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arXiv2018

Susceptibility of Methicillin Resistant Staphylococcus aureus to Vancomycin using Liposomal Drug Delivery System

Staphylococcus aureus responsible for nosocomial infections is a significant threat to the public health. The increasing resistance of S.aureus to various antibiotics has drawn it to a prime focus for research on designing an appropriate drug delivery system. Emergence of Methicillin Resistant Staphylococcus aureus (MRSA) in 1961, necessitated the use of vancomycin "the drug of last resort" to treat these infections. Unfortunately, S.aureus has already started gaining resistances to vancomycin. Liposome encapsulation of drugs have been earlier shown to provide an efficient method of microbial inhibition in many cases. We have studied the effect of liposome encapsulated vancomycin on MRSA and evaluated the antibacterial activity of the liposome-entrapped drug in comparison to that of the free drug based on the minimum inhibitory concentration (MIC) of the drug. The MIC for liposomal vancomycin was found to be about half of that of free vancomycin. The growth response of MRSA showed that the liposomal vancomycin induced the culture to go into bacteriostatic state and phagocytic killing was enhanced. Administration of the antibiotic encapsulated in liposome thus was shown to greatly improve the drug delivery as well as the drug resistance caused by MRSA.

q-bio.TO↗

arXiv2018

On the dynamics of a cancer tumor growth model with multiphase structure

In this paper, we study a phase-space analysis of a mathematical model of tumor growth with an immune response. Mathematical analysis of the model equations with multipoint initial condition, regarding to dissipativity, boundedness of solutions, invariance of non-negativity, nature of equilibria, local and global stability will be investigated. We study some features of behavior of one three-dimensional tumor growth model with dynamics described in terms of densities of three cells populations: tumor cells, healthy host cells and effector immune cells. We find the upper and lower bounds for the effector immune cells population. Further, we derive sufficient conditions under which trajectories from the positive domain of feasible multipoint initial conditions tend to one of equilibrium points. Here cases of the small tumor mass equilibrium point; the healthy equilibrium point; the "death" equilibrium point are examined. Biological implications of our results are considered

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arXiv2018

Translating the Architectural Complexity of the Colon or Polyp into a Sinusoid Wave for Classification via the Fast Fourier Transform

There is no method to quantify the spatial complexity within colon polyps. This paper describes a spatial transformation that translates the tissue architecture within a polyp, or a normal colon lining, into a complex sinusoid wave composed of discrete points. This sinusoid wave can then undergo the Fast Fourier Transform to obtain a spectrum of frequencies that represents the sinusoid wave. This spectrum can then serve as a signature of the spatial complexity [an index] within the polyp. By overlaying vertical lines that radiate from the bottom middle [like a fold-out fan] of an image of a polyp stained by hematoxylin and eosin, the image is segmented into sectors. Each vertical line also forms an angle with the horizontal axis of the image, ranging from 0 degrees to 180 degrees rising counter clockwise. Each vertical line will intersect with various features of the polyp [border of lumens, border of epithelial lining]. Each of these intersections is a point that can be characterized by its distance from the origin [this distance is also a magnitude of that point]. Thus, each intersection between radial line and polyp feature can be mapped by polar coordinates [radius length, angle measure]. By summing the distance of all points along the same radial line, each radial line that divides the image becomes one value. Plotting these values [y variable] against the angle of each radial line from the horizontal axis [x variable] results in a sinusoid wave consisting of discrete points. This method is referred to as the Linearized Compressed Polar Coordinates [LCPC] Transform. The LCPC transform, in conjunction with the Fast Fourier Transform, can reduce the complexity of visually hidden histological grades in colon polyps into categories of similar wave frequencies [each histological grade has a signature consisting of a handful of frequencies].

q-bio.QM↗

arXiv2018

A Mathematical Model for Tumor Cell Population Dynamics Based on Target Theory and Tumor Lifespan

Radiation Therapy (XRT) is one of the most common cancer treatment methods. In this paper, a new mathematical model is proposed for the population dynamics of heterogeneous tumor cells following external beam radiation treatment. According to the Target Theory, the tumor population is divided into m different subpopulations based on the diverse effects of ionizing radiation on human cells. A hybrid model con- sists of a system of differential equations with random variable coefficients representing the transition rates between subpopulations is proposed. This model is utilized to sim- ulate the dynamics of cell subpopulations within a tumor. The model also describes the cell damage heterogeneity and the repair mechanism between two consecutive dose fractions. As such, a new definition of tumor lifespan based on population size is intro- duced. Finally, the stability of the system is studied by using the Gershgorin theorem. It is proven that the probability of target inactivity post radiation plays the most important role in the stability of the system.

