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Abstract Age-related macular degeneration (AMD) is a major cause of vision loss among adults. We investigated the protective effects of passion fruit seed extract (PFSE) and its rich polyphenol piceatannol in an AMD cell model in which human retinal pigment epithelial ARPE-19 cells were exposed to hydrogen peroxide (H2O2). Using a cell viability WST-8 assay, we revealed that PFSE and piceatannol increased the cellular viability of ARPE-19 cells by 130% and 133%, respectively. Moreover, PFSE and piceatannol recovered the cell viability of ARPE-19 cells, which had decreased to 60% owing to H2O2-induced damage, to approximately 84% and 89%, respectively. In addition, we found that the treatment of ARPE-19 cells with H2O2 decreased the mitochondrial and glycolytic ATP production rate to approximately 54% that of healthy control ARPE-19 cells using a Seahorse extracellular flux analyzer. Furthermore, pretreatment with PFSE and piceatannol restored the oxidative stress-induced decrease in the mitochondrial and glycolytic ATP production rate to approximately 97% and 82%, respectively. These results indicated the cytoprotective effects of PFSE and piceatannol against oxidative stress in human ARPE-19 cells by resolving the dysfunction of mitochondrial and glycolytic energy metabolism.

Abstract When someone violates a social norm, others may think that some sanction would be appropriate. We examine how the experience of emotions like anger and disgust relate to the judged appropriateness of sanctions, in a pre-registered analysis of data from a large-scale study in 56 societies. Across the world, we find that individuals who experience anger and disgust over a norm violation are more likely to endorse confrontation, ostracism and, to a smaller extent, gossip. Moreover, we find that the experience of anger is consistently the strongest predictor of judgments of confrontation, compared to other emotions. Although the link between state-based emotions and judgments may seem universal, its strength varies across countries. Aligned with theoretical predictions, this link is stronger in societies, and among individuals, that place higher value on individual autonomy. Thus, autonomy values may increase the role that emotions play in guiding judgments of social sanctions.

Abstract 3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) is a metabolite produced by the gut microbiota through the conversion of 4-hydroxy-3-methoxycinnamic acid (HMCA), which is a widely distributed hydroxycinnamic acid-derived metabolite found abundantly in plants. Several beneficial effects of HMPA have been suggested, such as antidiabetic properties, anticancer activities, and cognitive function improvement, in animal models and human studies. However, the intricate molecular mechanisms underlying the bioaccessibility and bioavailability profile following HMPA intake and the substantial modulation of metabolic homeostasis by HMPA require further elucidation. In this study, we effectively identified and characterized HMPA-specific GPR41 receptor, with greater affinity than HMCA. The activation of this receptor plays a crucial role in the anti-obesity effects and improvement of hepatic steatosis by stimulating the lipid catabolism pathway. For the improvement of metabolic disorders, our results provide insights into the development of functional foods, including HMPA, and preventive pharmaceuticals targeting GPR41.

Abstract Osteosarcoma is rare but is the most common bone tumor. Diagnostic tools such as magnetic resonance imaging development of chemotherapeutic agents have increased the survival rate in osteosarcoma patients, although 5-year survival has plateaued at 70%. Thus, development of new treatment approaches is needed. Here, we report that IL-17, a proinflammatory cytokine, increases osteosarcoma mortality in a mouse model with AX osteosarcoma cells. AX cell transplantation into wild-type mice resulted in 100% mortality due to ectopic ossification and multi-organ metastasis. However, AX cell transplantation into IL-17-deficient mice significantly prolonged survival relative to controls. CD4-positive cells adjacent to osteosarcoma cells express IL-17, while osteosarcoma cells express the IL-17 receptor IL-17RA. Although AX cells can undergo osteoblast differentiation, as can patient osteosarcoma cells, IL-17 significantly inhibited that differentiation, indicating that IL-17 maintains AX cells in the undifferentiated state seen in malignant tumors. By contrast, IL-17RA-deficient mice transplanted with AX cells showed survival comparable to wild-type mice transplanted with AX cells. Biopsy specimens collected from osteosarcoma patients showed higher expression of IL-17RA compared to IL-17. These findings suggest that IL-17 is essential to maintain osteosarcoma cells in an undifferentiated state and could be a therapeutic target for suppressing tumorigenesis.

