↗
arXiv2017

Multi-radial LBP Features as a Tool for Rapid Glomerular Detection and Assessment in Whole Slide Histopathology Images

We demonstrate a simple and effective automated method for the segmentation of glomeruli from large (~1 gigapixel) histopathological whole-slide images (WSIs) of thin renal tissue sections and biopsies, using an adaptation of the well-known local binary patterns (LBP) image feature vector to train a support vector machine (SVM) model. Our method offers high precision (>90%) and reasonable recall (>70%) for glomeruli from WSIs, is readily adaptable to glomeruli from multiple species, including mouse, rat, and human, and is robust to diverse slide staining methods. Using 5 Intel(R) Core(TM) i7-4790 CPUs with 40 GB RAM, our method typically requires ~15 sec for training and ~2 min to extract glomeruli reproducibly from a WSI. Deploying a deep convolutional neural network trained for glomerular recognition in tandem with the SVM suffices to reduce false positives to below 3%. We also apply our LBP-based descriptor to successfully detect pathologic changes in a mouse model of diabetic nephropathy. We envision potential clinical and laboratory applications for this approach in the study and diagnosis of glomerular disease, and as a means of greatly accelerating the construction of feature sets to fuel deep learning studies into tissue structure and pathology.

q-bio.TO↗
arXiv2018

Microstructurally-based constitutive modelling of the skin - Linking intrinsic ageing to microstructural parameters

A multiphasic constitutive model of the skin that implicitly accounts for the process of intrinsic (i.e.\ chronological) ageing via variation of the constitutive parameters is proposed. The structurally-motivated constitutive formulation features distinct mechanical contributions from collagen and elastin fibres. The central hypothesis underpinning this study is that the effects of ageing on the mechanical properties of the tissue are directly linked to alterations in the microstructural characteristics of the collagen and elastin networks. Constitutive parameters in the model, corresponding to different ages, are identified from published experimental data on bulge tests of human skin. The identification procedure is based on an inverse finite element method. The numerical results demonstrate that degradation of the elastin meshwork and variations in anisotropy of the collagen network are plausible mechanisms to explain ageing in terms of macroscopic tissue stiffening. Whereas alterations in elastin affect the low-modulus region of the skin stress-strain curve, those related to collagen have an impact on the linear region.

physics.bio-ph↗
arXiv2017

Study of fluid flow within the hearing organ

Georg Von Bekesy was awarded a nobel price in 1961 for his pioneering work on the cochlea function in the mammalian hearing organ. He postulated that the placement of sensory cells in the cochlea corresponds to a specific frequency of sound. This theory, known as tonotopy, is the ground of our understanding on this complex organ. With the advance of technologies, this knowledge broaden continuously and seems to confirm Bekesy initial observations. However, a mystery still lies in the center of this organ: how does its microscopic tissues exactly act together to decode the sounds that we perceive? One of these tissues, the Reissner membrane, forms a double cell layer elastic barrier separating two fundamental ducts of this organ. Yet, until recently, this membrane, was not considered in the modelling of the inner ear due to its smallness. Nowadays, objects of this size are at the reach of the medical imagining and measuring expertise. Newly available observations coupled with the increasing availability of computational resources should enable modellers to consider the impact of these microscopic tissues in the inner ear mechanism. In this report, we explore the potential fluid-structure interactions happening in the inner ear, more particularly on the Reissner membrane. This study aims at answering two separate questions. Can nowadays computational fluid dynamics solvers simulate interaction with inner ear microscopic tissues? Has the Reissner membrane function on the auditory system been overlooked?

physics.bio-ph↗
arXiv2017

Newborn skin reflection: Proof of concept for a new approach for predicting gestational age at birth. A cross-sectional study

Current methods to assess the gestational age during prenatal care or at birth are a global challenge. Disadvantages, such as low accessibility, high costs, and imprecision of clinical tests and ultrasonography measurements, may compromise health decisions at birth, based on the gestational age. Newborns organs and tissues can indirectly indicate their physical maturity, and we hypothesized that evolutionary changes in their skin, detected using an optoelectronic device meter, may aid in estimating the gestational age. This study analyzed the feasibility of using newborn skin reflectance to estimate the gestational age at birth noninvasively. A cross-sectional study evaluated the skin reflectance of selected infants, preferably premature, at birth. The first-trimester ultrasound was the reference for gestational age. A prototype of a new noninvasive optoelectronic device measured the backscattering of light from the skin, using a light emitting diode at wavelengths of 470 nm, 575 nm, and 630 nm. Univariate and multivariate regression analysis models were employed to predict gestational age, combining skin reflectance with clinical variables for gestational age estimation. The gestational age at birth of 115 newborns from 24.1 to 41.8 weeks of gestation correlated with the light at 630 nm wavelength reflectance 3.3 mm/6.5 mm ratio distant of the sensor, at the forearm and sole . The best-combined variables to predict the gold standard gestational age at birth was the skin reflectance at wavelengths of 630 nm and 470 nm in combination with birth weight, phototherapy, and adjusted to include incubator stay, and sex. The main limitation of the study is that it was very specific to the premature population we studied and needs to be studied in a broader spectrum of newborns.

