A gene network inference method from continuous-value gene expression data of wild-type and mutants.

In this paper we introduce a new inference method of a gene regulatory network from steady-state gene expression data. Our method determines a regulatory structure consistent with an observed set of steady-state expression profiles, each generated from wild-type and single deletion mutant of the target network. Our method derives the regulatory relationships in the network using a graph theoretic approach. The advantage of our method is to be able to deal with continuous values of steady-state data, while most of the methods proposed in past use a Boolean network model with binary data. Performance of our method is evaluated on simulated networks with varying the size of networks, indegree of each gene, and the data characteristics (continuous-value/binary), and is compared with that of predictor method proposed by Ideker et al. As a result, we show the superiority of using continuous values to binary values, and the performance of our method is much better than that of the predictor method.

Bio-calculus: Its Concept and Molecular Interaction.

The way for expressing biological systems is a key element of usability. Expressions used in the biological society and those in the computer science society have their own merits. But they are too different for one society to utilize the expressions of the other society. In this paper, we design the bio-calculus that attempts to bridge this gap. We provide syntax which is similar to conventional expressions in biology and at the same time specifies information needed for simulation analysis. The information and mathematical background of bio-calculus is what is desired for the field of computer science. We show the practicality of bio-calculus by describing and simulating some molecular interactions with bio-calculus.

Towards Automatic Construction of Cell-Lineage of C. elegans from Nomarski DIC Microscope Images.

This study aims at automatic construction of a cell lineage from 4D (multi-focal, time-lapse) images, which are taken using a Nomarski DIC (differential-interference contrast) microscope. A system with such abilities would be a powerful tool for studying embryo genesis and gene function based on mutants, whose cell lineage may differ from that of wild types. We have designed and implemented a system for this purpose, and examined its ability through computational experiments. The procedure of our system consists of two parts: (1) Image processing which detect the positions of the nuclei from each 2D microscope image, and (2) Constructing a hypothetical cell lineage based on the information obtained in (1). We have also developed a tool which allows a human expert to easily filter out erroneous nuclei candidates generated in (1). We present computational results and also discuss other ideas which may improve the performance of our system.

Adrenocorticotropin-independent macronodular adrenocortical hyperplasia associated with multiple colon adenomas/carcinomas which showed a point mutation in the APC gene.

We report a male Japanese with corticotropin (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH) associated with multiple colon adenomas/carcinomas. The plasma cortisol level was elevated with no diurnal rhythm and was not suppressed with dexamethasone. Basal plasma ACTH was unmeasurable but subnormally increased after administration of metyrapone or corticotropin releasing hormone. Both adrenals were resected and weighed 90g; the histopathologic findings were similar to those of AIMAH as previously reported. At least 21 colon lesions which were adenomas or carcinomas, were resected endoscopically or surgically. This is the second reported case of the association of AIMAH with multiple colon polyps. An APC gene point mutation was detected in the colon cancer tissue by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP)/direct sequencing analysis at the putative splice acceptor site consensus sequence. However, no abnormality of APC gene was detected in the adrenocortical hyperplastic tissue. The possible etiological coexistence of these two diseases is discussed.

Splenic macrophages can modify steroidogenesis of Leydig cells.

A large amount of LH/hCG treatment given to male rats is known to suppress the enzyme activity of cytochrome P450c17 in Leydig cells for 48 h. A high dose LH/hCG injection is also known to allow immunocytes, such as macrophages, to migrate into the testicular interstitial compartment. It has not been known, however, whether these cells play a role in that suppression. In this study, we examined if splenic macrophages have any effects on testosterone secretion from Leydig cells by culturing rat testicular interstitial cells (TIC). Splenic macrophages co-cultured with TIC significantly suppressed testosterone secretion. Macrophages co-cultured reduced both progesterone to testosterone conversion and the amount of cytochrome P450c17 mRNA. The conditioned medium (SMCM), prepared by culturing macrophages for 12 h, significantly reduced either testosterone secretion from TIC or progesterone to testosterone conversion by TIC. These results indicate that splenic macrophages suppress testosterone secretion from Leydig cells by suppressing the cytochrome P450c17 enzyme in vitro, and that this effect is mediated at least in part by some soluble factors secreted from macrophages. Splenic macrophages migrating into the testis after LH/hCG stimulation could play a role in suppressing cytochrome P450c17 in Leydig cells.

[Experimental studies on endocrine therapy for rat hepatocellular carcinoma].

Androgen receptor (AnR) and estrogen receptor (ER) are known to exist in human hepatocellular carcinoma (HCC), but the low binding capacity casts doubts on the efficacy of endocrinotherapy. However, we focussed on the favorable dissociation constant and displacement of AnR and ER. Efficacy of endocrinotherapy for HCC was investigated using rat HCC cell line (AH66F) resembling the properties of human HCC and sex hormone receptors. In rat HCC AH66F, we confirmed that the AnR and ER were both positive and were mentioned binding capacity, dissociation constant and displacement resembled those of human HCC. In rat HCC AH66F, administrations of Tamoxifen converted AnR and ER responses to negative. Rat HCC AH66F was transplanted intraperitoneally to Donryu rats, various endocrinotherapies administered and the number of survival days compared with a control group. In male and female rats, the number of survival days was both in the orchidectomied (p < 0.01) and the Tamoxifen treated (p < 0.001) group significantly prolonged. However, in the group treated with medroxyprogesterone acetate no significant differences were observed. Also, in experiments with AnR (-) and ER (-) rat HCC cell line AH60C all endocrinotherapies were ineffective. Above results confirmed the efficacy of endocrinotherapy for rat HCC with positive sex hormone receptors.