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Abstract Background The activation of melanocortin 1 receptor (MC1R) on melanocytes stimulates the production of eumelanin. A tridecapeptide α melanocyte‐stimulating hormone (αMSH) is known to induce skin pigmentation. Objectives We characterised the properties of a novel oral MC1R agonist dersimelagon (MT‐7117) with respect to its specific binding to MC1R, downstream signalling and eumelanin production in experimental models. Methods The competitive binding and production of intracellular cyclic adenosine 3′, 5′‐monophosphate in cells expressing recombinant melanocortin receptors were examined. A mouse melanoma cell line B16F1 was used for the evaluation of in vitro melanin production. The in vitro activity of MT‐7117 was determined with αMSH and [Nle4, D‐Phe7]‐αMSH (NDP‐αMSH) as reference comparators. The change of coat colour and skin pigmentation were evaluated after repeat administration of MT‐7117 by oral gavage to C57BL/6J‐Ay/+ mice and cynomolgus monkeys, respectively. Results MT‐7117 showed the highest affinity for human MC1R compared to the other melanocortin receptors evaluated and agonistic activity for human, cynomolgus monkey and mouse MC1R, with EC50 values in the nanomolar range. In B16F1 cells, MT‐7117 increased melanin production in a concentration‐dependent manner. In vivo, MT‐7117 (≥0.3 mg/kg/day p.o.) significantly induced coat colour darkening in mice. MT‐7117 (≥1 mg/kg/day p.o.) induced significant skin pigmentation in monkeys and complete reversibility was observed after cessation of its administration. Conclusions MT‐7117 is a novel oral MC1R agonist that induces melanogenesis in vitro and in vivo, suggesting its potential application for the prevention of phototoxic reactions in patients with photodermatoses, such as erythropoietic protoporphyria and X‐linked protoporphyria.

The objective of this study is to analyze incidence and risk factors for intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) in major burn patients. A prospective cohort study was conducted at a Burns Treatment Center, including all patients with a burned body surface area =20% admitted from August 2015 to January 2018. Intra-abdominal pressure was measured periodically during the first week of ICU stay. Sixty-four patients were analyzed, with median age of 39 years (interquartile range ITQ: 28-53) and 66% were male. Median burned body surface area was 30% (ITQ: 20-46). Twenty-eight (56%) patients presented criteria for IAH and seven (14%) developed clinical signs compatible with ACS. Burn severity was greater in the group that developed IAH, represented by the ABSI score. This group also presented higher values of creatinine and positive fluid balance. The group of patients with ACS showed a higher frequency of alterations in renal and respiratory functions. The organ systems most frequently affected in groups with diagnostic criteria for IAH and ACS were renal, cardiovascular and respiratory. Mortality rate at hospital outcome was 56%. In conclusion, the incidence of IAH during the study period was high in patients with extensive burns. The occurrence of ACS was associated with organic dysfunctions of the respiratory, cardiovascular and renal systems. The factors associated with intra-abdominal hypertension were age, extension of burned body surface, inhalation injury, and need for mechanical ventilation. [ABSTRACT FROM AUTHOR]

Hair-derived keratin biomaterials composed mostly of reduced keratin proteins (kerateines) have demonstrated their utility as carriers of biologics and drugs for tissue engineering. Electrostatic forces between negatively-charged keratins and biologic macromolecules allow for effective drug retention; attraction to positively-charged growth factors like bone morphogenetic protein 2 (BMP-2) has been used as a strategy for osteoinduction. In this study, the intermolecular surface and bulk interaction properties of kerateines were investigated. Thiol-rich kerateines were chemisorbed onto gold substrates to form an irreversible 2-nm rigid layer for surface plasmon resonance analysis. Kerateine-to-kerateine cohesion was observed in pH-neutral water with an equilibrium dissociation constant (KD) of 1.8 × 10(-4) M, indicating that non-coulombic attractive forces (i.e. hydrophobic and van der Waals) were at work. The association of BMP-2 to kerateine was found to be greater (KD = 1.1 × 10(-7) M), within the range of specific binding. Addition of salts (phosphate-buffered saline; PBS) shortened the Debye length or the electrostatic field influence which weakened the kerateine-BMP-2 binding (KD = 3.2 × 10(-5) M). BMP-2 in bulk kerateine gels provided a limited release in PBS (~ 10% dissociation in 4 weeks), suggesting that electrostatic intermolecular attraction was significant to retain BMP-2 within the keratin matrix. Complete dissociation between kerateine and BMP-2 occurred when the PBS pH was lowered (to 4.5), below the keratin isoelectric point of 5.3. This phenomenon can be attributed to the protonation of keratin at a lower pH, leading to positive-positive repulsion. Therefore, the dynamics of kerateine-BMP-2 binding is highly dependent on pH and salt concentration, as well as on BMP-2 solubility at different pH and molarity. The study findings may contribute to our understanding of the release kinetics of drugs from keratin biomaterials and allow for the development of better, more clinically relevant BMP-2-conjugated systems for bone repair and regeneration.

