In Vivo Generation of Engraftable Murine Hematopoietic Stem Cells by Gfi1b, c-Fos, and Gata2 Overexpression within Teratoma.

Generation of hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs) could potentially provide unlimited HSCs for clinical transplantation, a curative treatment for numerous blood diseases. However, to date, bona fide HSC generation has been largely unsuccessful in vitro. We have previously described proof of concept for in vivo HSC generation from PSCs via teratoma formation. However, our first-generation system was complex and the output low. Here, we further optimize this technology and demonstrate the following: (1) simplified HSC generation using transcription factor overexpression; (2) improved HSC output using c-Kit-deficient host mice, and (3) that teratomas can be transplanted and cryopreserved. We demonstrate that overexpression of Gfi1b, c-Fos, and Gata2, previously reported to transdifferentiate fibroblasts into hematopoietic progenitors in vitro, can induce long-term HSC formation in vivo. Our in vivo system provides a useful platform to investigate new strategies and re-evaluate existing strategies to generate HSCs and study HSC development

Sequential Approximate Optimization using Radial Basis Function network for engineering optimization

金沢大学理工研究域機械工学系This paper presents a Sequential Approximate Optimization (SAO) procedure that uses the Radial Basis Function (RBF) network. If the objective and constraints are not known explicitly but can be evaluated through a computationally intensive numerical simulation, the response surface, which is often called meta-modeling, is an attractive method for finding an approximate global minimum with a small number of function evaluations. An RBF network is used to construct the response surface. The Gaussian function is employed as the basis function in this paper. In order to obtain the response surface with good approximation, the width of this Gaussian function should be adjusted. Therefore, we first examine the width. Through this examination, some sufficient conditions are introduced. Then, a simple method to determine the width of the Gaussian function is proposed. In addition, a new technique called the adaptive scaling technique is also proposed. The sufficient conditions for the width are satisfied by introducing this scaling technique. Second, the SAO algorithm is developed. The optimum of the response surface is taken as a new sampling point for local approximation. In addition, it is necessary to add new sampling points in the sparse region for global approximation. Thus, an important issue for SAO is to determine the sparse region among the sampling points. To achieve this, a new function called the density function is constructed using the RBF network. The global minimum of the density function is taken as the new sampling point. Through the sampling strategy proposed in this paper, the approximate global minimum can be found with a small number of function evaluations. Through numerical examples, the validities of the width and sampling strategy are examined in this paper. © 2010 Springer Science+Business Media, LLC

Global optimization by generalized random tunneling algorithm (5th report, approximate optimization using RBF network)

金沢大学大学院自然科学研究科知的システム創成In practical applications, it is important to reduce the function evaluations in the simulation, and obtain the approximate optimum with high accuracy. To achieve these objectives, the integrative optimization system using the RBF Network (RBFN) and the Generalized Random Tunneling Algorithm (GRTA) is proposed in this paper. This system consists of three parts. (1) Construction of the response surface, (2) Optimization by the GRTA, and (3) Adding the sampling points. The RBFN is used to construct the response surface. The radius on RBFN, which affects the accuracy of response surface, is an important parameter. Firstly new equation for the radius is proposed, based on the examination of existing equation. Secondly a simple sampling strategy to obtain an optimum with high accuracy is also proposed. In general, the objective function and the constraints are approximated, separately. However, the optimum of response surface will often violate the constraints. To avoid such situations, the augmented objective function is utilized in this paper. Then the proposed sampling strategy is applied. Through typical benchmark problems, the validity and effectiveness are examined

Differential evolution as the global optimization technique and its application to structural optimization

金沢大学理工研究域機械工学系In this paper, the basic characteristics of the differential evolution (DE) are examined. Thus, one is the meta-heuristics, and the other is the global optimization technique. It is said that DE is the global optimization technique, and also belongs to the meta-heuristics. Indeed, DE can find the global minimum through numerical experiments. However, there are no proofs and useful investigations with regard to such comments. In this paper, the DE is compared with the generalized random tunneling algorithm (GRTA) and the particle swarm optimization (PSO) that are the global optimization techniques for continuous design variables. Through the examinations, some common characteristics as the global optimization technique are clarified in this paper. Through benchmark test problems including structural optimization problems, the search ability of DE as the global optimization technique is examined. © 2011 Elsevier B.V. All rights reserved

