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Immunomodulatory role of an Ayurvedic formulation on imbalanced immune-metabolics during inflammatory responses of obesity and pre-diabetic disease

Obesity and related type 2 diabetes are associated with a low level chronic inflammatory state with disease status increasing at epidemic proportions worldwide. It is now universally accepted that the underlying immune-inflammatory responses mediated within the adipose tissue in obesity are central to the development of disease. Once initiated, chronic inflammation associated with obesity leads to the modulation of immune cell function. In the present study we aimed to investigate the effect of an ayurvedic formulation (named as Kal-1, an abbreviation derived from the procuring source) on diet-induced obesity and type II diabetes using C57BL/6J mice. The study was planned into two groups using obese and pre-diabetic mouse model. The mice were fed on high-fat with increased diet and, different amounts (5, 20 and 75 μg) of Kal-1 were given with disease progression for 21 weeks in first group whereas mice were first put on the same diet for 21 weeks and then treated with same amounts of Kal-1. A significant reduction in body weight and fat pads, fasting blood glucose levels, insulin levels and biochemical parameters like triglycerides and cholesterol were observed in obese and diabetic mice+Kal-1 than control (lean) mice fed on low fat diet, though the optimum amounts of Kal-1 were 20 and 75 μg in first and second group respectively. A noteworthy immunological correction in important readouts viz. resistin, leptin, HMW adiponection and an array of pro- & anti-cytokines (IL-4, IL-10, IL-1α, IL-1β, IL-4, IL-6, IL-10, TNF-α and MCP-1) was also observed in both the groups with the mentioned amount of Kal-1. We conclude that Kal-1 has immunomodulatory potential for diet-induced obesity and associated metabolic disorders.

q-bio.TO↗

Vascular phyllotaxis transition and an evolutionary mechanism of phyllotaxis

Leaves of vascular plants are arranged regularly around stems, a phenomenon known as phyllotaxis. A constant angle between two successive leaves is called divergence angle. On the one side, the divergence angle $α_0$ of an initial pattern of leaf primordia at a shoot apex is most commonly an irrational number of about 137.5 degrees, called limit divergence. On the other side, the divergence $α$ of a final pattern of leaf traces in the vascular system of a mature stem is expressed in terms of a sequence of rational numbers, 1/2, 1/3, 2/5, 3/8, 5/13, 8/21, called phyllotactic fractions. The mathematical relationship between the initial divergence $α_0$, the final divergence $α$, and the number of internodes traversed by the leaf traces $n_c$ is investigated by means of a theoretical model of vascular phyllotaxis. It is shown that continuous changes of the trace length $n_c$ induce transitions between the fractional orders in the vascular structure. The vascular phyllotaxis transition suggests an evolutionary mechanism for the phenomenon of phyllotaxis. To provide supporting evidence for the model and mechanism, available experimental results for fossil remains of Lepidodendron and the vascular structure of Linum and Populus are analyzed with the model.

physics.bio-ph↗

The Origin, Evolution and Development of Bilateral Symmetry in Multicellular Organisms

A computational theory and model of the ontogeny and development of bilateral symmetry in multicellular organisms is presented. Understanding the origin and evolution of bilateral organisms requires an understanding of how bilateral symmetry develops, starting from a single cell. Bilateral symmetric growth of a multicellular organism from a single starter cell is explained as resulting from the opposite handedness and orientation along one axis in two daughter founder cells that are in equivalent developmental control network states. Several methods of establishing the initial orientation of the daughter cells (including oriented cell division and cell signaling) are discussed. The orientation states of the daughter cells are epigenetically inherited by their progeny. This results in mirror development with the two founding daughter cells generating complementary mirror image multicellular morphologies. The end product is a bilateral symmetric organism. The theory gives a unified explanation of diverse phenomena including symmetry breaking, situs inversus, gynandromorphs, inside-out growth, bilaterally symmetric cancers, and the rapid, punctuated evolution of bilaterally symmetric organisms in the Cambrian Explosion. The theory is supported by experimental results on early embryonic development. The theory makes precise testable predications.

q-bio.TO↗

The effect of low doses of cadmium and zinc chloride on the Blood-Testis Barrier of Sprague Dawley rats

