Formalizing Statistical Causality via Modal Logic

We propose a formal language for describing and explaining statistical causality. Concretely, we define Statistical Causality Language (StaCL) for expressing causal effects and specifying the requirements for causal inference. StaCL incorporates modal operators for interventions to express causal properties between probability distributions in different possible worlds in a Kripke model. We formalize axioms for probability distributions, interventions, and causal predicates using StaCL formulas. These axioms are expressive enough to derive the rules of Pearl's do-calculus. Finally, we demonstrate by examples that StaCL can be used to specify and explain the correctness of statistical causal inference

Sound and Relatively Complete Belief Hoare Logic for Statistical Hypothesis Testing Programs

We propose a new approach to formally describing the requirement for statistical inference and checking whether a program uses the statistical method appropriately. Specifically, we define belief Hoare logic (BHL) for formalizing and reasoning about the statistical beliefs acquired via hypothesis testing. This program logic is sound and relatively complete with respect to a Kripke model for hypothesis tests. We demonstrate by examples that BHL is useful for reasoning about practical issues in hypothesis testing. In our framework, we clarify the importance of prior beliefs in acquiring statistical beliefs through hypothesis testing, and discuss the whole picture of the justification of statistical inference inside and outside the program logic

The mechanical stimulation of cells in 3D culture within a self-assembling peptide hydrogel

The aim of this present study was to provide a scaffold as a tool for the investigation of the effect of mechanical stimulation on three-dimensionally cultured cells. For this purpose, we developed an artificial self-assembling peptide (SPG-178) hydrogel scaffold. The structural properties of the SPG-178 peptide were confirmed by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and transmission electron microscopy (TEM). The mechanical properties of the SPG-178 hydrogel were studied using rheology measurements. The SPG-178 peptide was able to form a stable, transparent hydrogel in a neutral pH environment In the SPG-178 hydrogel, mouse skeletal muscle cells proliferated successfully (increased by 12.4 +/- 1.5 times during 8 days of incubation; mean +/- SEM). When the scaffold was statically stretched, a rapid phosphorylation of ERK was observed (increased by 2.8 +/- 0.2 times; mean +/- SEM). These results demonstrated that the developed self-assembling peptide gel is non-cytotoxic and is a suitable tool for the investigation of the effect of mechanical stimulation on three-dimensional cell culture

NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3β resulting in the stabilization of MYCN in human neuroblastomas.

The rearrangement of pre-existing genes has long been thought of as the major mode of new gene generation. Recently, de novo gene birth from non-genic DNA was found to be an alternative mechanism to generate novel protein-coding genes. However, its functional role in human disease remains largely unknown. Here we show that NCYM, a cis-antisense gene of the MYCN oncogene, initially thought to be a large non-coding RNA, encodes a de novo evolved protein regulating the pathogenesis of human cancers, particularly neuroblastoma. The NCYM gene is evolutionally conserved only in the taxonomic group containing humans and chimpanzees. In primary human neuroblastomas, NCYM is 100% co-amplified and co-expressed with MYCN, and NCYM mRNA expression is associated with poor clinical outcome. MYCN directly transactivates both NCYM and MYCN mRNA, whereas NCYM stabilizes MYCN protein by inhibiting the activity of GSK3β, a kinase that promotes MYCN degradation. In contrast to MYCN transgenic mice, neuroblastomas in MYCN/NCYM double transgenic mice were frequently accompanied by distant metastases, behavior reminiscent of human neuroblastomas with MYCN amplification. The NCYM protein also interacts with GSK3β, thereby stabilizing the MYCN protein in the tumors of the MYCN/NCYM double transgenic mice. Thus, these results suggest that GSK3β inhibition by NCYM stabilizes the MYCN protein both in vitro and in vivo. Furthermore, the survival of MYCN transgenic mice bearing neuroblastoma was improved by treatment with NVP-BEZ235, a dual PI3K/mTOR inhibitor shown to destabilize MYCN via GSK3β activation. In contrast, tumors caused in MYCN/NCYM double transgenic mice showed chemo-resistance to the drug. Collectively, our results show that NCYM is the first de novo evolved protein known to act as an oncopromoting factor in human cancer, and suggest that de novo evolved proteins may functionally characterize human disease