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arXiv2018

High-throughput, high-resolution registration-free generated adversarial network microscopy

We combine generative adversarial network (GAN) with light microscopy to achieve deep learning super-resolution under a large field of view (FOV). By appropriately adopting prior microscopy data in an adversarial training, the neural network can recover a high-resolution, accurate image of new specimen from its single low-resolution measurement. Its capacity has been broadly demonstrated via imaging various types of samples, such as USAF resolution target, human pathological slides, fluorescence-labelled fibroblast cells, and deep tissues in transgenic mouse brain, by both wide-field and light-sheet microscopes. The gigapixel, multi-color reconstruction of these samples verifies a successful GAN-based single image super-resolution procedure. We also propose an image degrading model to generate low resolution images for training, making our approach free from the complex image registration during training dataset preparation. After a welltrained network being created, this deep learning-based imaging approach is capable of recovering a large FOV (~95 mm2), high-resolution (~1.7 μm) image at high speed (within 1 second), while not necessarily introducing any changes to the setup of existing microscopes.

eess.IV↗

arXiv2018

Novel digital tissue phenotypic signatures of distant metastasis in colorectal cancer

Distant metastasis is the major cause of death in colorectal cancer (CRC). Patients at high risk of developing distant metastasis could benefit from appropriate adjuvant and follow-up treatments if stratified accurately at an early stage of the disease. Studies have increasingly recognized the role of diverse cellular components within the tumor microenvironment in the development and progression of CRC tumors. In this paper, we show that a new method of automated analysis of digitized images from colorectal cancer tissue slides can provide important estimates of distant metastasis-free survival (DMFS, the time before metastasis is first observed) on the basis of details of the microenvironment. Specifically, we determine what cell types are found in the vicinity of other cell types, and in what numbers, rather than concentrating exclusively on the cancerous cells. We then extract novel tissue phenotypic signatures using statistical measurements about tissue composition. Such signatures can underpin clinical decisions about the advisability of various types of adjuvant therapy.

cs.CV↗

arXiv2018

Thermodynamic Mechanism of Life and Aging

Life is a complex biological phenomenon represented by numerous chemical, physical and biological processes performed by a biothermodynamic system/cell/organism. Both living organisms and inanimate objects are subject to aging, a biological and physicochemical process characterized by changes in biological and thermodynamic state. Thus, the same physical laws govern processes in both animate and inanimate matter. All life processes lead to change of an organism's state. The change of biological and thermodynamic state of an organism in time underlies all of three kinds of aging (chronological, biological and thermodynamic). Life and aging of an organism both start at the moment of fertilization and continue through entire lifespan. Fertilization represents formation of a new organism. The new organism represents a new thermodynamic system. From the very beginning, it changes its state by changing thermodynamic parameters. The change of thermodynamic parameters is observed as aging and can be related to change in entropy. Entropy is thus the parameter that is related to all others and describes aging in the best manner. In the beginning, entropy change appears as a consequence of accumulation of matter (growth). Later, decomposition and configurational changes dominate, as a consequence of various chemical reactions (free radical, decomposition, fragmentation, accumulation of lipofuscin-like substances...).