Background: Cadmium chloride is an environmental toxic that affects the male reproductive system. This study was directed 1) to evaluate whether long-term oral exposures to low doses of Cd in rats causes morphological changes, 2) the immunohistochemical TJ and AJ protein expression; and 3) to evidence that zinc exposure can modify Cd effects. Methods: Testis of normal rats and rats that have received Cd or Cd+Zn in drinking water during 12 months did not show any morphological change. Immunohistochemistry was used to identify BTB integrity, claudin-1, ZO-1, N-Cadherin and β-catenin were detected by immunohistochemistry and IOD were measure. Results: No immunoexpression changes of claudin-1 and ZO-1 were observed. Cd + Zn group showed a significant increase of IOD of N-Cadherin, and a significant decrease of β-catenin and transferrin immunoexpression was observed. Conclusions: Ours findings showed that the intake of low oral doses of cadmium chloride over a long time period of time did not cause morphological variation on rat testis. Neither alteration on BTB was found. Zinc chloride was able to strengthen TJ and AJ, and decrease transferrin. Key words: Testis prostate, cadmium, zinc, TJ, AJ, immunohistochemistry

q-bio.TO↗

How to Grow an Organism Inside-Out: Evolution of an internal skeleton from an external skeleton in bilateral organisms

An intriguing unanswered question about the evolution of bilateral animals with internal skeletons is how an internal skeleton evolved in the first place. Computational modeling of the development of bilateral symmetric organisms suggests an answer to this question. Our hypothesis is that an internal skeleton may have evolved from a bilaterally symmetric ancestor with an external skeleton. By growing the organism inside-out an external skeleton becomes an internal skeleton. Our hypothesis is supported by a computational theory of bilateral symmetry that allows us to model and simulate this process. Inside-out development is achieved by an orientation switch. Given the development of two bilateral founder cells that generate a bilateral organism, a mutation that reverses the internal mirror orientation of those bilateral founder cells leads to inside-out development. The new orientation is epigenetically inherited by all progeny. A key insight is that each cell contained in the newly evolved organism with the internal skeleton develops according to the very same downstream developmental control network that directs the development of its exoskeletal ancestor. The networks and their genomes are are identical, but the interpretation is different because of the cell's inverted orientation. The result is inside-out bilateral symmetric development generating an inside-out organism with an internal skeleton.

q-bio.TO↗

Immunoexpression of Nm23: correlation with traditional prognostic markers in breast carcinoma

Fifty cases of breast carcinoma were investigated for Nm23, LPA1, Ki67 and p53 antigen expression, using immunohistochemical techniques. Correlation between markers was studied. Nm23 showed an inverse correlation with LPA1 and Ki67, and positive with p53. Nm23/LPA1presented significant (p<0.001) negative correlation with p53, but not difference were observed with Ki67. It can be concluded that: 1) Nm23 and LPA1 tend to be inversely correlated; 2) Nm23 correlates positively with p53, regardless of tumour type and patient's hormonal status; 3) Nm23 shows a reverse trend in comparison with Ki67. However, more studies are needed to determinate if hormone receptors play some role in the inverse relationship between Nm23-LPA1 and to know the tumour type implication in these relationships.

q-bio.TO↗

Zinc Uptake and Radial Transport in Roots of Arabidopsis thaliana: A Modelling Approach to Understand Accumulation

Zinc uptake in roots is believed to be mediated by ZIP (ZRT-, IRT-like Proteins) transporters. Once inside the symplast, zinc is transported to the pericycle, where it exits by means of HMA (Heavy Metal ATPase) transporters. The combination of symplastic transport and spatial separation of influx and efflux produces a pattern in which zinc accumulates in the pericycle. Here, mathematical modelling was employed to study the importance of ZIP regulation, HMA abundance and symplastic transport in creation of the radial pattern of zinc in primary roots of Arabidopsis thaliana. A comprehensive one-dimensional dynamic model of radial zinc transport in roots was developed and used to conduct simulations. The model accounts for the structure of the root consisting of symplast and apoplast and includes effects of water flow, diffusion, and cross-membrane transport via transporters. It also incorporates the radial geometry and varying porosity of root tissues, as well as regulation of ZIP transporters. Steady state patterns were calculated for various zinc concentrations in the medium, water influx and HMA abundance. The experimentally observed zinc gradient was reproduced very well. Increase of HMA or decrease in water influx led to loss of the gradient. The dynamic behaviour for a change in medium concentration and water influx was also simulated showing short adaptation times in the range of seconds to minutes. Slowing down regulation led to oscillations in expression levels, suggesting the need for rapid regulation and existence of buffering agents. The model captures the experimental findings very well and confirms the hypothesis that low abundance of HMA4 produces a radial gradient in zinc concentration. Surprisingly, transpiration was found to be also a key parameter. The model suggests that ZIP regulation takes place on a comparable time scale as symplastic transport.

