Importance of Metabolic Rate to the Relationship Between the Number of Genes in a Functional Category and Body Size in Peto\u27s Paradox for Cancer

Elucidation of tumour suppression mechanisms is a major challenge in cancer biology. Therefore, Peto\u27s paradox, or low cancer incidence in large animals, has attracted focus. According to the gene-abundance hypothesis, which considers the increase/decrease in cancer-related genes with body size, researchers evaluated the associations between gene abundance and body size. However, previous studies only focused on a few specific gene functions and have ignored the alternative hypothesis (metabolic rate hypothesis): in this hypothesis, the cellular metabolic rate and subsequent oxidative stress decreases with increasing body size. In this study, we have elected to explore the gene-abundance hypothesis taking into account the metabolic rate hypothesis. Thus, we comprehensively investigated the correlation between the number of genes in various functional categories and body size while at the same time correcting for the mass-specific metabolic rate (Bc). A number of gene functions that correlated with body size were initially identified, but they were found to be artefactual due to the decrease in Bc with increasing body size. By contrast, immune system-related genes were found to increase with increasing body size when the correlation included this correction for Bc. These findings support the gene-abundance hypothesis and emphasize the importance of also taking into account the metabolic rate when evaluating gene abundance–body size relationships. This finding may be useful for understanding cancer evolution and tumour suppression mechanisms as well as for determining cancer-related genes and functions

Development of a mesoscopic framework spanning nanoscale protofibril dynamics to macro-scale fibrin clot formation

Thrombi form a micro-scale fibrin network consisting of an interlinked structure of nanoscale protofibrils, resulting in haemostasis. It is theorized that the mechanical effect of the fibrin clot is caused by the polymeric protofibrils between crosslinks, or to their dynamics on a nanoscale order. Despite a number of studies, however, it is still unknown, how the nanoscale protofibril dynamics affect the formation of the macro-scale fibrin clot and thus its mechanical properties. A mesoscopic framework would be useful to tackle this multi-scale problem, but it has not yet been established. We thus propose a minimal mesoscopic model for protofibrils based on Brownian dynamics, and performed numerical simulations of protofibril aggregation. We also performed stretch tests of polymeric protofibrils to quantify the elasticity of fibrin clots. Our model results successfully captured the conformational properties of aggregated protofibrils, e.g., strain-hardening response. Furthermore, the results suggest that the bending stiffness of individual protofibrils increases to resist extension.Takeishi Naoki, Shigematsu Taiki, Enosaki Ryogo, Ishida Shunichi, Ii Satoshi and Wada Shigeo 2021Development of a mesoscopic framework spanning nanoscale protofibril dynamics to macro-scale fibrin clot formationJ. R. Soc. Interface.182021055420210554 http://doi.org/10.1098/rsif.2021.055

AJK2011-04001 A FULL EULERIAN FINITE DIFFERENCE METHOD FOR HYPERELASTIC PARTICLES IN FLUID FLOWS

ABSTRACT A full Eulerian finite difference method has been developed for solving a dynamic interaction problem between Newtonian fluid and hyperelastic material. It facilitates to simulate certain classes of problems, such that an initial and neutral configuration of a multi-component geometry converted from voxel-based data is provided on a fixed Cartesian mesh. A solid volume fraction, which has been widely used for multiphase flow simulations, is applied to describing the multicomponent geometry. The temporal change in the solid deformation is described in the Eulerian frame by updating a left Cauchy-Green deformation tensor, which is used to express constitutive equations for incompressible hyperelastic materials. The present Eulerian approach is confirmed to well reproduce the material deformation in the lid-driven flow and the particle-particle interaction in the Couette flow computed by means of the finite element method. It is applied to a Poiseuille flow containing biconcave neo-Hookean particles. The deformation, the relative position and orientation of a pair of particles are strongly dependent upon the initial configuration. The increase in the apparent viscosity is dependent upon the developed arrangement of the particles. INTRODUCTION Numerical simulations of Fluid-Structure Interaction (FSI) problems would make it possible to predict the effect of a medical treatment and help one decide the treatment strategy in clinical practice. In particular, a blood flow simulation is expected to contribute to assisting the surgical planning of a cardiovascular disease and a brain aneurysm. Recently, there are growing expectations for its applications along with a progress in imaging and computational technologies. It is also expected to contribute to the field of life science, such as in the understanding of the very essence of life and the demonstration of pathological mechanisms. It is of great importance to develop numerical techniques suitable for the characteristics of body tissues, which are flexible and complicated in shape, when attempting to rationalize and to generalize the fluidstructure coupled analyses. The expectations include the further understandings of the micro/mesoscopic behavior of the flexibly deformable Red Blood Cells (RBCs) in plasma useful for evaluating the macroscopic blood rheology, and the thrombosis formation as aggregation of platelets, of which th