As described by Carter et al. (J. Biol. Chem. 1951. 192: 197-207), O-methyl derivatives of sphingosine are formed upon acid hydrolysis of sphingolipids in the presence of methanol. In the present study, we have isolated four O-methyl ethers of C18-sphingosine by medium pressure liquid chromatography of their diacetate derivatives, i.e., (2S,3R,4E)-1-acetoxy-2-acetamido-3-methoxy-4-octadecene, its (2S,3S) epimer, (2R,3E,5R)-1-acetoxy-2-acetamido-5-methoxy-3-octadecene, and its (2R,5S) epimer. Structures were determined by physical, chromatographic, and spectral properties. The 5-O-methyl ethers, which were the predominant byproducts of sphingolipid hydrolysis, were easily distinguished from the 3-O-methyl ethers by chromatography, and all four isomers could be differentiated by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. NMR analysis of the original N-acetate and diacetate samples of O-methylsphingosines I and II of Carter et al. demonstrated that they correspond to the 5-O-methyl ethers (2R,5R and 2R,5S, respectively), with purities of approximately 90-99%. Resolution enhancement of the 126-MHz 13C NMR spectra of the O-methyl ethers and D-erythro-C18-sphingosine (Ia) afforded distinct signals for nearly all carbon atoms. 13C NMR assignments of carbons 7-15 were made from their lanthanide-induced shifts, and revised assignments for olefinic carbons of Ia were established based upon 1H-13C shift correlation experiments.

The natural abundance 13C nuclear magnetic resonance spectra of a number of 9 alpha-fluoro and 9 alpha-hydroxy-delta 8(14)-15-ketosterols and their derivatives have been studied. Peak assignments for individual carbons of 9 alpha-fluoro-5 alpha-cholest-8(14)-en-3 beta-ol-15-one, 9 alpha-hydroxy-5 alpha-cholest-8(14)-en-3 beta-ol-15-one, 5 alpha-cholest-8(14)-ene-3,15-dione, 9 alpha-fluoro-5 alpha-cholest-8(14)-ene-3,15-dione, 9 alpha-hydroxy-5 alpha-cholest-8(14)-ene-3,15-dione, 3 beta-benzoyloxy-5 alpha-cholest-8(14)-en-3 beta-ol-15-one, 3 beta-benzoyloxy-9 alpha-fluoro-5 alpha-cholest-8(14)-en-15-one, 3 beta-benzoyloxy-5 alpha-cholest-8(14)-en-9 alpha-ol-15-one, 3 beta-acetoxy-9 alpha-fluoro-5 alpha-cholest-8(14)-en-15-one, and 3 beta-acetoxy-5 alpha-cholest-8(14)-en-9 alpha-ol-15-one have been made. Also presented herein are: 1) considerations of the substituent effects of the 9 alpha-hydroxy and 9 alpha-fluoro groups on carbon shieldings, 2) demonstration that the state of oxidation of C-3 in the various delta 8(14)-15-ketosteroids affects the olefinic carbon shieldings due to an apparent long range through space effect of the electric field on the olefinic carbon shieldings, 3) the results of analyses of 13C-19F spin-spin couplings, and 4) the results of considerations of 13C nuclear magnetic resonance studies of the concerned compounds with respect to the conformation of ring B in the various 9 alpha-substituted sterols.

Reported herein are the results of investigations of the effects of a number of 14 alpha-alkyl-substituted 15-oxygenated sterols, prepared by chemical synthesis, on sterol biosynthesis and the levels of 3-hydroxy-3-methylglutaryl CoA reductase activity in L cells and in primary cultures of fetal mouse liver cells grown in serum-free media. Several of the compounds, most notably 14 alpha-ethyl-5 alpha-cholest-7-en-3 beta, 15 alpha-diol and 14 alpha-ethyl-5 alpha-cholest-7-en-15 alpha-ol-3-one, were found to be extraordinarily potent inhibitors of sterol synthesis in these cells. For example, the latter compound caused a 50% inhibition of the incorporation of labeled acetate into digitonin-precipitable sterols in L cells in culture at a concentration of 6 X 10(-9) M.

A relatively simple method is described for the isolation of zymosterol (5 alpha-cholesta-8, 24-dien-3 beta-ol) of high purity from baker's yeast. Also presented are detailed spectral properties, including 13C NMR spectral analyses, of zymosterol and its acetate derivative.

An explanation of relations between the large scale structure of the universe and the tiny scale structure of the particle physics, e.g. the observed mysterious relation between the dark energy density and the dark matter of the universe and the neutrino mass and the SUSY breaking mass scale of the particle physics may be given by the nonlinear supersymmetric general relativity NLSUSY GR. NLSUSY GR shows that considering the physics beforeof the big bang BB of the universe may be significant and may give new insight to unsolved problems of the low energy particle physics, cosmology and their relations. [ABSTRACT FROM AUTHOR]

Abstract  Symbiotic dinoflagellates of the species Amphidinium are expected to be pharmaceutically useful microalgae because they produce antitumor macrolides. A microalgae production system with a large number of cells at a high density has been developed for the efficient production of macrolide compounds. In the present study, the effects of culture conditions on the cellular growth rate of dinoflagellates were investigated to determine the optimum culture conditions for obtaining high yields of microalgae. Amphidinium species was cultured under conditions with six temperature levels (21–35°C), six levels of photosynthetic photon flux density (15–70 μmol photons m−2 s−1), three levels of CO2 concentration (0.02–0.1%), and three levels of O2 concentration (0.2–21%). The number of cells cultured in a certain volume of solution was monitored microscopically and the cellular growth rate was expressed as the specific growth rate. The maximum specific growth rate was 0.022 h−1 at a temperature of 26°C and O2 concentration of 5%, and the specific growth rate was saturated at a CO2 concentration of 0.05%, a photosynthetic photon flux density of 35 μmol photons m−2 s−1 and a photoperiod of 12 h day−1 upon increasing each environmental parameter. The results demonstrate that Amphidinium species can multiply efficiently under conditions of relatively low light intensity and low O2 concentration. [ABSTRACT FROM AUTHOR]