q-bio.TO↗

Colorectal cancers differ in respect of PARP-1 protein expression

Recent findings raise the possibility of PARP inhibitor therapy in colorectal cancers(CRCs). However, the extent of PARP-1 protein expression in clinical specimens of CRC is not known. Using immunohistochemistry we assessed PARP-1 protein expression in tissue microarrays of 151 CRCs and its association with the patient's age, sex, Astler-Coller stage, grade and site of the tumor. High PARP nuclear immunoreactivity was found in 68.2% (103/151) of all cases. In turn, 31.8% (48/151)of tumors showed low PARP expression, including 9 (6%) PARP-1 negative CRCs. There was a significant association of PARP-1 expression with the site of CRC and Astler-Coller stage. A high PARP expression was noted in 79.1% of colon vs. 53.9% of rectal tumors (p = 0.001). The mean PARP-1 score was 1.27 times higher in colon vs. rectal cancers (p = 0.009) and it was higher in stage B2 vs. stage C of CRCs (p = 0.018). In conclusion, the level of PARP-1 protein nuclear expression is associated with the tumor site and heterogeneous across clinical specimens of CRC, with the majority of CRCs expressing a high level but minority - low or no PARP-1 expression. These findings may have a clinical significance because the assessment of PARP-1 expression in tumor samples may improve selection of patients with CRC for PARP inhibitor therapy.

q-bio.SC↗

On applications of conservation laws in pharmacokinetics

There has been certain criticism raised by A. Rescigno [2,8,9,12-15] against the standard formulation of pharmacokinetics. In 2011 it has been suggested that inconsistencies in pharmacokinetics should be eliminated after deriving "pharmacokinetic parameters" from conservation laws [3]. In the following text a simple system of conservation laws for extra - vascular administration of a drug is explicitly given and preliminary discussion concerning this issue is included.

q-bio.TO↗

On the Way to More Convenient Description of Drug-Plasma Protein Binding

The theoretical case is considered where the total amount of plasma protein is conserved, but the drug is eliminated after its single application. After a single drug application at time t = 0, the total drug concentration is measured at times ti,...,tk and the total drug concentration at time ti is denoted by ϕi. Our discussion is limited to one protein binding site. The quantity of plasma protein (Λ), the association constant (Ka) and the total concentration of the drug ϕi at time ti are considered as independent variables. Free drug concentration, plasma protein bound concentration and free drug fraction are given as functions of these "new" variables. The aim of this communication is to derive the formula that allows to calculate the free drug concentration at any time after the drug application, based on 3 parameters: the association constant of the drug, the total plasma concentration of the drug and the concentration of the protein. If the plasma protein quantity (Λ) and the association constant (Ka) are known, then from the knowledge of the total drug concentration ϕi at time ti it is possible to determine the free drug concentration at time ti.

q-bio.TO↗

Automated Image Analysis of Hodgkin lymphoma

Hodgkin lymphoma is an unusual type of lymphoma, arising from malignant B-cells. Morphological and immunohistochemical features of malignant cells and their distribution differ from other cancer types. Based on systematic tissue image analysis, computer-aided exploration can provide new insights into Hodgkin lymphoma pathology. In this paper, we report results from an image analysis of CD30 immunostained Hodgkin lymphoma tissue section images. To the best of our knowledge, this is the first systematic application of image analysis to a set of tissue sections of Hodgkin lymphoma. We have implemented an automatic procedure to handle and explore image data in Aperio's SVS format. We use pre-processing approaches on a down-scaled image to separate the image objects from the background. Then, we apply a supervised classification method to assign pixels to predefined classes. Our pre-processing method is able to separate the tissue content of images from the image background. We analyzed three immunohistologically defined groups, non-lymphoma and the two most common forms of Hodgkin lymphoma, nodular sclerosis and mixed cellularity type. We found that nodular sclerosis and non-lymphoma images exhibit different amounts of CD30 stain, whereas mixed cellularity type exhibits a large variance and overlaps with the other groups. The results can be seen as a first step to computationally identify tumor regions in the images. This allows us to focus on these regions when performing computationally expensive tasks like object detection in the high-resolution image.

q-bio.TO↗

Pulsatile flow and heat transfer of a magneto-micropolar fluid through a stenosed artery under the influence of body acceleration

With an aim to investigate the effect of externally imposed body acceleration and magnetic field on pulsatile flow of blood through an arterial segment having stenosis is under consideration in this paper. The flow of blood is presented by a unsteady micropolar fluid and the heat transfer characteristics have been taken into account. The non-linear equations that governing the flow are solved numerically using finite difference technique by employing a suitable coordinate transformation. The numerical results have been observed for axial and microrotation component of velocity, fluid acceleration, wall shear stress(WSS), flow resistance, temperature and the volumetric flow rate. It thus turns out that the rate of heat transfer increases with the increase of Hartmann number $H$, while the wall shear stress has a reducing effect on the Hartmann number $H$ and an enhancing effect on microrotation parameter $K$ as well as the constriction height $δ$.

math.NA↗

Mathematical modelling of blood flow through a tapered overlapping stenosed artery with variable viscosity

