Thrombomodulin (TM) is an important regulator of intravascular blood coagulation and inflammation. TM inhibits the procoagulant and proinflammatory activities of thrombin and promotes the thrombin-induced activation of protein C (PC) bound to the endothelial PC receptor (EPCR). Activated PC (APC) inactivates coagulation factors Va and VIIIa, thereby inhibiting blood clotting. Additionally, APC bound to EPCR exerts anti-inflammatory and cytoprotective effects on vascular endothelial cells. TM also protects cells in blood vessels from inflammation caused by pathogen-associated and damaged cell-associated molecules. Excessive anticoagulant, anti-inflammatory, and tissue regenerative effects in the TM-PC pathway are controlled by PC inhibitor. A recombinant TM drug (TMα), a soluble form of natural TM developed from the cloned human TM gene, has been evaluated for efficacy in many clinical trials and approved as a treatment for disseminated intravascular coagulation (DIC) caused by diseases such as sepsis, solid tumors, hematopoietic tumors, and trauma. It is currently widely used to treat DIC in Japan.

Chloroplasts are photosynthetic organelles that evolved through the endosymbiosis between cyanobacteria-like symbionts and hosts. Many studies have attempted to isolate intact chloroplasts to analyze their morphological characteristics and photosynthetic activity. Although several studies introduced isolated chloroplasts into the cells of different species, their photosynthetic activities have not been confirmed. In this study, we isolated photosynthetically active chloroplasts from the primitive red alga Cyanidioschyzon merolae and incorporated them in cultured mammalian cells via co-cultivation. The incorporated chloroplasts retained their thylakoid structure in intracellular vesicles and were maintained in the cytoplasm, surrounded by the mitochondria near the nucleus. Moreover, the incorporated chloroplasts maintained electron transport activity of photosystem II in cultured mammalian cells for at least 2 days after the incorporation. Our top-down synthetic biology-based approach may serve as a foundation for creating artificially photosynthetic animal cells.

Nonhuman primates, particularly macaque and marmoset monkeys, serve as invaluable models for studying complex brain functions and behavior. However, the lack of suitable genetic neuromodulation tools has constrained research at the network level. This review examines the application of a chemogenetic technology, specifically, designer receptors exclusively activated by designer drugs (DREADDs), to nonhuman primates. DREADDs offer a means of reversibly controlling neuronal activity within a specific cell type or neural pathway, effectively targeting multiple brain regions simultaneously. The combination of DREADDs with imaging techniques, such as positron emission tomography and magnetic resonance imaging, has significantly enhanced nonhuman primate research, facilitating the precise visualization and manipulation of specific brain circuits and enabling the detailed monitoring of changes in network activity, which can then be correlated with altered behavior. This review outlines these technological advances and considers their potential for enhancing our understanding of primate brain circuit function and developing novel therapeutic approaches for treating brain diseases.

In 1929, Matuyama published his paper on the magnetization of mostly Quaternary volcanic rocks. In this paper, he described the results of paleomagnetic measurements of volcanic rocks from Japan and nearby areas and concluded that the latest transition of the magnetic field from reversed to normal state occurred in the early Quaternary. In the 1960s, two groups of scientists from the USA and Australia quite vigorously conducted studies of both magnetization and age of volcanic rocks. By about 1966, they completed the reversal timescale for the last 4 million years, which was to become the basis for many earth science studies. For easy reference, they suggested to call the most recent normal or reversed periods as Brunhes, Matuyama, Gauss, and Gilbert polarity epochs, with the names taken from the scientists who made very important contributions to paleomagnetism. Chron is now the official term for the epoch, and each chron is specified by a combination of a number and a character showing the polarity. However, the names of polarity epochs were already so popular that they are still quite frequently used in scientific papers. The Matuyama epoch is between 0.773 and 2.595 million years before present. Moreover, its lower limit is now used to define the start of the Quaternary.

Y. Goto and M. Kakizaki produced a rat model of non-insulin dependent diabetes mellitus (NIDDM) by repetitive selective breeding of rats with slightly impaired glucose tolerance. In contrast to most obese diabetes models, which were genetically modified animals created by inducing a gene mutation, this rat was a unique model because it was a spontaneous diabetes model created by selective breeding. Furthermore, when it became clear that this rat was a non-obese diabetic model that exhibited hyperglycemia due to a decrease in insulin secretion capacity, it was recognized as a valuable model for elucidating non-obese, hypoinsulinemic diabetes commonly seen in East Asians. Diabetes is becoming an important health problem worldwide, especially in the East Asian region, thus Goto-Kakizaki (GK) rats are becoming increasingly important as a model of non-insulin dependent diabetes mellitus.