A gene for a putative two-component histidine kinase, which is homologous to os-1 from Neurospora crassa, was cloned and sequenced from the plant-pathogenic fungus Cochliobolus heterostrophus. The predicted protein possessed the conserved histidine kinase domain, the response regulator domain, and six tandem repeats of 92-amino-acids at the N-terminal end that are found in histidine kinases from other filamentous fungi. Introduction of the histidine kinase gene complemented the deficiency of the C. heterostrophus dic1 mutant, suggesting that the Dic1 gene product is a histidine kinase. Dic1 mutants are resistant to dicarboximide and phenylpyrrole fungicides, and they are sensitive to osmotic stress. We previously classified dic1 alleles into three types, based on their phenotypes. To explain the phenotypic differences among the dic1 mutant alleles, we cloned and sequenced the mutant dic1 genes and compared their sequences with that of the wild-type strain. Null mutants for Dic1, and mutants with a deletion or point mutation in the N-terminal repeat region, were highly sensitive to osmotic stress and highly resistant to both fungicides. A single amino acid change within the kinase domain or the regulator domain altered the sensitivity to osmotic stress and conferred moderate resistance to the fungicides. These results suggest that this predicted protein, especially its repeat region, has an important function in osmotic adaptation and fungicide resistance. [ABSTRACT FROM AUTHOR]

Epoxide hydrolases (EHs) play pivotal roles in detoxification, catabolism, and signaling by converting epoxides into diols and have been implicated in several diseases, such as cancers and diabetes. EH homologs in insects are designated as Juvenile hormone epoxide hydrolases (JHEHs) due to their catalytic activity toward Juvenile hormone (JH). However, the biological function of JHEHs has been controversial in the fruit fly Drosophila melanogaster. In this study, we generated and characterized flies deficient in Jheh1 and Jheh2 genes. We found that Jheh1/2 deficiency caused a developmental delay and enhanced the growth retardation effects of caffeine and paraquat. Additionally, we observed that the deficiency reduced tolerance to cold stress. These results indicate that JHEHs are required for growth promotion and stress tolerance. Metabolomic and transcriptomic analyses revealed that Jheh1/2 deficiency impaired glucose metabolism and downregulated genes involved in glycolysis and the TCA cycle. Furthermore, transgenic overexpression of Jheh1 increased glycolytic metabolites and restored the Jheh1/2 deficiency-associated phenotype. These results demonstrate that JHEHs play a crucial role in glucose metabolism in Drosophila, providing a valuable model to study the mechanisms underlying the function of EHs in energy metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Mesothelioma is a highly aggressive tumor affecting an increasing number of patients worldwide. Owing to the poor clinical outcomes associated with current therapies, the development of novel therapies that target cancer stem cells (CSCs) is desirable. Here, we examined the applicability of our previously established hydrogel-based rapid CSC generation method to human mesothelioma cell lines and further analyzed the characteristics of the induced mesothelioma stem cell (MesoSC) -like cells. Human mesothelioma cell lines cultured on hydrogels presented increased expression of pan-stem cell markers and acquired spheroid formation and early tumorigenicity, suggesting that MesoSC-like cells are highly malignant. Microarray analysis demonstrated that the expression of SLC13A5, a citrate transporter involved in TCA cycle, was significantly induced in the resulting MesoSC-like cells. The overexpression of SLC13A5 resulted in a metabolic shift toward oxidative phosphorylation, increased phosphorylation of ERK and YAP, and increased SOX2 expression, leading to increased cisplatin resistance. scRNA-seq database analysis revealed that clinical mesothelioma samples contained a small number of SLC13A5-expressing cells. Our findings suggest that the hydrogel-based CSC generation method is also effective for human mesothelioma cells and that SLC13A5 may contribute to MesoSC survival. The new properties of MesoSCs revealed in this study may provide clues for establishing future treatments., (© 2025 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Parkinson's disease (PD) is a neurodegenerative disease primarily affecting the central nervous system and impacting both the motor system and non-motor systems. Although administration of L-DOPA is effective, it is not a fundamental treatment and has side effects such as diurnal fluctuation and dyskinesia, highlighting the need for new treatment methods. There is a growing interest in dopaminergic neuron transplantation as a potential treatment. Dopaminergic neurons derived from pluripotent stem (iPS) cells provide a valuable source for transplantation therapies. Developing an efficient method to differentiate iPS cells into dopaminergic cells is essential for cell transplantation therapy. While Cell differentiation is typically controlled by the addition of specific reagents, the physical characteristics of culture substrate, especially in the charge and stiffness, are also crucial factors in regulating differentiation. In this research, we show that two newly developed electrically charged polymeric hydrogels composed of cationic (C) and anionic (A) monomers inratio of 1-9 and 2 to 8 can significantly promote Dopaminergic neuron differentiation. Our findings emphasize the importance of culture substrates in effective dopaminergic cell differentiation., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Dersimelagon is a novel investigational orally administered selective agonist of the melanocortin-1 receptor. The drug-drug interaction (DDI) potential of dersimelagon was investigated in both nonclinical (in vitro) and clinical studies. The in vitro inhibition of CYP/UGT isoforms and efflux/uptake transporters by dersimelagon was assessed. The impact of 300-mg dersimelagon on the pharmacokinetics (PK) of substrate drugs and the effect of co-administering verapamil on 100-mg dersimelagon PK (as substrate drug) were investigated in healthy participants in a Phase 1 study. DDIs were assessed based on ratios of C max and AUC 0-∞ of substrate drug administered alone and with dersimelagon (or verapamil). Relatively potent in vitro inhibition of CYP2C9, CYP3A, UGT1A1, BCRP, P-gp, and OATPs by dersimelagon was observed. In the clinical study, exposures of atorvastatin (CYP3A, P-gp, BCRP, OATP substrate) rosuvastatin (BCRP and OATP substrate), and β-hydroxy simvastatin (metabolite of simvastatin) increased 2- to 3-fold (atorvastatin: C max LS mean ratio = 198.0%; AUC 0-∞ ratio = 196.6%; rosuvastatin: C max ratio = 316.5%, AUC 0-∞ ratio = 206.0%) when co-administered with dersimelagon. Midazolam (CYP3A substrate), digoxin (P-gp), pravastatin (OATP), and simvastatin (CYP3A) did not show any clinically relevant DDI effects when co-administered with dersimelagon. Dersimelagon exposure increased ~25% when co-administered with verapamil, an effect not considered clinically relevant. Dersimelagon 300 mg did not elicit major DDIs involving CYP/UGT enzymes and drug transporters; however, dersimelagon may have potential for clinically relevant DDIs with drugs that are substrates for BCRP, such as atorvastatin and rosuvastatin, and caution should be exercised when co-administering 300-mg dersimelagon with these statin drugs. Trial Registration: ClinicalTrials.gov: NCT04793295, NCT04402489, NCT04440592, NCT02834442, NCT03520036, NCT03503266., (© 2025 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Neural networks (NNs) possess the capability to learn complex data relationships, recognize inherent patterns by emulating human brain functions, and generate predictions based on novel data. We conducted deep learning utilizing an NN to differentiate between Parkinson's disease (PD) and the parkinsonian variant (MSA-P) of multiple system atrophy (MSA). The distinction between PD and MSA-P in the early stages presents significant challenges. Considering the recently reported heterogeneity and random distribution of lesions in MSA, we performed an analysis employing an NN with voxel-based morphometry data from the entire brain as input variables. The NN's accuracy in distinguishing MSA-P from PD demonstrates sufficient practicality for clinical application., Competing Interests: Declaration of competing interest None., (Copyright © 2025. Published by Elsevier B.V.)