q-bio.OT↗

arXiv2018

Similarities vs. key discrepancy between tuberculosis and cancer

In 2015 in the United States 612,000 persons died from cancer whereas only 470 died from tuberculosis (TB), a disease which was the main cause of death around 1900. How can one explain such a key discrepancy in treatment progress? A statistical comparison between TB and cancer will give some clues. However, TB and cancer also share several important features. Both TB and cancer can affect several organs, e.g. lungs, brain, bones, intestines, skin. What in cancer is called malignant neoplasm (tumor) is called granuloma in TB. By isolating malignant cells (versus bacteria) from the rest of the body, such clusters protect the host's organism but at the same time they are "secure beachheads" from where malignant cells (versus infected macrophages) can wander off to new locations. Thus, metastatic tumors have a TB parallel in the form of secondary granulomas. In order to investigate more closely this parallel we use the age-specific response of organs. Called spectrometric analysis in a previous paper (Berrut et al. 2017), this method provides information about how fast tumors develop and how serious they become. A convenient characterization of the response to TB of organ j is given by the following (age-dependent) death ratio: Tj(t)=(death by TB of type j)/(all TB deaths) The development of cancer tumors can be described by a similar function Cj(t). We compare the organs' responses in all cases for which specific death data are available. It appears that for the same organ Tj(t) is similar in shape to Cj(t). For instance, with regard to brain tumors, both TB and cancer mortality peak around the age of 10. Such observations may bring to light vulnerabilities in the way the immune system provides protection to various organs.

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arXiv2018

Histological insight into the hepatic tissue of the Nile monitor (Varanus niloticus)

The liver of reptiles is considered an important study model for the interaction between environment and hepatic tissue. Little is known about the histology of the liver of reptiles. The aim of the current study was to elucidate the histological architecture of the liver of the Nile monitor (Varanus niloticus). Liver fragments from the Nile monitor were collected in the summer season and processed for the light and electron microscopy. The liver of the Nile monitor was bi-lobed and the right lobe was found to be larger than the left lobe. Histological examination revealed indistinct lobulation of the liver, and the central vein, sinusoids and portal area were haphazardly organized. The hepatic parenchyma consisted of hepatocytes arranged in glandular-like alveoli or tubules separated by a network of twisted capillary sinusoids. The hepatocytes were polyhedral in shape with vacuolated cytoplasm and the nucleus was single rounded, eccentric, large and vesicular with a distinct nucleolus. The hepatocytes contained numerous lipid droplets, abundant glycogen granules and well-developed RER and mitochondria. The hepatocytes appeared to secrete into the bile canaliculi through the disintegration of their dark cytoplasm into the bile canaliculi. The space of Disse separating between the hepatocytes and sinusoids contained many recesses. The portal area contained branches of the portal vein, hepatic artery, bile duct and lymphatic vessels embedded in a connective tissue. Some non-parenchymal cells were described such as Kupffer cells, heterophils, melano-macrophages, intercalated cells, myofibroblasts in addition to the endothelium of the sinusoids. This is the first report about the histological structure of the liver of the Egyptian Nile monitor. The result presented here should be considered a baseline knowledge to compare with the pathological affections of the liver in this species.

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arXiv2018

Adipochondrocytes in rabbit auricular cartilage

Chondrocytes are described as one cell population in different cartilage types. The auricular cartilage in mouse and rat contains unique chondrocytes similar in morphology to white adipocytes and known as lipochondrocytes. Lipochondrocytes were not mentioned in other species. The current study aimed to explore the existence of this cell type in rabbits. The auricles of adult male white rabbits were harvested and processed for histological examination with light and electron microscopy. With the light microscopy, the auricular cartilage of adult rabbits contained central large rounded adipocyte-like chondrocytes, termed in the current study adipochondrocytes The adipochondrocytes were embedded in relatively wide lacunae and had large lipid droplets with a rim of cytoplasm. The scanning electron microscopy confirmed this result. With the transmission electron microscopy, the adipochondrocytes showed dark nucleus and electron-dense cytoplasm with few organelles and cytoplasmic processes. The adipochondrocytes of the auricular cartilage in adult rabbits were unique cell type and different from chondrocytes in other cartilage subtypes. This result should be considered during cartilage transplant. Further studies are suggested to investigate the development and physiological roles of adipochondrocytes in the auricular cartilage in rabbits.

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arXiv2018

Influence of pulsatile blood flow on allometry of aortic wall shear stress

Shear stress plays an important role in the creation and evolution of atherosclerosis. An key element for in-vivo measurements and extrapolations is the dependence of shear stress on body mass. In the case of a Poiseuille modeling of the blood flow, P. Weinberg and C. Ethier have shown that shear stress on the aortic endothelium varies like body mass to the power $-\frac{3}{8}$, and is therefore 20-fold higher in mice than in men. However, by considering a more physiological oscillating Poiseuille + Womersley combinated flow in the aorta, we show that results differ notably: at larger masses ($M>10 \ kg$) shear stress varies as body mass to the power $-\frac{1}{8}$ and modifies the man to mouse ratio to 1:8. The allometry and values of temporal gradient of shear stress also change: $\partialτ/\partial t$ varies as $M^{-3/8}$ instead of $M^{-5/8}$ at larger masses, and the 1:150 ratio from man to mouse becomes 1:61. Lastly, we show that the unsteady component of blood flow does not influence the constant allometry of peak velocity on body mass: $u_{max} \propto M^{0}$. This work extends our knowledge on the dependence of hemodynamic parameters on body mass and paves the way for a more precise extrapolation of in-vivo measurements to humans and bigger mammals.