Cell proliferation is a fundamental characteristic of organisms, driven by the holistic functions of multiple proteins encoded in the genome. However, the individual contributions of thousands of genes and the millions of protein molecules they express to cell proliferation are still not fully understood, even in simple eukaryotes. Here, we present a genome-wide translation map of cells during proliferation in the unicellular alga Cyanidioschyzon merolae, based on the sequencing of ribosome-protected messenger RNA fragments. Ribosome profiling has revealed both qualitative and quantitative changes in protein translation for each gene during cell division, driven by the large-scale reallocation of ribosomes. Comparisons of ribosome footprints from non-dividing and dividing cells allowed the identification of proteins involved in cell proliferation. Given that in vivo experiments on two selected candidate proteins identified a division-phase-specific mitochondrial nucleoid protein and a mitochondrial division protein, further analysis of the candidate proteins may offer key insights into the comprehensive mechanism that facilitate cell and organelle proliferation.

Calcium ions (Ca) play critical roles in various biological phenomena. The free Ca concentration in the cytoplasm of a resting cell is at the 10 M level, whereas that outside the cell is 10 M, creating a 10,000-fold gradient of Ca concentrations across the cell membrane, separating the intracellular and extracellular solutions. When a cell is activated by external stimuli, the intracellular Ca concentration increases to levels of 10-10 M through Ca entry from the extracellular solution via plasma membrane Ca channels and/or Ca release from intracellular stores. This transient increase in Ca functions as an important signal mediated by Ca sensors. Thus, Ca signals are transmitted to intracellular loci such as distinct, localized targets of Ca sensors. Among numerous Ca sensors present in cells, calmodulin is a highly conserved and ubiquitous Ca sensor..

In 1935, Shiro Akabori began research on the preparation of taka-amylase A with a purity suitable for chemical research, with the intention of elucidating the chemical nature of the enzyme. He succeeded in developing a method to efficiently obtain crystallized taka-amylase A from Aspergillus oryzae. Using crystallized taka-amylase A as the starting material, a series of studies were conducted to determine its amino acid composition and sequence, sugar chain structure, and three-dimensional structure. Based on these results, the molecular structure and catalytic mechanism of taka-amylase A were elucidated. The scientific achievements from research on taka-amylase A significantly enhanced Japan's capabilities in protein research, represented by the fact that taka-amylase A was the first amylase in the world for which both chemical and crystallographic structures were elucidated.

In the world history of cancer research, three achievements in Japan were groundbreaking. First, in 1915, Katsusaburo Yamagiwa and Koichi Ichikawa induced skin cancer on the ears of rabbits by the repeated application of coal tar. This achievement was the world's first generation of artificial cancers in experimental animals. Second, in 1932, Takaoki Sasaki and Tomizo Yoshida observed liver cancer in rats fed on rice inoculated with ortho(o)-aminoazotoluene. This achievement was the first ever artificial cancer in the internal organs of experimental animals. Third, in 1967, Takashi Sugimura gave N-methyl-N'-nitro-N-nitrosoguanidine, a known chemical mutagen, to mice in drinking water and induced stomach cancer. This achievement was the first artificial production of stomach cancer and provided experimental evidence that cancer is a disease originated from DNA abnormalies. In commemoration of the publication of the 100th volume of the Proceedings of Japan Academy, Series B, from articles previously published in the Proceedings, two papers related to the achievements of Takaoki Sasaki have been selected and republished with this article.

Biomimetic molecular designs can yield superior biomaterials. Polymers with a phosphorylcholine group, a polar group of phospholipid molecules, are particularly interesting. A methacrylate monomer, 2-methacryloyloxyethyl phosphorylcholine (MPC), was developed using efficient synthetic reactions and purification techniques. This process has been applied in industrial production to supply MPC globally. Polymers with various structures can be readily synthesized using MPC and their properties have been studied. The MPC polymer surface has a highly hydrated structure in biological conditions, leading to the prevention of adsorption of proteins and lipid molecules, adhesion of cells, and inhibition of bacterial adhesion and biofilm formation. Additionally, it provides an extremely lubricious surface. MPC polymers are used in various applications and can be stably immobilized on material surfaces such as metals and ceramics and polymers such as elastomers. They are also stable under sterilization and in vivo conditions. This makes them ideal for application in the surface treatment of various medical devices, including artificial organs, implanted in humans.