Abstract During progression of knee osteoarthritis (OA), gait biomechanics changes three-dimensionally; however, its characteristics and trunk posture according to OA severity remain unknown. The present study investigated three-dimensional knee joint biomechanics and trunk posture according to knee OA severity. Overall, 75 patients (93 knees) with medial knee OA [Kellgren-Lawrence grade ≥ 2, grade 2: 20 patients with 24 knees (mean 60.0 years old); grade 3: 25 with 28 knees (mean 62.0 years old); grade 4: 30 with 41 knees (mean 67.9 years old)] and 14 healthy controls (23 knees, mean 63.6 years old) underwent gait analysis using an optical motion capture system and point cluster technique. In grade 2 knee OA, the relative contribution of the knee adduction moment (KAM) increased significantly (P

Abstract Lumbar spinal stenosis (LSS) is a degenerative disease characterized by intermittent claudication and numbness in the lower extremities. These symptoms are caused by the compression of nerve tissue in the lumbar spinal canal. Ligamentum flavum (LF) hypertrophy and spinal epidural lipomatosis in the spinal canal are known to contribute to stenosis of the spinal canal: however, detailed mechanisms underlying LSS are still not fully understood. Here, we show that surgically harvested LFs from LSS patients exhibited significantly increased thickness when transthyretin (TTR), the protein responsible for amyloidosis, was deposited in LFs, compared to those without TTR deposition. Multiple regression analysis, which considered age and BMI, revealed a significant association between LF hypertrophy and TTR deposition in LFs. Moreover, TTR deposition in LF was also significantly correlated with epidural fat (EF) thickness based on multiple regression analyses. Mesenchymal cell differentiation into adipocytes was significantly stimulated by TTR in vitro. These results suggest that TTR deposition in LFs is significantly associated with increased LF hypertrophy and EF thickness, and that TTR promotes adipogenesis of mesenchymal cells. Therapeutic agents to prevent TTR deposition in tissues are currently available or under development, and targeting TTR could be a potential therapeutic approach to inhibit LSS development and progression.

Stomata-small pores generally found on the leaves of plants-control gas exchange between plant and the atmosphere. Elucidating the mechanism that underlies such control through the regulation of stomatal opening/closing is important to understand how plants regulate photosynthesis and tolerate against drought. However, up-to-date, molecular components and their function involved in stomatal regulation are not fully understood. We challenged such problem through a chemical genetic approach by isolating and characterizing synthetic molecules that influence stomatal movement. Here, we describe that a small chemical collection, prepared during the development of C-H amination reactions, lead to the discovery of a Stomata Influencing Molecule (SIM); namely, a sulfonimidated oxazole that inhibits stomatal opening. The starting molecule SIM1 was initially isolated from screening of compounds that inhibit light induced opening of dayflower stomata. A range of SIM molecules were rapidly accessed using our state-of-the-art C-H amination technologies. This enabled an efficient structure-activity relationship (SAR) study, culminating in the discovery of a sulfonamidated oxazole derivative (SIM*) having higher activity and enhanced specificity against stomatal regulation. Biological assay results have shed some light on the mode of action of SIM molecules within the cell, which may ultimately lead to drought tolerance-conferring agrochemicals through the control of stomatal movement.

Abstract We designed and developed two new types of hydrogen fuel cell (HFC) buses (motorcoach and minibus) with a mobile laboratory system. Feasibility studies have been performed for mobile laboratory testing, particularly for the laboratory performance of COVID-19 RT-PCR (PCR). We evaluated the driving range capability, PCR sample size capacity, turnaround time (TAT), and analytical performance for the detection of SARS-CoV-2. Saliva samples were used for the current study, and the analytical performance was compared with that of the reference PCR. The estimated driving range and sample size capacity of the HFC and HFC minibus were 432 km and 2847 samples, respectively, for the HFC motorcoach and 313 km and 1949 samples for the HFC minibus. For the TAT, the median time between sample submission and completion of PCR was 86 min for the motorcoach and 76 min for the minibus, and the median time between sample submission and electronic reporting of the result to each visitor was 182 min for the motorcoach and 194 min for the minibus. A secondary analysis of 1574 HFC mobile laboratory testing samples was conducted, and all negative samples were found to be negative by reference PCR. Furthermore, all samples were confirmed to be positive by reference PCR or other molecular examinations.