Multi-objective Particle Swarm Optimization considering the diversity of the inferior solutions

In this paper, a simple method for the multi-objective optimization problems by the Particle Swarm Optimization (PSO) is proposed. The objectives of the Multi Objective Evolutionary Algorithms (MOEA) are summarized as follows : (1) To find the pareto optimal solutions, (2) To find the pareto optimal solutions as diverse as possible. To achieve these objectives by the PSO for the single objective problems, we propose how to define the g-best in this swarm without introducing some new parameters. That is, one particle among the non-inferior solutions is selected as the g-best to achieve the diversity among the non inferior solutions. The relative distance in the objective space is utilized to select the gbest among the non-inferior solutions. Additionally, some particles among the non inferior solutions are also selected as the gbest of the inferior solutions to find the pareto optimal solutions. The absolute distance in the objective space is utilized to select the g-best of the inferior solutions. We also show the geometric interpretation about the movement of particles. The validity of proposed approach is examined through typical numerical examples

Effects of dietary inulin, statin, and their co-treatment on hyperlipidemia, hepatic steatosis and changes in drug-metabolizing enzymes in rats fed a high-fat and high-sucrose diet

<p>Abstract</p> <p>Background</p> <p>Rats fed a high-fat and high-sucrose (HF) diet develop hepatic steatosis and hyperlipidemia. There are several reports that a change in nutritional status affects hepatic levels of drug-metabolizing enzymes. Synthetic inulin is a dietary component that completely evades glucide digestion. Supplementing a HF diet with inulin ameliorates hypertriglycemia and hepatic steatosis, but not hypercholesterolemia. This study aimed at distinguishing the effects of synthetic inulin and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin), which inhibit cholesterol biosynthesis.</p> <p>Methods</p> <p>We examined effects of co-treatment with synthetic inulin (5%) and fluvastatin (0, 4, and 8 mg/kg, <it>per os</it>) on body weight, epidydimal white adipose tissue weight, serum and hepatic lipid profiles, and hepatic cytochrome P450 (CYP) mRNA and protein profiles in rats fed a standard diet or a HF diet for 3 weeks.</p> <p>Results</p> <p>Treatment with the synthetic inulin (5%) or fluvastatin at 4 mg/kg (lethal dose in rats fed the HF diet, 8 mg/kg) ameliorated the elevation in hepatic triacylglycerol and total cholesterol levels in rats fed the HF diet. Whereas co-treatment with the inulin (5%) and fluvastatin (4 mg/kg) had a tendency to more strongly suppress the elevation in serum levels of very low density lipoprotein triacylglycerol than either treatment alone, no additive or synergistic effect was found in decrease in hepatic lipid levels. Hepatic levels of CYP1A1/2 and CYP2E1 mRNA and protein and methoxyresorufin <it>O</it>-demethylase and ethoxyresorufin <it>O</it>-deethylase activities were reduced in rats fed the HF diet. The synthetic inulin alleviated the reduction in hepatic levels of CYP1A1/2 and CYP2E1 mRNA and protein more strongly than fluvastatin, and no synergistic effects were observed on co-treatment. Furthermore, hepatic levels of aryl hydrocarbon receptor mRNA were decreased in rats fed the HF diet and recovered to near normal values with the intake of dietary inulin, which correlated with change in CYP1A1/2.</p> <p>Conclusions</p> <p>Dietary inulin alone was effective to prevent the development of hepatic steatosis, ameliorate nutritional effects, and alleviate the hepatic change in the expression of CYP1A1/2 and CYP2E1, while co-treatment with statin did not have additive or synergistic effects and statin may cause adverse effects in rats fed the HF diet.</p