Λ = Λ(1405) plays an essential role in the formation of kaonic nuclear clusters (KNC). The simplest KNC, Kpp, has the structure Λp = (Kp)p, in which a real kaon migrates between two nucleons, mediating super-strong Λp attraction. Production data of Kpp have been accumulated by DISTO, J-PARC E27 and J-PARC E15 experiments. For KKpp the attractive covalent bond of ΛΛ is doubly enhanced compared to the Λp one. Consequently, Λ multiplet, (Λ), with m(m－1)/2 bonds becomes more stable than its corresponding neutron aggregate, (n), at m = 8－12, suggesting the possible existence of stable Λ matter. A long-lived strangelet of (Λ) is presumed as a precursor. The production of KKpp by high-energy pp or heavy-ion collisions is awaited as a doorway to so-far unknown Λ matter.

Herein, the first English article demonstrating the Yagi-Uda antenna is introduced. The article was originally published in the Proceedings of the Imperial Academy of Japan in 1926.

The formation of autophagosomes is a pivotal step in autophagy, a lysosomal degradation system that plays a crucial role in maintaining cellular homeostasis. After autophagy induction, phase separation of the autophagy-related (Atg) 1 complex occurs, facilitating the gathering of Atg proteins and organizes the autophagosome formation site, where the initial isolation membrane (IM)/phagophore is generated. The IM then expands after receiving phospholipids from endomembranes such as the endoplasmic reticulum. This process is driven by the collaboration of lipid transfer (Atg2) and scrambling (Atg9) proteins. The IM assumes a cup shaped morphology and undergoes closure, resulting in the formation of a double membrane-bound autophagosome. The Atg8 lipidation system is hypothesized to be a pivotal factor in this process. This review presents an overview of the current understanding of these processes and discusses the basic mechanisms of autophagosome formation.

This review describes the development of evolutionary studies of sex based on the volvocine lineage of green algae, which was facilitated by whole-genome analyses of both model and non-model species. Volvocine algae, which include Chlamydomonas and Volvox species, have long been considered a model group for experimental studies investigating the evolution of sex. Thus, whole-genomic information on the sex-determining regions of volvocine algal sex chromosomes has been sought to elucidate the molecular genetic basis of sex evolution. By 2010, whole genomes were published for two model species in this group, Chlamydomonas reinhardtii and Volvox carteri. Recent improvements in sequencing technology, particularly next-generation sequencing, allowed our studies to obtain complete genomes for non-model, but evolutionary important, volvocine algal species. These genomes have provided critical details about sex-determining regions that will contribute to our understanding of the diversity and evolution of sex.

Lifestyle, especially diet, significantly impacts cancer development. Sugimura, T. et al. discovered that grilled fish smoke and charred parts are highly mutagenic in Salmonella typhimurium. They identified two novel mutagenic heterocyclic amines (HCAs), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and its derivative, Trp-P-2, from tryptophan pyrolysate. Published in Proc. Jpn. Acad. (53, 58-61, 1977), their findings initiated the identification of over 10 mutagenic HCAs in cooked foods, most of them newly registered. These 10 HCAs were demonstrated to induce cancers in organs including the liver, colon, breast, and prostate in mice and rats. HCAs are metabolized primarily by CYP1A2 to hydroxyamino derivatives. Their ester forms then adduct at guanine bases, altering genes such as Apc and β-catenin. Quantification of HCAs in cooked foods and human samples, along with epidemiological observations, suggests HCAs likely contribute to human cancers.

K. Shibata is the ancestor of the research on anthocyanins in Japan and proposed metal complex theory against the pH theory by R. Willstätter. Shibata's successors, S. Hattori and K. Hayashi, made efforts to clarify blue flower coloration by metal complexation and found commelinin, a self-assembled supramolecular metal complex pigment, in blue dayflower, Tsuyukusa. The author introduces two key reports on blue flower coloration published in the Proceedings of the Japan Academy and describes the subsequent development of the study.