Pancreatic cancer is known as one of the poor prognostic cancers, and the most of patients are unable to undergo radical resection due to local progression or distant metastasis at initial diagnosis. In spite of the advancements in surgery and chemotherapy, there are many cases of recurrence after surgery or chemoradiotherapy mainly due to the presence of cancer stem cells (CSCs). CSCs are potential therapeutic target, but current issue is that an identification of CSCs is difficult since they are only present in a small number of tumor cells. Here we demonstrate that hydrogel PCDME can rapidly induce pancreatic cancer cell spheroids with elevated levels of stem cell markers including Sox2, Oct3/4, and Nanog, and the growth rate was reduced. CSCs showed activation of YAP/TAZ signaling, and microarray analysis showed markedly elevated expression of thioredoxin-interacting protein (TXNIP). Primary pancreatic cancer cells also increased TXNIP in addition to stemness markers on gel. In metabolic analysis, CSCs showed a shift of energy production from glycolysis to oxidative phosphorylation (OXPHOS). Furthermore, knockdown of TXNIP on PCDME gel using shRNAs decreased growth speed and in vivo tumorigenicity, suggesting that TXNIP may be involved in CSCs induction., Competing Interests: Declaration of competing interest None of the authors have a conflict of interest to disclose., (Copyright © 2025. Published by Elsevier Inc.)