Fragmented Flying Geese (FFG) and Intra-Regional Agglomeration: Towards a Model Explaining Location Shifting of Japanese Multinational Corporations and the Electric Value Chains of ASEAN Economies

In this article, we study corporate behavior and develop a model for trends and factors in Japanese Multinational Corporations (MNCs) in the electrical and electronic industry that have played an important role in the economic development of East and Southeast Asia. We focus on Thailand, where Japanese MNCs are still increasing, and examine the practical applicability of the model. Basically, the model will be developed based on the existing flying geese model and regional agglomeration, but it will also be developed to explain new events such as progress in the division of labor by fragmentation and intra-regional agglomeration in East and Southeast Asia. Japanese MNCs in the electrical and electronic industry have shifted their production bases to developing countries one after another, as a variant of the third type of flying geese model. While the network of the international division of labor is forming with the development of fragmentation, the area around the eastern seaboard from Bangkok is playing an increasingly important role in the network of Japanese companies. In that sense, this study contributes to the body of literature on flying geese models with a modified model embodied with dynamic and systematic features of the ASEAN integrated economies

Fragmented Flying Geese (FFG) and Intra-Regional Agglomeration: Towards a Model Explaining Location Shifting of Japanese Multinational Corporations and the Electric Value Chains of ASEAN Economies

In this article, we study corporate behavior and develop a model for trends and factors in Japanese Multinational Corporations (MNCs) in the electrical and electronic industry that have played an important role in the economic development of East and Southeast Asia. We focus on Thailand, where Japanese MNCs are still increasing, and examine the practical applicability of the model. Basically, the model will be developed based on the existing flying geese model and regional agglomeration, but it will also be developed to explain new events such as progress in the division of labor by fragmentation and intra-regional agglomeration in East and Southeast Asia. Japanese MNCs in the electrical and electronic industry have shifted their production bases to developing countries one after another, as a variant of the third type of flying geese model. While the network of the international division of labor is forming with the development of fragmentation, the area around the eastern seaboard from Bangkok is playing an increasingly important role in the network of Japanese companies. In that sense, this study contributes to the body of literature on flying geese models with a modified model embodied with dynamic and systematic features of the ASEAN integrated economies

Secondary Structure of Human De Novo Evolved Gene Product NCYM Analyzed by Vacuum-ultraviolet Circular Dichroism

NCYM, a cis-antisense gene of MYCN, encodes a Homininae-specific protein that promotes the aggressiveness of human tumors. Newly evolved genes from non-genic regions are known as de novo genes, and NCYM was the first de novo gene whose oncogenic functions were validated in vivo. Targeting NCYM using drugs is a potential strategy for cancer therapy; however, the NCYM structure must be determined before drug design. In this study, we employed vacuum-ultraviolet circular dichroism to evaluate the secondary structure of NCYM. The SUMO-tagged NCYM and the isolated SUMO tag in both hydrogenated and perdeuterated forms were synthesized and purified in a cell-free in vitro system, and vacuum-ultraviolet circular dichroism spectra were measured. Significant differences between the tagged NCYM and the isolated tag were evident in the wavelength range of 190–240 nm. The circular dichroism spectral data combined with a neural network system enabled to predict the secondary structure of NCYM at the amino acid level. The 129-residue tag consists of α-helices (approximately 14%) and β-strands (approximately 29%), which corresponded to the values calculated from the atomic structure of the tag. The 238-residue tagged NCYM contained approximately 17% α-helices and 27% β-strands. The location of the secondary structure predicted using the neural network revealed that these secondary structures were enriched in the Homininae-specific region of NCYM. Deuteration of NCYM altered the secondary structure at D90 from an α-helix to another structure other than α-helix and β-sheet although this change was within the experimental error range. All four nonsynonymous single-nucleotide polymorphisms (SNPs) in human populations were in this region, and the amino acid alteration in SNP N52S enhanced Myc-nick production. The D90N mutation in NCYM promoted NCYM-mediated MYCN stabilization. Our results reveal the secondary structure of NCYM and demonstrated that the Homininae-specific domain of NCYM is responsible for MYCN stabilization