Abstract To examine the association between hip fracture and associated factors, including polypharmacy, and develop an optimal predictive model, we conducted a population-based matched case–control study using the health insurance claims data on hip fracture among Japanese patients. We included 34,717 hospitalized Japanese patients aged ≥ 65 years with hip fracture and 34,717 age- and sex- matched controls who were matched 1:1. This study included 69,434 participants. Overall, 16 variable comorbidities and 60 variable concomitant medications were used as explanatory variables. The participants were added to early elderly and late elderly categories for further analysis. The odds ratio of hip fracture increased with the number of medications only in the early elderly. AUC was highest for early elderly (AUC, 0.74, 95% CI 0.72–0.76). Use of anti-Parkinson’s drugs had the largest coefficient and was the most influential variable in many categories. This study confirmed the association between risk factors, including polypharmacy and hip fracture. The risk of hip fracture increased with an increase in medication number taken by the early elderly and showed good predictive accuracy, whereas there was no such association in the late elderly. Therefore, the early elderly in Japan should be an active target population for hip fracture prevention.

Abstract Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve heart failure (HF) outcomes across a range of patient characteristics. A hypothesis that SGLT2i induce metabolic change similar to fasting has recently been proposed to explain their profound clinical benefits. However, it remains unclear whether SGLT2i primarily induce this change in physiological settings. Here, we demonstrate that empagliflozin administration under ad libitum feeding did not cause weight loss but did increase transcripts of the key nutrient sensors, AMP-activated protein kinase and nicotinamide phosphoribosyltransferase, and the master regulator of mitochondrial gene expression, PGC-1α, in quadriceps muscle in healthy mice. Expression of these genes correlated with that of PPARα and PPARδ target genes related to mitochondrial metabolism and oxidative stress response, and also correlated with serum ketone body β-hydroxybutyrate. These results were not observed in the heart. Collectively, this study revealed that empagliflozin activates transcriptional programs critical for sensing and adaptation to nutrient availability intrinsic to skeletal muscle rather than the heart even in normocaloric condition. As activation of PGC-1α is sufficient for metabolic switch from fatigable, glycolytic metabolism toward fatigue-resistant, oxidative mechanism in skeletal muscle myofibers, our findings may partly explain the improvement of exercise tolerance in patients with HF receiving empagliflozin.

Abstract The Kuroshio Extension (KE) flows eastward at the northern boundary of the North Pacific subtropical gyre. By transporting large amounts of seawater with heat, the KE contributes significantly to the formation of sea surface temperature (SST) fields. Recently, poleward shifts of major ocean gyres in the world ocean, including the North Pacific subtropical gyre, have been highlighted based on basin-scale changes in SST and sea surface height (SSH) distributions. However, a detailed investigation of the long-term meridional KE movement has not been presented. Investigation of KE path changes helps provide insights into long-term changes in the physical fields in the western North Pacific. In this study, we identified the KE path from satellite-derived SSH and surface current velocity data using a front identification method and showed that the KE migrated northward by approximately 210 km during 1993–2021. We further explored the cause of the northward KE shift based on atmospheric reanalysis data and numerical experiments using a high-resolution ocean general circulation model. It was revealed that the northward KE shift is mostly caused by the trend of wind stress curl in the North Pacific during 1993–2021.

Abstract Optimal conditions for wound healing require a smooth transition from the early stage of inflammation to proliferation, and during this time alternatively activated (M2) macrophages play a central role. Recently, heat-killed lactic acid bacteria (LAB), such as Lactobacillus plantarum (L. plantarum) have been reported as possible modulators affecting the immune responses in wound healing. However, how signaling molecules regulate this process after the administration of heat-killed LAB remains unclear. In this study, we examined the effect of heat-killed L. plantarum KB131 (KB131) administration on wound healing and the contribution of CARD9, which is an essential signaling adaptor molecule for NF-kB activation upon triggering through C-type lectin receptors, in the effects of this bacterium. We analyzed wound closure, histological findings, and inflammatory responses. We found that administration of KB131 accelerated wound closure, re-epithelialization, granulation area, CD31-positive vessels, and α-SMA-positive myofibroblast accumulated area, as well as the local infiltration of leukocytes. In particular, M2 macrophages were increased, in parallel with CCL5 synthesis. The acceleration of wound healing responses by KB131 was canceled in CARD9-knockout mice. These results indicate that the topical administration of KB131 accelerates wound healing, accompanying increased M2 macrophages, which suggests that CARD9 may be involved in these responses.