Background: A new circulating biomarker superior to carbohydrate antigen 19-9 (CA19-9) is needed for diagnosing pancreatobiliary cancer (PBca). The aim of this study was to identify serum microRNA (miRNA) signatures comprising reproducible and disease-related miRNAs., Methods: This multicenter study involved patients with treatment-naïve PBca and healthy participants. The optimized serum processing conditions were evaluated using t-distributed stochastic neighbor embedding (t-SNE) visualization. Serum miRNA candidates for disease association were selected using weighted gene coexpression network analysis (WGCNA). A miRNA signature combining multiple serum miRNAs was tested in exploratory, validation, and independent validation sets. The synthesis and secretion of diagnostic miRNAs were evaluated using human pancreatic cancer cells., Results: In total, 284 (150 healthy and 134 PBca) of 827 serum samples were processed within 2 h of blood collection before freezing, distributed in the same area as that in the t-SNE map, and assigned to an exploratory set. The 193 optimized samples were assigned to either the validation (50 healthy, 47 PBca) or independent validation (50 healthy, 46 PBca) set. Index-1, a combination of five serum miRNAs (hsa-miR-1343-5p, hsa-miR-4632-5p, hsa-miR-4665-5p, hsa-miR-665, and hsa-miR-6803-5p) with disease association in WGCNA, showed a sensitivity and specificity of > 80% and an AUC outperforming that of CA19-9 in the exploratory, validation, and independent validation sets. The AUC of Index-1 was superior to that of CA19-9 (0.856 vs. 0.649, p = 0.038) for detecting T1 tumors. miR-665, a component of Index-1, was expressed in human pancreatic cancer cells, and its transfection inhibited cell growth., Conclusions: The serum miRNA signature Index-1 is useful for detecting PBca and could facilitate the early diagnosis of PBca. These findings can help improve clinical PBca detection by providing an optimized biomarker that overcomes the limitations of the current standard., Competing Interests: Declarations. Ethics approval and consent to participate: This prospective observational study was approved by the ethics review committee of the National Cancer Center Hospital East and National Cancer Center Hospital (approval no. 2016–049, 2020–449) and the institutional review boards of collaborating institutions. The study for time-course effects was approved by the Human Tissue Samples Ethics Committee for R&D of Toray Industries, Inc. (HC2017-10, HC2021-3, and HC2021-18). All the studies complied with the principles of the Declaration of Helsinki and the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects. Written informed consent was obtained from all participants. Consent for publication: Not applicable. Competing interests: S.M. received honoraria and grants from Toray Industries, Inc., and grants from the Japan Agency for Medical Research and Development (AMED) under Grant Numbers 15ck0106027h0002 and 16ck106027h0003 during the submitted work, as well as research funding from Ajinomoto Co., Inc., PFDeNA Co., Ltd., and Mitsui Chemicals Inc. outside the submitted work. M.I. received research funding from Astellas Pharma Inc., Nihon Servier Co., Ltd., and Novartis Pharma K.K. and received honoraria from Guardant Health Japan Corp., Nihon Servier Co., Ltd., Taiho Pharmaceutical Co., Ltd., M.S.D. K.K., NIPPON KAYAKU Co., Ltd., Yakult Honsha Co., Ltd., Boehringer Ingelheim GmbH, D.F.P. (Delta Fly Pharma) Inc., Merus N.V., Invitae Corp., and Novartis Pharma K.K. outside the submitted work. M.U. received grants from Toray Industries, Inc., during the submitted work, as well as research funding from Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., M.S.D. K.K., Nihon Servier Co., Ltd., Ono Pharmaceutical Co., Ltd., Incyte Biosciences Japan G.K., Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim GmbH, Eisai Co., Ltd., Novartis Pharma K.K., Astellas Pharma Inc., J-pharma Co., Ltd., DFP (Delta Fly Pharma) Inc., Novocure GmbH, and Chiome Bioscience Inc. and honoraria from Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., Yakult Honsha Co., Ltd., M.S.D. K.K., Nihon Servier Co., Ltd., Ono Pharmaceutical Co., Ltd., Incyte Biosciences Japan G.K., Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim GmbH, J-pharma Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Novartis Pharma K.K. outside the submitted work. K.H2. received honoraria and research funding from Toray Industries, Inc., during the submitted work. K.T. received research funding from Toray Industries, Inc., during the submitted work, received research funding from Hitachi High-Tech Corporation and H.U. Group Research Institute G.K., and holds a patent with H.U. Group Research Institute G.K. outside the submitted work. M.T., I.M., T.K., H.Y., H.I1, H.I2, E.H., K.N., M.N., and A.O. received research funding from Toray Industries, Inc., during the submitted work. H.S. is an employee of Toray Industries, Inc., and received grants from AMED under grant numbers 15ck0106027h0002 and 16ck106027h0003 during the submitted work. S.T. is an employee of Toray Industries, Inc., and received grants from AMED under grant numbers 15ck0106027h0002 and 16ck106027h0003 during the submitted work. The other authors declare that they have no competing interests., (© 2025. The Author(s).)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Histological chorioamnionitis (HCA) is a form of maternal immune activation (MIA) linked to an increased risk of neurodevelopmental disorders in offspring. Our previous study identified neurodevelopmental impairments in an MIA mouse model mimicking HCA. Thus, this study investigated the role of CD11c + microglia, key contributors to myelination through IGF-1 production, in this pathology. In the mouse model, the CD11c + microglial population was significantly lower in the MIA group than in the control group on postnatal day 3 (PN3d). Furthermore, myelination-related protein levels significantly decreased in the MIA group at PN8d. In humans, preterm infants with HCA exhibited higher IL-6 and IL-17A cord-serum levels and lower IGF-1 levels than those without HCA, followed by a higher incidence of delayed myelination on magnetic resonance imaging at the term-equivalent age. In silico analysis revealed that the transient induction of CD11c + microglia during early development occurred similarly in mice and humans. Notably, a lack of high CD11c + microglial population has been observed in children with neurodevelopmental disorders. This study reports impaired induction of CD11c + microglia during postnatal development in a mouse model of MIA associated with delayed myelination. Our findings may inform strategies for improving outcomes in infants with HCA., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Ionizing radiation induces various types of DNA damage, and the reparability and lethal effects of DNA damage differ depending on its spatial density. Elucidating the structure of radiation-induced clustered DNA damage and its repair processes will enhance our understanding of the lethal impact of ionizing radiation and advance progress toward precise therapeutics. Previously, we developed a method to directly visualize DNA damage using atomic force microscopy (AFM) and classified clustered DNA damage into simple base damage clusters (BDCs), complex BDCs and complex double-strand breaks (DSBs). This study investigated the repair of each type of damage in DNA-repair-deficient human TK6 cells and elucidated the association between each type of clustered DNA damage and the pathway responsible for its repair postirradiation with low linear energy transfer (LET) radiation (X-rays) and high-LET radiation (Fe-ion beams) in cells. We found that base excision repair and, surprisingly, nucleotide excision repair restored simple and complex BDCs. In addition, the number of complex DSBs in wild-type cells increases 1 h postirradiation, which was most likely caused by BDC cleavage initiated with DNA glycosylases. Furthermore, complex DSBs, which are likely associated with lethality, are repaired by homologous recombination with little contribution from nonhomologous-end joining., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The environmental risk assessment (ERA) of genetically modified (GM) crops in Japan requires collecting data from a comparative study of a GM and non-GM control in an in-country confined field trial (CFT). This in-country CFT requirement is used to address concerns that differences in the local environmental conditions may lead to differences in growth and/or risks of GM crops. However, this requirement for in-country CFT has recently been exempted for certain GM maize and GM cotton traits, and instead CFT data from other countries are used to inform the ERA of these GM events. However, in-country CFTs continue to be required for GM B. napus. Our objective is to assess whether using B. napus as a host crop increases the potential for differences between GM B. napus and conventional B. napus that may have an impact on biodiversity occurring only under the Japanese environment. In this paper agronomic data was compiled from seven local CFTs of GM B. napus events to assess the potential for differences between GM and non-GM B. napus for three key areas; competitiveness, potential to produce harmful substances, and outcrossing. Considering these elements, the need for conducting CFTs locally for ERA of future GM B. napus traits is discussed. The assessment concluded that conducting CFT locally is not necessary for GM B. napus events if traits do not bring competitive advantage or produce harmful substances only under Japanese environment., Competing Interests: Declarations. Conflict of interest: KT and SN are both employed by Bayer CropScience. KI and KI are both employed by BASF. MT declares that she has no conflict of interest., (© 2025. The Author(s).)