A full Eulerian finite difference approach for solving fluid-structure coupling problems

A new simulation method for solving fluid-structure coupling problems has been developed. All the basic equations are numerically solved on a fixed Cartesian grid using a finite difference scheme. A volume-of-fluid formulation (Hirt and Nichols (1981, J. Comput. Phys., 39, 201)), which has been widely used for multiphase flow simulations, is applied to describing the multi-component geometry. The temporal change in the solid deformation is described in the Eulerian frame by updating a left Cauchy-Green deformation tensor, which is used to express constitutive equations for nonlinear Mooney-Rivlin materials. In this paper, various verifications and validations of the present full Eulerian method, which solves the fluid and solid motions on a fixed grid, are demonstrated, and the numerical accuracy involved in the fluid-structure coupling problems is examined.Comment: 38 pages, 27 figures, accepted for publication in J. Comput. Phy

Hedgehog Promotes Neovascularization in Pancreatic Cancers by Regulating Ang-1 and IGF-1 Expression in Bone-Marrow Derived Pro-Angiogenic Cells

http://creativecommons.org/licenses/by/2.0/ PublisherBackground: The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that the oncogenic function of Hh in PDAC involves signaling in the stromal cells rather than cell autonomous effects on the tumor cells. However, the origin and nature of the stromal cell type(s) that are responsive to Hh signaling remained unknown. Since Hh signaling plays a crucial role during embryonic and postnatal vasculogenesis, we speculated that Hh ligand may act on tumor vasculature specifically focusing on bone marrow (BM)-derived cells. Methodology/Principal Findings: Cyclopamine was utilized to inhibit the Hh pathway in human PDAC cell lines and their xenografts. BM transplants, co-culture systems of tumor cells and BM-derived pro-angiogenic cells (BMPCs) were employed to assess the role of tumor-derived Hh in regulating the BM compartment and the contribution of BM-derived cells to angiogenesis in PDAC. Cyclopamine administration attenuated Hh signaling in the stroma rather than in the cancer cells as reflected by decreased expression of full length Gli2 protein and Gli1 mRNA specifically in the compartment. Cyclopamine inhibited the growth of PDAC xenografts in association with regression of the tumor vasculature and reduced homing of BM-derived cells to the tumor. Host-derived Ang-1 and IGF-1 mRNA levels were downregulated by cyclopamine in the tumor xenografts. In vitro co-culture and matrigel plug assays demonstrated that PDAC cell-derived Shh induced Ang-1 and IGF-1 production in BMPCs, resulting in their enhanced migration and capillary morphogenesis activity. Conclusions/Significance: We identified the BMPCs as alternative stromal targets of Hh-ligand in PDAC suggesting that the tumor vasculature is an attractive therapeutic target of Hh blockade. Our data is consistent with the emerging concept that BM-derived cells make important contributions to epithelial tumorigenesis

増強されたECHアンテナシステムを用いたLHDにおけるECCD適用性の向上

The power injection system for electron cyclotron heating (ECH) and electron cyclotron current drive (ECCD) was modified and upgraded. An outside horizontal port 2-O on the Large Helical Device (LHD) was furnished with two antenna systems for the EC-waves of the frequencies of 77 and 154 GHz, respectively. In addition to them, two new antenna systems for 77 and 154 GHz waves were installed in the 2-O port. Each antenna in the 2-O port has wide range of EC-wave beam direction control so that these are suitable for ECCD which requires toroidally oblique EC-wave beam injection. In the LHD 18th experimental campaign in 2014-2015, an ECCD experiment with second harmonic resonance condition, on-axis magnetic field of 1.375 T for 77 GHz waves, was performed in which some combination patterns of two 77 GHz ECCDs were applied. The discharges of dual co- and dual counter-ECCDs showed remarkable plasma currents of ∼±26 kA in both of the co- and counter-directions, by 6 s pulse duration and injection powers of 366 and 365 kW. The new antenna has nearly the same capability for ECCD with that of the existing antenna. The improvement in the flexibility of the ways of applying plural ECCDs will offer a highly useful tool for investigations on the phenomena concerning with the plasma current such as magnetohydro-dynamics