q-bio.TO↗
arXiv2017

Detection of Cancer Stages via Fractal Dimension Analysis of Optical Transmission Imaging of Tissue Micro Arrays (TMA)

Cancer is an epidemic worldwide. At present one in four persons has cancer and this statistic will change to one in a two person in the near future. It is now known that war against cancer is the early, curable detection and treatment. Affordable, quick and easy detection methods are, therefore, essential. Standard pathologist way of detecting cancer is looking at the stained biopsy tissue samples under microscope, brings lots of human error. A tissue is a spatial heterogeneous medium and it has fractal properties due to its self-similarity in mass distribution. It is now known that with the progress of cancer the tissue heterogeneity changes due to more mass accumulations and rearrangement of intracellular macromolecules such as DNA and lipids etc. Furthermore, there are tissue micro array (TMA) samples available that provides array of hundred samples in one glass slides. In this study, using reflectance microscopy we have analyzed the fractal dimension of 5μm colon TMA samples to correctly distinguish between normal, adjacent to cancer, benign, stage-1 and stage-2 colon cancers. This fractal property of the tissues is also supported by entropy and spatial correlation calculations. The application of this method for diagnostic applications is also discussed.

q-bio.TO↗
arXiv2017

Simulating Organogenesis in COMSOL: Tissue Mechanics

During growth, tissue expands and deforms. Given its elastic properties, stresses emerge in an expanding and deforming tissue. Cell rearrangements can dissipate these stresses and numerous experiments confirm the viscoelastic properties of tissues [1]-[4]. On long time scales, as characteristic for many developmental processes, tissue is therefore typically represented as a liquid, viscous material and is then described by the Stokes equation [5]-[7]. On short time scales, however, tissues have mainly elastic properties. In discrete cell-based tissue models, the elastic tissue properties are realized by springs between cell vertices [8], [9]. In this article, we adopt a macroscale perspective of tissue and consider it as homogeneous material. Therefore, we may use the "Structural Mechanics" module in COMSOL Multiphysics in order to model the viscoelastic behavior of tissue. Concretely, we consider two examples: first, we aim at numerically reproducing published [10] analytical results for the sea urchin blastula. Afterwards, we numerically solve a continuum mechanics model for the compression and relaxation experiments presented in [4].

q-bio.TO↗
arXiv2017

A Circulating Biomarker-based Framework for Diagnosis of Hepatocellular Carcinoma in a Clinically Relevant Model of Non-alcoholic Steatohepatitis; An OAD to NASH

Although cirrhosis is a key risk factor for the development of hepatocellular carcinoma (HCC), mounting evidence indicates that in a subset of patients presenting with non-alcoholic steatohepatitis (NASH), HCC manifests in the absence of cirrhosis. Given the sheer size of the non-alcoholic fatty liver disease (NAFLD) epidemic, and the dismal prognosis associated with late-stage primary liver cancer, there is an urgent need for HCC surveillance in the NASH patient. In the present study, adult male mice randomized to control diet or a fast food diet (FFD) were followed for up to 14 mo and serum level of a panel of HCC-relevant biomarkers was compared with liver biopsies at 3 and 14 mo. Both NAFLD Activity Score (NAS) and hepatic hydroxyproline content were elevated at 3 and 14 mo on FFD. Picrosirius red staining of liver sections revealed a filigree pattern of fibrillar collagen deposition with no cirrhosis at 14 mo on FFD. Nevertheless, 46% of animals bore one or more tumors on their livers confirmed as HCC in hematoxylin-eosin-stained liver sections. Receiver operating characteristic (ROC) curves analysis for serum levels of the HCC biomarkers osteopontin (OPN), alpha-fetoprotein (AFP) and Dickkopf-1 (DKK1) returned concordance-statistic/area under ROC curve of > 0.89. These data suggest that serum levels of OPN (threshold, 218 ng/mL; sensitivity, 82%; specificity, 86%), AFP (136 ng/mL; 91%; 97%) and DKK1 (2.4 ng/mL; 82%; 81%) are diagnostic for HCC in a clinically relevant model of NASH

q-bio.TO↗
arXiv2017

A new role for exhaled nitric oxide as a functional marker of peripheral airway caliber changes: a theoretical study