Pharmacological activation of G protein-coupled receptor 119 (GPR119) produces pleiotropic beneficial effects, including the promotion of insulin secretion from pancreatic β-cells, enhancement of glucagon-like peptide (GLP)-1 secretion from intestinal L cells, glucose-dependent insulin secretion, and food intake and body weight gain suppression. Thus, GPR119 has attracted attention as a promising new target for type 2 diabetes mellitus (T2DM) treatment. Here, we identified a new small GPR119 agonist, NCP-322. This compound showed potent enhancing effects on insulin and GLP-1 secretion, which played a role in pancreatic β-cells and intestinal L cells. In the oral glucose tolerance test, NCP-322 administration reduced glycemic excursions that were only exhibited during hyperglycemia. Furthermore, NCP-322 administration did not induce hypoglycemia, the main side effect of antidiabetic drugs. These results suggest the promising therapeutic potential of NCP-322 for T2DM treatment.

Leukemia stem cells (LSCs), capable of simultaneous self-renewal and differentiation, are resistant to chemotherapy and the cause of relapse in refractory cases of leukemia. As a method to rapidly generate LSCs has not been established, research on LSCs as therapeutic targets has been hampered. Here, we demonstrate that K562 leukemia cells acquired LSC properties with increase in stemness markers such as CD34, Oct3/4, and Nanog and metabolic alterations towards OXPHOS by culturing cells on synthetic polymer hydrogels. In this hydrogel-generated LSCs, single-cell RNA sequencing identified the increase in expression levels of AKR1B1 and TSPYL5, which play an essential role for stemness generation. Decrease in expression of CD34, Oct3/4, and Nanog were observed in K562 cells with knockdown of AKR1B1 and TSPYL5. These results indicate that cell culturing on synthetic polymer hydrogels can be a useful system to generate LSCs and AKR1B1 and TSPYL5 may become therapeutic targets for LSCs., Competing Interests: Declaration of competing interest The authors declare neither competing interests nor conflict of financial interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cancer stem cells (CSCs) cause therapy-resistance and recurrence, therefore an establishment of therapeutic approaches targeting CSCs is essential for eradicating cancers; however, a lot of aspects of the mechanisms of CSCs generation remain unclear. We previously demonstrated that human glioblastoma cell lines cultured on double-network (DN) hydrogel were rapidly reprogrammed into CSCs. To elucidate molecular mechanisms underlying CSCs generation, we here focused on the elastic modulus of hydrogels mimicking the stiffness of tumor tissues. Mouse NIH3T3 fibroblasts transformed with representative oncogenes H-Ras and Src were employed as cancer model cells, and cultured on (2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) gel with different elastic modulus. The H-Ras-, but not Src-, transformed NIH3T3 cells induced stem cell properties on the PAMPS gel, particularly with elastic modulus of approximately 10 kPa that mimics general tumor tissues. On the gels, expression levels of stemness markers such as Sox2, Nanog, and Oct4 were increased in the parental and H-Ras-transformed cells. Pull-down assay demonstrated that multiple proteins in H-Ras-transformed cells bound to the PAMPS gels with 9.3 kPa stiffness, and desmoplakin was identified as one of the gel-bound proteins by LC-MS/MS analysis. Among Ca 2+ channels functioning as mechanosensors, the expression levels of TRPC and TRPV families were efficiently increased on the gel with approximately 10 kPa, as well as stemness markers. These data suggest that tumor tissues with the stiffness of 10 kPa effectively trigger the signals for generating CSCs through alterations of membrane structures and Ca 2+ influx, which will be beneficial for developing novel therapeutic applications targeting CSCs., Competing Interests: Declaration of competing interest None of the authors have a conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Patients with metastatic pancreatic ductal adenocarcinoma survive longer if disease spreads to the lung but not the liver. Here we generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype. We developed a primary organotropism (pORG) gene set enriched in liver cohort versus lung cohort primary tumors. We identified ongoing replication stress response pathways in high pORG/liver cohort tumors, whereas low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid pancreatic ductal adenocarcinoma is associated with tolerance to ongoing replication stress, limited tumor immunity and less-favorable outcomes, whereas low replication stress, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes., Competing Interests: Competing interests: Disclosures relevant to PDAC are as follows. R.C.S. declares Scientific Advisory Board (SAB)/consultancy for Rappta Therapeutics, PanCAN, PRECEDE, MOHCCN & PanCuRx Canada and Precision Panc CRUK; sponsored research for Cardiff Oncology, AstraZeneca. G.B.M. declares SAB/consultancy for Amphista, Astex, AstraZeneca, BlueDot, Chrysallis Biotechnology, Ellipses Pharma, ImmunoMET, Infinity, Ionis, Lilly, Medacorp, Nanostring, Nuvectis, PDX Pharmaceuticals, Roche, Signalchem Lifesciences, Tarveda, Turbine and Zentalis Pharmaceuticals; Stock/options/financial for AstraZeneca, Catena Pharmaceuticals, ImmunoMet, SignalChem, Tarveda and Turbine; licensed technology HRD assay to Myriad Genetics and Digital Spatial Profiler patents with Nanostring. L.M.C. declares consulting services for Cell Signaling Technologies, AbbVie, the Susan G Komen Foundation and Shasqi, received reagents and/or research support from Cell Signaling Technologies, Syndax Pharmaceuticals, ZelBio, Hibercell and Acerta Pharma, and participates in advisory boards for Pharmacyclics, Syndax, Carisma, Verseau, CytomX, Kineta, Hibercell, Cell Signaling Technologies, Alkermes, Zymeworks, Genenta Sciences, Pio Therapeutics, PDX Pharmaceuticals, NextCure, the AstraZeneca Partner of Choice Network, the Lustgarten Foundation and the NIH–NCI-Frederick National Laboratory Advisory Committee. J.R.B. declares SAB for Perthera, Advisory for IDEAYA and is an editor for Springer and Taylor & Francis publishing. The other authors declare no competing interests., (© 2025. The Author(s).)