This paper presents a theoretical study of blood flow through a tapered and overlapping stenosed artery under the action of an externally applied magnetic field. The fluid (blood) medium is assumed to be porous in nature. The variable viscosity of blood depending on hematocrit (percentage volume of erythrocytes) is taken into account in order to improve resemblance to the real situation. The governing equation for laminar, incompressible and Newtonian fluid subject to the boundary conditions is solved by using a well known Frobenius method. The analytical expressions for velocity component, volumetric flow rate, wall shear stress and pressure gradient are obtained. The numerical values are extracted from these analytical expressions and are presented graphically. It is observed that the influence of hematocrit, magnetic field and the shape of artery have important impact on the velocity profile, pressure gradient and wall shear stress. Moreover, the effect of primary stenosis on the secondary one has been significantly observed.

math.NA↗

Simulation Organogenesis in COMSOL: Deforming and Interacting Domains

Organogenesis is a tightly regulated process that has been studied experimentally for decades. We are developing mechanistic models for the morphogenesis of limbs, lungs, and kidneys with a view to integrate available knowledge and to better understand the underlying regulatory logic. In our previous paper on simulating organogenesis in COMSOL (German et al COMSOL Conf Procedings 2011) we discussed methods to efficiently solve such models, predominantly on a static domain. Organ size, however, changes dramatically during development, and tissues are composed of several layers that may expand both together or independently. Moreover, the developing organ are typically embedded in an environment, and diffusional exchange with this environment can affect the patterning process. Here we discuss methods to build and efficiently solve models involving large deformation of composite domains in COMSOL Multiphysics.

q-bio.TO↗

Analytical Solution of the Proprio-Graviceptive equation for shoot gravitropism of plants

We derive the analytical solutions to the second order generalised gravi-proprioceptive equation given in our recent paper [Bastien et al. 2012]. These equations show how plants adjust to the surrounding gravitation field and highlight the fact that the plant must be able to not only sense its local posture with respect to the gravitational field, but also to sense its own local curvature. In [Bastien et al. 2012] we obtained explicit analytical solutions of these equations in terms of (sums of) Bessel functions, and in the present paper we derive these solutions.

q-bio.TO↗

Acoustic Noise of MRI Scans of the Internal Auditory Canal and Potential for Intracochlear Physiological Changes

Magnetic resonance imaging (MRI) is a widely used medical imaging technique to assess the health of the auditory (vestibulocochlear) nerve. A well known problem with MRI machines is that the acoustic noise they generate during a scan can cause auditory temporary threshold shifts (TTS) in humans. In addition, studies have shown that excessive noise in general can cause rapid physiological changes of constituents of the auditory within the cochlea. Here, we report in-situ measurements of the acoustic noise from a 1.5 Tesla MRI machine (GE Signa) during scans specific to auditory nerve assessment. The measured average and maximum noise levels corroborate earlier investigations where TTS occurred. We briefly discuss the potential for physiological changes to the intracochlear branches of the auditory nerve as well as iatrogenic misdiagnoses of intralabyrinthine and intracochlear schwannomas due to hypertrophe of the auditory nerve within the cochlea during MRI assessment.

physics.med-ph↗

Nuclear flow in a filamentous fungus

The syncytial cells of a filamentous fungus consist of a mass of growing, tube-like hyphae. Each extending tip is fed by a continuous flow of nuclei from the colony interior, pushed by a gradient in turgor pressure. The myco-fluidic flows of nuclei are complex and multidirectional, like traffic in a city. We map out the flows in a strain of the model filamentous fungus {\it N. crassa} that has been transformed so that nuclei express either hH1-dsRed (a red fluorescent nuclear protein) or hH1-GFP (a green-fluorescent protein) and report our results in a fluid dynamics video.

physics.flu-dyn↗

Digestion Modelling in the Small Intestine : Impact of Dietary Fibre

In this work, we continue the modelling of the digestion in the small intestine, started in a previous article, by investigating the effects of dietary fibre. We recall that this model aims at taking into account the three main phenomena of the digestion, namely the transit of the bolus, the degradation of feedstuffs and the absorption through the intestinal wall. In order to study the role of dietary fibre on digestion, we model their two principal physiochemical characteristics which interact with the function of the small intestine, i.e. viscosity and water holding capacity. This leads us to consider some features of digestion which have not been taken into account previously, in particular the interrelationship between the evolution of dry matter and water in the bolus. The numerical results are in agreement with the positive effect of insoluble dietary fibre on the velocity of bolus along the small intestine and on its degradation. These results highlight the negative effect of soluble dietary fibre on digestion. Although, this model is generic and contains a large number of parameters, to our knowledge, it is among the first qualitative dynamical modelling of fibre influence on intestinal digestion.

math.DS↗