physics.bio-ph↗

arXiv2018

Validation of a fractional model for erythrocyte sedimentation rate

We present the validation of a recent fractional mathematical model for erythrocyte sedimentation proposed by Sharma et al. \cite{GMR}. The model uses a Caputo fractional derivative to build a time fractional diffusion equation suitable to predict blood sedimentation rates. This validation was carried out by means of erythrocyte sedimentation tests in laboratory. Data on sedimentation rates (percentages) were analyzed and compared with the analytical solution of the time fractional diffusion equation. The behavior of the analytical solution related to each blood sample sedimentation data was described and analyzed.

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arXiv2018

Spatial dynamics of flower organ formation

Understanding the emergence of biological structures and their changes is a complex problem. On a biochemical level, it is based on gene regulatory networks (GRN) consisting on interactions between the genes responsible for cell differentiation and coupled in a greater scale with external factors. In this work we provide a systematic methodological framework to construct Waddington's epigenetic landscape of the GRN involved in cellular determination during the early stages of development of angiosperms. As a specific example we consider the flower of the plant \textit{Arabidopsis thaliana}. Our model, which is based on experimental data, recovers accurately the spatial configuration of the flower during cell fate determination, not only for the wild type, but for its homeotic mutants as well. The method developed in this project is general enough to be used in the study of the relationship between genotype-phenotype in other living organisms.

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arXiv2018

Fertilizer usage and cadmium in soils, crops and food

Phosphate fertilizers were first implicated by Schroeder and Balassa in 1963 for increasing the Cd concentration in cultivated soils and crops. This suggestion has become a part of the accepted paradigm on soil toxicity. Consequently, stringent fertilizer control programs to monitor Cd have been launched. Attempts to link Cd toxicity and fertilizers to chronic diseases are common. A re-assessment of this "accepted" paradigm is timely, given the larger body of data available today. The data show that both the input and output of Cd per hectare from fertilizers are negligibly small compared to the total amount of Cd/hectare usually present in the soil itself. Calculations based on current agricultural practices are used to show that it will take about 18 centuries to double the ambient soil-cadmium level, and about 8 centuries to double the soil-fluoride level, even after neglecting leaching and other removal effects. Hence the concern of long-term agriculture should be the depletion of available phosphate fertilizers, rather than the contamination of the soil by trace metals or fluoride. This conclusion is confirmed by showing that the claimed correlations between fertilizer input and cadmium accumulation in crops are not robust. Alternative scenarios that explain the data are examined. Thus soil acidulation on fertilizer loading, and the effect of magnesium, zinc, and fluoride ions contained in fertilizers are considered using recent Cd$^{2+}$, Mg$^{2+}$ and F$^-$ ion-association theories. The protective role of ions like Zn, Se, Fe, etc., is emphasized, and the question of cadmium toxicity in the presence of other ions is considered. These help to clarify and rectify difficulties found in the standard point of view. This analysis does not modify the accepted views on Cd contamination by airborne delivery, smoking, and industrial activity, or P-contamination causing algal blooms.

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arXiv2018

Umbilical Cord Blood Banking and its Therapeutic Uses

Umbilical cord blood (UBC) can be viewed as the most promising source of stem cells, in which collection cost is minimal and its benefits are immense. The cord blood is used to treat malignant and nonmalignant diseases; this is due to its progenitor characteristics know as stem cells.Its properties of being, immunologically immature and high plasticity has made it superior to other sources of stem cells. The stem cells collected from cord blood have neutral differentiation capabilities which allow medical professionals to produce functional neural cells from these stem cells.Cord Blood Banking (CBB) is the storing of the umbilical cord blood which is collected immediately after the delivery of the baby. Great care and concern are needed for proper storage of these progenitor cells, hence cord blood banks come into the play, they are of 3 types which are: public, private and direct donation banks.Clinical trials are still at its very early stages having abundances to still be uncovered but results were obtained have demonstrated high potential and more scope towards effective development therapies and treatments for rare disorders.