Abstract Iron availability limits marine ecosystem activities in large areas of the ocean. However, the sources and seasonal supply of iron, critically important for controlling surface ocean biogeochemistry and carbon cycling, are poorly understood. The western subarctic Pacific is a high-nutrient and low-chlorophyll region, and despite high concentrations of macronutrients, iron limits phytoplankton production in summer. Here, we determine the seasonal deposition flux of Asian dust using scanning electron microscope–cathodoluminescence analysis of single quartz particles derived from the western subarctic Pacific during 2003–2022 to trace provenance. We found a high (up to 6.9 mg m−2 day−1) deposition flux of Asian dust in May, June, and early July, with an annual average of 1.0 ± 0.2 mg m−2 day−1. The supply of dissolved-iron flux calculated from Asian dust was 0.9 ± 0.3 µg m−2 day−1 during the high productivity season (April–July), which is approximately half that from the deeper part of the ocean, calculated from vertical profiles of dissolved iron. Our study provides a reliable approach for estimating iron supply from dust to the surface ocean that may be critical for sustaining biological productivity under future ocean stratification, which suppresses nutrient supply from the subsurface ocean.

Abstract Cusp-shaped fluctuations of the sea surface temperature (SST) front in the tropical Pacific, now known as tropical instability waves (TIWs), were discovered by remote sensing in the 1970s. Their discovery was followed by both theoretical and analytical studies, which, along with in situ observations, identified several possible generation mechanisms. Although modeling studies have shown that TIWs strongly influence the heat budget, their influence on local variations of realistically initialized predictions is not yet understood. We here evaluate a series of medium-range (up to ~ 10 days) coupled atmosphere–ocean predictions by a coupled model with different horizontal resolutions. Observational SST, surface wind stress, heat flux, and pressure data showed that representation of temporally and spatially local variations was improved by resolving fine-scale SST variations around the initialized coarse-scale SST front fluctuations of TIWs. Our study thus demonstrates the advantage of using high-resolution coupled models for medium-range predictions. In addition, analysis of TIW energetics showed two dominant sources of energy to anticyclonic eddies: barotropic instability between equatorial zonal currents and baroclinic instability due to intense density fronts. In turn, the eddy circulation strengthened both instabilities in the resolved simulations. This revealed feedback process refines our understanding of the generation mechanisms of TIWs.

Abstract In recent years, computer simulation has been increasingly used to predict changes in actual ecosystems. In these studies, snapshots of ecosystems at certain points in time were instantly constructed without considering their evolutionary histories. However, it may not be possible to correctly predict future events unless their evolutionary processes are considered. In this study, we developed a new ecosystem model for reproducing the evolutionary process on an oceanic island, targeting Nakoudojima Island of the Ogasawara Islands. This model successfully reproduced the primitive ecosystem (the entire island covered with forest) prior to the invasion of alien species. Also, by adding multiple alien species to this ecosystem, we were able to reproduce temporal changes in the ecosystem of Nakoudojima Island after invasion of alien species. Then, we performed simulations in which feral goats were eradicated, as had actually been done on the island; these suggested that after the eradication of feral goats, forests were unlikely to be restored. In the ecosystems in which forests were not restored, arboreous plants with a high growth rate colonized during the early stage of evolution. As arboreous plants with a high growth rate consume a large amount of nutrient in soil, creating an oligotrophic state. As a result, plants cannot grow, and animal species that rely on plants cannot maintain their biomass. Consequently, many animals and plants become extinct as they cannot endure disturbances by alien species, and the ecosystem loses its resilience. Therefore, even if feral goats are eradicated, forests are not restored. Thus, the founder effect from the distant past influences future ecosystem changes. Our findings show that it is useful to consider the evolutionary process of an ecosystem in predicting its future events.

Abstract All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8+ T cell depletion antagonized ATRA’s anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA’s anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice—a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4+ T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4+ more than CD8+ T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers.

Abstract Multi-wavelength visible light emitters play a crucial role in current solid-state lighting. Although they can be realized by combining semiconductor light-emitting diodes (LEDs) and phosphors or by assembling multiple LED chips with different wavelengths, these design approaches suffer from phosphor-related issues or complex assembly processes. These challenges are significant drawbacks for emerging applications such as visible light communication and micro-LED displays. Herein we present a platform for tailored emission wavelength integration on a single chip utilizing epitaxial growth on flexibly-designed three-dimensional topographies. This approach spontaneously arranges the local emission wavelengths of InGaN-based LED structures through the local In composition variations. As a result, we demonstrate monolithic integration of three different emission colors (violet, blue, and green) on a single chip. Furthermore, we achieve flexible spectral control via independent electrical control of each component. Our integration scheme opens the possibility for tailored spectral control in an arbitrary spectral range through monolithic multi-wavelength LEDs.