Flavonoids, such as quercetin and kaempferol, and their glycosides, are widely distributed in vegetables and fruits. Sugimura, T. et al. investigated the mutagenicity of flavone derivatives, and found that quercetin and kaempferol showed high mutagenic activities in Salmonella typhimurium TA98 with S9 mix, comparable to that of the typical carcinogen, benzo[a]pyrene. These novel findings were published in Proc. Jpn. Acad. Ser. B 53, 194-197, 1977. Other research groups also reported the mutagenic properties of flavone derivatives in S. typhimurium strains. These observations led to the commencement of long-term animal carcinogenesis experiments involving quercetin. A USA-Turkey joint study reported that feeding rats with 0.1% quercetin in the diet produced carcinomas. However, Japanese scientists showed no carcinogenicity with quercetin in rats, mice, or hamsters, even at 10% in the diet. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Quercetin in F344/N Rats concluded that there was no evidence of its carcinogenic activity. Therefore, the potential risk of quercetin in human cancers is likely to be negligible. These flavonoid issues provided a warning regarding the simplistic understanding that mutagens are carcinogens, and microbial tests alone are inadequate for safety assessment; therefore, and a battery of tests for genotoxicity is recommended. Thus, the informative report in 1977 made significant contributions to initiating and promoting genotoxicity studies of flavonoids.

Regulation of membrane protein integration involves molecular devices such as Sec-translocons or the insertase YidC. We have identified an integration-promoting factor in the inner membrane of Escherichia coli called membrane protein integrase (MPIase). Structural analysis revealed that, despite its enzyme-like name, MPIase is a glycolipid with a long glycan comprising N-acetyl amino sugars, a pyrophosphate linker, and a diacylglycerol (DAG) anchor. Additionally, we found that DAG, a minor membrane component, blocks spontaneous integration. In this review, we demonstrate how they contribute to Sec-independent membrane protein integration in bacteria using a comprehensive approach including synthetic chemistry and biophysical analyses. DAG blocks unfavorable spontaneous integrations by suppressing mobility in the membrane core, whereas MPIase compensates for this. Moreover, MPIase plays critical roles in capturing a substrate protein to prevent its aggregation, attracting it to the membrane surface, facilitating its insertion into the membrane, and delivering it to other factors. The combination of DAG and MPIase efficiently regulates the integration of membrane proteins.

Neural circuits are initially created with excessive synapse formation until around birth and undergo massive reorganization until they mature. During postnatal development, necessary synapses strengthen and remain, whereas unnecessary ones are weakened and eventually eliminated. These events, collectively called "synapse elimination" or "synapse pruning", are thought to be fundamental for creating functionally mature neural circuits in adult animals. In the cerebellum of neonatal rodents, Purkinje cells (PCs) receive synaptic inputs from multiple climbing fibers (CFs). Then, inputs from a single CF are strengthened and those from the other CFs are eliminated, and most PCs become innervated by single CFs by the end of the third postnatal week. These events are regarded as a representative model of synapse elimination. This review examines the molecular and cellular mechanisms of CF synapse elimination in the developing cerebellum and argues how autism spectrum disorder (ASD)-related genes are involved in CF synapse development. We introduce recent studies to update our knowledge, incorporate new data into the known scheme, and discuss the remaining issues and future directions.

Catalase, a heme-containing antioxidant enzyme, was once considered essential for human survival. It is widely distributed in the human body and is particularly abundant in red blood cells. The term "acatalasemia" first appeared in the Proceedings of the Japan Academy in 1951, drawing global attention to families genetically deficient in catalase. This deficiency not only altered the significance of catalase but also played a pioneering role in human genetics during an era of limited genetic methodology. In this article, we examine the discovery of acatalasemia by an otolaryngologist during surgery on an 11-year-old girl. This remarkable journey led to epoch-making research spanning biochemistry, hematology, and human genetics.

This review outlines research on chemical biology using mainly microbial metabolites for agricultural applications. We established the RIKEN Natural Products Depository (NPDepo), housing many microbial metabolites, to support academic researchers who focus on drug discovery. We studied methods to stimulate secondary metabolism in microorganisms to collect various microbial products. The switch of secondary metabolism in microorganisms changes depending on the culture conditions. We discovered compounds that activate biosynthetic gene clusters in actinomycetes and filamentous fungi. Using these compounds, we succeeded in inducing the production of active compounds. Two approaches for screening bioactive compounds are described. One is phenotypic screening to explore antifungal compounds assisted by artificial intelligence (AI). AI can distinguish the morphological changes induced by antifungal compounds in filamentous fungi. The other is the chemical array method for detecting interactions between compounds and target proteins. Our chemical biology approach yielded many new compounds as fungicide candidates.