q-bio.CB↗

arXiv2018

Precision medicine as a control problem: Using simulation and deep reinforcement learning to discover adaptive, personalized multi-cytokine therapy for sepsis

Sepsis is a life-threatening condition affecting one million people per year in the US in which dysregulation of the body's own immune system causes damage to its tissues, resulting in a 28 - 50% mortality rate. Clinical trials for sepsis treatment over the last 20 years have failed to produce a single currently FDA approved drug treatment. In this study, we attempt to discover an effective cytokine mediation treatment strategy for sepsis using a previously developed agent-based model that simulates the innate immune response to infection: the Innate Immune Response agent-based model (IIRABM). Previous attempts at reducing mortality with multi-cytokine mediation using the IIRABM have failed to reduce mortality across all patient parameterizations and motivated us to investigate whether adaptive, personalized multi-cytokine mediation can control the trajectory of sepsis and lower patient mortality. We used the IIRABM to compute a treatment policy in which systemic patient measurements are used in a feedback loop to inform future treatment. Using deep reinforcement learning, we identified a policy that achieves 0% mortality on the patient parameterization on which it was trained. More importantly, this policy also achieves 0.8% mortality over 500 randomly selected patient parameterizations with baseline mortalities ranging from 1 - 99% (with an average of 49%) spanning the entire clinically plausible parameter space of the IIRABM. These results suggest that adaptive, personalized multi-cytokine mediation therapy could be a promising approach for treating sepsis. We hope that this work motivates researchers to consider such an approach as part of future clinical trials. To the best of our knowledge, this work is the first to consider adaptive, personalized multi-cytokine mediation therapy for sepsis, and is the first to exploit deep reinforcement learning on a biological simulation.

cs.LG↗

arXiv2018

Correlated random walks of human embryonic stem cell in-vitro

We perform a detailed analysis of the migratory motion of human embryonic stem cells in two-dimensions, both when isolated and in close proximity to another cell, recorded with time-lapse microscopic imaging. We show that isolated cells tend to perform an unusual locally anisotropic walk, moving backwards and forwards along a preferred local direction correlated over a timescale of around 50 minutes and aligned with the axis of the cell elongation. Increasing elongation of the cell shape is associated with increased instantaneous migration speed. We also show that two cells in close proximity tend to move in the same direction, with the average separation of 70 um or less and the correlation length of around 25 um, a typical cell diameter. These results can be used as a basis for the mathematical modelling of the formation of clonal hESC colonies.

q-bio.CB↗

arXiv2018

Quantitative analysis of the potential role of basal cell hyperplasia in the relationship between clonal expansion and radon concentration

Applying the two-stage clonal expansion model to epidemiology of lung cancer among uranium miners, it has been revealed that radon acts as a promoting agent facilitating the clonal expansion of already mutated cells. Clonal expansion rate increases non-linearly by radon concentration showing a plateau above a given exposure rate. The underlying mechanisms remain unclear. Earlier we proposed that progenitor cell hyperplasia may be induced upon chronic radon exposure. The objective of the present study is to test whether the induction of hyperplasia may provide a quantitative explanation for the plateau in clonal expansion rate. For this purpose, numerical epithelium models were prepared with different number of basal cells. Cell nucleus hits were computed by an own-developed Monte-Carlo code. Surviving fractions were estimated based on the number of cell nucleus hits. Cell division rate was computed supposing equilibrium between cell death and cell division. It was also supposed that clonal expansion rate is proportional to cell division rate, and therefore the relative increase in cell division rate and clonal expansion rate are the same functions of exposure rate. While the simulation results highly depend on model parameters with high uncertainty, a parameter set has been found resulting in a cell division rate exposure rate relationship corresponding to the plateau in clonal expansion rate. Due to the high uncertainty of the applied parameters, however, further studies are required to decide whether the induction of hyperplasia is responsible for the non-linear increase in clonal expansion rate or not. Nevertheless the present study exemplifies how computational modelling can contribute to the integration of observational and experimental radiation protection research.

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