We previously reported that administration of a streptococcal preparation (OK432) inhibited insulitis and development of autoimmune diabetes in nonobese diabetic (NOD) mice and BB rats as animal models of insulin-dependent diabetes mellitus. In this study, we screened various cytokines that could be induced by OK432 in vivo, for their preventive effect against diabetes in NOD mice. Among recombinant mouse IFN'y, human ILla, human IL2, mouse granulocyte-macrophage colony-stimulating factor and human TNFa, only human TNFa suppressed insulitis and significantly (P < 0.001) inhibited development of diabetes. NOD mice were the lowest producers of the mRNA of TNF and serum TNF on stimulation with OK432 or with IFNy plus LPS, compared with C57BL/6, C3H/He, and Balb/c mice. The results imply a role for low productivity of TNF in the pathogenesis of autoimmune diabetes in NOD mice. IntroductionDiabetes develops spontaneously in the nonobese diabetic

The structure of dextran B-1355-S (soluble fraction) has been investigated.

Recently, the use of three-dimensional neural tissues cultured in vitro and called "cerebral organoids" has advanced recapitulation of neural development and disease modeling studies. Along with such advances, cerebral organoid research, and associated concerns call for the elucidation of two points: (1) how cerebral organoid research is currently progressing and the future directions it is likely to take, especially in functional assessment of organoids, and (2) how we should solve ethical issues of possible consciousness in cerebral organoid research. This paper aims first to explore these two issues, and then to present implications and prospects for future cerebral organoid research.

In 2008, researchers created human three-dimensional neural tissueknown as the pioneering work of "brain organoids." In recent years, some researchers have transplanted human brain organoids into animal brains for applicational purposes. With these experiments have come many ethical concerns. It is thus an urgent task to clarify what is ethically permissible and impermissible in brain organoid research. This paper seeks (1) to sort out the ethical issues related to brain organoid research and application and (2) to propose future directions for additional ethical consideration and policy debates in the field. Toward (1), this paper first outlines the current state of brain organoid research, and then briefly responds to previously raised related ethical concerns. Looking next at anticipated scientific developments in brain organoid research, we will discuss (i) ethical issues related to in vitro brain organoids, (ii) ethical issues raised when brain organoids form complexes or have relationships with other entities, and (iii) ethical issues of research ethics and governance. Finally, in pursuit of (2), we propose research policies that are mindful of the ethics of brain organoid research and application and also suggest the need for an international framework for research and application of brain organoids.

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