Background: Neoadjuvant chemotherapy followed by surgery (NAC-S) is the standard therapy for locally advanced esophageal squamous cell carcinoma (ESCC) in Japan., Objective: The aim of this phase II trial was to assess the efficacy and safety of the addition of adjuvant S-1 after R0 resection in ESCC patients who received NAC-S., Patients and Methods: Key eligibility criteria included clinical stage IB-III (without T4 disease) ESCC, age 20-75 years, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients received adjuvant therapy with four cycles of S-1 (80 mg/m 2 /day) administered orally for 4 weeks of 6-week cycles. The primary endpoint was 3 year relapse-free survival (RFS). If the lower confidence limit for 3 year RFS was >50%, we judged that the primary endpoint of this study was met., Results: A total of 52 patients were enrolled between January 2016 and January 2019. Two patients were excluded from analysis; five patients were determined to have R1 or R2 resection, and seven patients did not receive adjuvant S-1. The 3-year RFS and overall survival rates in the intention-to-treat population were 72.3% (90% confidence interval [CI] 59.9-81.5) and 85.0% (90% CI 73.9-91.6), indicating that the primary endpoint was met. Grade ≥3 adverse events with an incidence ≥10% included neutropenia (13.2%), anorexia (13.2%), and diarrhea (10.5%). There were no treatment-related deaths., Conclusion: Adjuvant S-1 after NAC-S showed promising efficacy with a manageable safety profile for patients with resectable ESCC and warrants further evaluation in larger studies., Competing Interests: Disclosure: Toshifumi Yamaguchi, Keisho Chin, Shinji Hato, Ken Kato, Hidenori Mukaida, Takako Yoshii, Masahiro Tsuda, Yasuhiro Tsubosa, Isao Oze, and Hideki Ishikawa have no conflicts of interest to declare and have no financial or funding support to disclose. Hisahiro Matsubara, Yuko Kitagawa, and Manabu Muto have received research funding from Taiho Pharmaceutical. Motoo Nomura has received honoraria from Bristol-Myers Squibb, MDS, Ono Pharmaceutical. Eishi Baba has received lectures fees from AstraZeneca, BMS, Chugai, Takeda, Gardant Health Japan, Ono, Astellas, Softbank, Daiichi-Sankyo, MSD, Yakult, Eli Lilly, Merk biopharm, Taiho, Tsumura, and Amgen Human Rights Statement and Informed Consent: All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent, or a substitute, was obtained from all patients before inclusion in the study., (© 2024. The Author(s).)

Methylotrophic yeast is a useful host for producing heterologous proteins using the unique and strong alcohol oxidase 1 (AOX1) promoter, which is induced by methanol and repressed by various carbon sources. However, methanol is preferably avoided in industrial-scale fermentation given its toxicity, flammability, and explosiveness. To develop a protein production system under reduced methanol supply conditions, we attempted to characterize the AOX1 promoter induction activity by comparing derepression conditions with methanol induction conditions. This comparison is important because decreasing methanol consumption would enhance the industrial value of Ogataea minuta for heterologous protein production. For such a comparison, an alcohol oxidase-deficient (Δaox) strain was generated, with methanol only being used for AOX1 promoter induction. We also developed a culture process in a jar fermentor using the O. minuta Δaox strain under mixed feed conditions to achieve heterologous protein production comparable to that of the wild-type strain under low-methanol conditions., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Early detection of gastric cancer can play a key role in improving prognosis. Recently, light-emitting diodes (LED) have been developed as novel endoscopic systems. However, the differences in the visibility of gastric neoplastic lesions between LED and laser endoscopy remains unclear. We conducted a prospective multicenter trial to evaluate the non-inferiority of LED endoscopy in the visibility of gastric neoplastic lesions undergoing endoscopic submucosal dissection (ESD) in comparison to laser endoscopy., Methods: A multicenter, prospective, cross-sectional study was conducted in patients undergoing ESD for gastric neoplastic lesions at five hospitals throughout Japan. Seventy patients with 74 lesions were included in this study. The primary endpoint was the non-inferiority of the difference in the individual scores of linked color imaging (LCI) and white-light imaging (WLI) for LED and laser endoscopy for gastric neoplastic lesions., Results: The mean individual score was 2.66 ± 1.02, 3.17 ± 0.83, 2.75 ± 1.05, and 3.21 ± 0.84 in LED-WLI, LED-LCI, laser-WLI, and laser-LCI, respectively. The difference in individual scores of LCI and WLI was 0.51 ± 0.77 and 0.46 ± 0.80 in LED and laser endoscopy, respectively. The mean difference between LED and laser endoscopy was 0.04 (95% confidence interval [CI]: - 0.05 to 0.13, P < 0.001)., Conclusions: This study revealed the non-inferiority of the differences in individual scores between LCI and WLI in the comparison of LED and laser endoscopy for gastric neoplastic lesions., Competing Interests: Declarations. Conflict of interest: Osamu Dohi received research funding from Fujifilm Co. Ltd. The other authors have no conflicts of interest to declare. Fujifilm Co. had no role in the design, conduct, data collection, data interpretation, or reporting of this study. Ethical approval: The study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the institutional review boards of the Kyoto Prefectural University of Medicine and other hospitals., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Polyzwitterions that show the alternation of net charge in response to external stimuli have attracted great attention as a new class of surface-polymers on nanomedicines. However, the correlation between their detailed molecular structures and expression of antifouling properties under physiological condition remain controversial. Herein, we synthesized a series of ethylenediamine-based polyzwitterions with carboxy groups/sulfonic groups and ethylene, propylene, and butylene spacers as potential surface-polymers for nanomedicines, allowing sensitive recognition of tumor acidic environments (pH = 6.5-5.5). Then, we evaluated their structure-based characteristics, including pH-dependent cellular uptakes and intracellular distributions. Additionally, the role of conformation stability, i.e. , Gibbs free energy changes, was to induce an intramolecular electrostatic interaction in the zwitterionic moieties. These results highlight the practicality of fine-tuning the design of zwitterionic moieties on polymers for the future development of nanomedicines that can recognize the narrow pH window in tumor acidic environments.