Though considered as an inflammation marker, exhaled nitric oxide (FENO) was shown to be sensitive to airway caliber changes to such an extent that it might be considered as a marker of them. It is thus important to understand how these changes and their localization mechanically affect the total NO flux penetrating the airway lumen (JawNO), hence FENO, independently from any inflammatory status change. A new model was used which simulates NO production, consumption and diffusion inside the airway epithelium wall, then, NO excretion through the epithelial wall into the airway lumen and, finally, its axial transport by diffusion and convection in the airway lumen. This model may also consider the presence of a mucus layer coating the epithelial wall. Simulations were performed that showed the great sensitivity of JawNO to peripheral airways caliber changes. Moreover, FENO showed distinct behaviors depending on the location of the caliber change. Considering a bronchodilation, absence of FENO change was associated with dilation of central airways, FENO increase with dilation up to pre-acinar small airways, and FENO decrease with intra-acinar dilation due to amplification of the back-diffusion flux. The presence of a mucus layer was also shown to play a significant role in FENO changes. Altogether, the present work provides theoretical evidences that specific FENO changes in acute situations are linked to specifically located airway caliber changes in the lung periphery. This opens the way for a new role for FENO as a functional marker of peripheral airway caliber change.

q-bio.TO↗
arXiv2017

Transscleral Micropulse Diode Laser for Treatment of Diabetic Retinopathy

In this study, we introduced a new simple effective technique for the treatment of diabetic retinopathy by the treatment of the periphery of the retina by transscleral micropulse diode laser (Taha Technique). Macular edema was improved and vitreous hemorrhage was disappeared in most of the cases.

q-bio.TO↗
arXiv2017

Extending the mathematical palette for developmental pattern formation: Piebaldism

Piebaldism usually manifests as white areas of fur, hair or skin due to the absence of pigment-producing cells in those regions. The distribution of the white and colored zones does not follow the classical Turing patterns. Here we present a modeling framework for pattern formation that enables to easily modify the relationship between three factors with different feedback mechanisms. These factors consist of two diffusing factors and a cell-autonomous immobile transcription factor. Globally the model allowed to distinguishing four different situations. Two situations result in the production of classical Turing patterns; regularly spaced spots and labyrinth patterns. Moreover, an initial slope in the activation of the transcription factor produces straight lines. The third situation does not lead to patterns, but results in different homogeneous color tones. Finally, the fourth one sheds new light on the possible mechanisms leading to the formation of piebald patterns exemplified by the random patterns on the fur of some cow strains and Dalmatian dogs. We demonstrate that these piebald patterns are of transient nature, develop from random initial conditions and rely on a system's bi-stability. The main novelty lies in our finding that the presence of a cell-autonomous factor not only expands the range of reaction diffusion parameters in which a pattern may arise, but also extends the pattern-forming abilities of the reaction-diffusion equations.

q-bio.TO↗
arXiv2017

A novel study of temperature effects on the viscoelastic behavior of articular cartilage

This paper presents a new approach to study the effects of temperature on the poro- elastic and viscoelastic behavior of articular cartilage. Biphasic solid-fluid mixture theory is applied to study the poro-mechancial behavior of articular cartilage in a fully saturated state. The balance of linear momentum, mass, and energy are considered to describe deformation of the solid skeleton, pore fluid pressure, and temperature distribution in the mixture. The mechanical model assumes both linear elastic and viscoelastic isotropic materials, infinitesimal strain theory, and a time-dependent response. The influence of temperature on the mixture behavior is modeled through temperature dependent mass density and volumetric thermal strain. The fluid flow through the porous medium is described by the Darcy's law. The stress-strain relation for time-dependent viscoelastic deformation in the solid skeleton is described using the generalized Maxwell model. A verification example is presented to illustrate accuracy and efficiency of the developed finite element model. The influence of temperature is studied through examining the behavior of articular cartilage for confined and unconfined boundary conditions. Furthermore, articular cartilage under partial loading condition is modeled to investigate the deformation, pore fluid pressure, and temperature dissipation processes. The results suggest significant impacts of temperature on both poro- elastic and viscoelastic behavior of articular cartilage.

physics.bio-ph↗
arXiv2017

Detecting Partial Rosettes in Tumor Histopathology Using The Cross Product

Tumors of the eye and nervous system often exhibit an arch-like arrangement of nuclei, called rosettes. Pathologists are able to identify rosettes [full circles] and the presence of partial rosettes [semi-circles] and interpret this as a sign of differentiation in a tumor. However, there is no objective method to quantitate the many partial rosettes that are obvious or not obvious to the naked eye. This paper proposes a mathematical algorithm to computationally detect the presence of obvious or non-obvious partial rosettes, henceforth referred to as Nguyen-Wu Partial Rosettes. Quantifying the degree of partial rosettes present in a tumor may allow pathologists to stratify tumors into more refined groups that may respond better to therapy or have different clinical outcomes. The Midline Cross Product [MCP] algorithm calculates the magnitude of two cross products and adds them together to obtain one value. Each of the two cross products results from [1] the line that connects the midpoints of longest lengths of two neighboring ovals, and [2] the line that extends from the midpoint from one longest length and is perpendicular to that longest length. The MCP algorithm makes nuclei that are arranged in consecutive rows and arches quantitatively distinct from nuclei that are arranged next to each other in a disorderly manner.

q-bio.TO↗