Proceedings of the Japan Academy. Series B, Physical and Biological Sciences最新文献

Structural studies of natural products have been a driving force in the development of organic chemistry throughout its long history, especially in the early years. Recently, structure determination based on new concepts has also gained momentum. In this review we will mainly discuss the functional structures of natural products that account for the mechanisms of action largely from our studies. The topics include marine natural products, amphidinols, and ladder-shaped polyether compounds, which are known as potent antifungal agents and important marine biotoxins, respectively. Nuclear magnetic resonance studies for determining the stereochemistry of amphidinol 3 and its conformation in lipid-bilayer membranes will be presented in detail.

In Japan, serious food poisoning among individuals who took supplement tablets for lowering plasma cholesterol levels have been publicized since late March 2024. The tablets were prepared from red yeast rice (RYR), a product of Monascus pilosus. Puberulic acid (PA) was detected as an unexpected compound in tablets that caused food poisoning. We conducted an on-site investigation at the RYR production factory to determine the cause of PA contamination of the tablets. Fungi capable of producing PA were detected in wipe samples from the factory and were identified as Penicillium adametzioides. To understand the route through which P. adametzioides contaminated RYR and produced PA, coculture experiments with M. pilosus and P. adametzioides were performed. P. adametzioides grew on rice covered with M. pilosus and produced PA. These results suggest that PA-producing P. adametzioides inhabited the RYR production factory and accidently contaminated the culture of M. pilosus. Consequently, RYR tablets contaminated with PA were manufactured and caused the food poisoning outbreak.

Enhancing the thermostability of cellulose-degrading enzymes is pivotal for establishing an efficient bioconversion system from cellulosic materials to value-added compounds. Here, by introducing random and saturation mutagenesis into the Thermoascus aurantiacus β-glucosidase gene, we generated a hyperthermostable mutant with five amino acid substitutions. Analysis of temperature-induced unfolding revealed the involvement of each replacement in the increased T_m value. Structural analysis showed that all replacements are located at the periphery of the catalytic pocket. D433N replacement, which had a pronounced thermostabilizing effect (ΔT_m ＝ 4.5°C), introduced an additional hydrogen bond with a backbone carbonyl oxygen in a long loop structure. The mutant enzyme expressed in Kluyveromyces marxianus exhibited a T_m of 82°C and hydrolyzed cellobiose with k_cat and K_m values of 200 s^－1 and 1.8 mM, respectively. When combined with a thermostable endoglucanase, the mutant enzyme released 20％ more glucose than wild-type enzyme from cellulosic material. The mutant enzyme is therefore a noteworthy addition to the existing repertoire of thermostable β-glucosidases.

Thrombomodulin (TM) is an important regulator of intravascular blood coagulation, fibrinolysis, 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. APC bound to EPCR exerts anti-inflammatory and cytoprotective effects on vascular endothelial cells. TM promotes the activation of thrombin-activatable fibrinolysis inhibitor, and also protects cells in blood vessels from inflammation caused by pathogen-associated and damaged cell-associated molecules. Excessive anticoagulant, fibrinolytic, anti-inflammatory, and tissue regenerative effects in the TM-PC pathway are controlled by PC inhibitor. A recombinant TM drug (TM), 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.

Evapotranspiration is a critical factor that plays a pivotal role in irrigation and water resource planning. It is also a major influence with regard to global warming issues. Therefore, several studies have been performed on the estimation methods for evapotranspiration; however, the most prevalent method used over a long period to estimate evapotranspiration is the complementary relationship approach. Recently, this method was modified to improve its symmetry and accuracy. However, to achieve better performance, a different evapotranspiration estimation method using an inverse analysis of the Bowen ratio was proposed by us in an earlier study. In order to present a performance comparison of these different estimation methods, the reproducibility of three types of complementary relationship methods and inverse analysis methods was assessed in this study. Our study utilized data from FLUXNET2015 and evaluated the performance of the methods using regression analysis and root mean square error (RMSE) with data from 15 test sites, mainly located in the U.S.A., for a total period of 132 years. From the results, it was observed that the inverse analysis approach demonstrated a slightly better performance than the complementary relationship methods. This study provides a valuable direction for future research works on the estimation of evapotranspiration.

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.

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 article is an explanatory review on a study of licorice stored in Shosoin Repository reported in this journal by Dr. Shoji Shibata in 2003 (Proc. Jpn. Acad. Ser. B 79, 176-180). The study using new technologies at that time for identification of plant species was a follow-up research of his own study performed half a century before. The study revised previous results and elucidated that the licorice stored in Shosoin Repository was derived from Glycyeehiza uralensis.

Over the past decades, the understanding of sleep has evolved to be a fundamental physiological mechanism integral to the processing of different types of memory rather than just being a passive brain state. The cyclic sleep substates, namely, rapid eye movement (REM) sleep and non-REM (NREM) sleep, exhibit distinct yet complementary oscillatory patterns that form inter-regional networks between different brain regions crucial to learning, memory consolidation, and memory retrieval. Technical advancements in imaging and manipulation approaches have provided deeper understanding of memory formation processes on multi-scales including brain-wide, synaptic, and molecular levels. The present review provides a short background and outlines the current state of research and future perspectives in understanding the role of sleep and its substates in memory processing from both humans and rodents, with a focus on cross-regional brain communication, oscillation coupling, offline reactivations, and engram studies. Moreover, we briefly discuss how sleep contributes to other higher-order cognitive functions.

Tissue-resident macrophages perform indispensable functions in the development, maintenance, and repair of tissues. Microglia are the primary resident immune cells in the central nervous system (CNS), functioning as intracerebral macrophages distributed throughout the brain parenchyma. In addition to microglia, there is another, less well-characterized type of macrophage known as CNS border-associated macrophages (CAMs), and the existence of these cells has been recognized for several decades. With recent advances in research technologies, an increasing number of studies have focused on CAMs, and our understanding of them has begun to improve. In this article, we review the cellular characteristics and functions of CAMs that have been elucidated thus far, with a particular focus on the similarities and differences between CAMs and microglia.