Brain-derived neurotrophic factor (BDNF) is essential for numerous neuronal functions, including learning and memory. The expression of BDNF is regulated by distinctive transcriptional and post-transcriptional mechanisms. The Bdnf gene in mice and rats comprises eight untranslated exons (exons I-VIII) and one exon (exon IX) that contains the pre-proBDNF coding sequence. Multiple splice donor sites on the untranslated exons and a single acceptor site upstream of the coding sequence result in the characteristic exon skipping patterns that generate multiple Bdnf mRNA variants, which are essential for the spatiotemporal regulation of BDNF expression, mRNA localization, mRNA stability, and translational control. However, the regulation of Bdnf pre-mRNA splicing remains unclear. Here, we focused on the splicing of Bdnf exon I-IX pre-mRNA. We first constructed a minigene to evaluate Bdnf exon I-IX pre-mRNA splicing. Compared with Bdnf exon I-IX pre-mRNA splicing in non-neuronal NIH3T3 cells, splicing was preferentially observed in primary cultures of cortical neurons. Additionally, a series of overexpression and knockdown experiments suggested that neuro-oncological ventral antigen (NOVA) 2 is involved in the neuron-selective splicing of Bdnf exon I-IX pre-mRNA. Supporting this finding, endogenous Nova2 mRNA expression was markedly higher in neurons, and a strong correlation between endogenous Bdnf exon I-IX and Nova2 mRNA was observed across several brain regions. Furthermore, Bdnf exon I-IX pre-mRNA splicing was facilitated by Ca 2+ signals evoked via L-type voltage-dependent Ca 2+ channels. Notably, among the Bdnf pre-mRNA splicing investigated in the current study, neuron-selective and activity-dependent splicing was observed in Bdnf exon I-IX pre-mRNA. In conclusion, Bdnf exon I-IX pre-mRNA splicing is preferentially observed in neurons and is facilitated in an activity-dependent manner. The neuron-selective and activity-dependent splicing of Bdnf exon I-IX pre-mRNA may contribute to the efficient induction of Bdnf exon I-IX expression in neurons., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective To evaluate the influence of sample collection time during esophagogastroduodenoscopy (EGD) on the accuracy of a newly approved point-of-care test (POCT)-based polymerase chain reaction kit for detecting Helicobacter pylori and clarithromycin susceptibility in gastric wash fluid. Methods Intragastric fluid was collected at three time points: Collection Time 1 (start of EGD), Collection Time 2 (during EGD), and Collection Time 3 (after indigo carmine spraying). POCT-based quantitative PCR (qPCR) targeting 23S rRNA domain V (2142/2143) was used to quantify H. pylori DNA in the collected fluid at all three time points and compared with qPCR targeting 16S rRNA. Patients Fifty patients with suspected H. pylori infection were consecutively enrolled in this study over a three-month period and underwent EGD. Results In 9 out of 50 EGD cases that were H. pylori-positive, no significant differences in H. pylori DNA content, quantified using POCT-based qPCR targeting 23S rRNA, were observed between the three collection times: 1 vs. 2, p=0.81; 2 vs. 3, p=0.59; 1 vs. 3. Collection Time 2 had the strongest inverse correlation with the urea breath test (r=-0.80, p=0.01) and was the only time-point at which POCT-based qPCR could detect H. pylori in case 15. Conclusion This study suggests that the optimal collection timing for the H. pylori detection POCT kit (within 60 min) using intragastric fluid (with no biopsy) may be during EGD (Collection Time 2). However, our study had a limited sample size, so the findings must be verified through large-scale, multicenter collaboration studies.

Background: Post-stroke delirium affects between 24% and 43% of patients, and negatively impacts patient outcomes. Recently, research attention has been on preventive interventions for delirium, with melatonin receptor agonists and orexin receptor antagonists reported to be effective in preventing delirium in intensive care unit patients. However, the efficacy of these agents in preventing post-stroke delirium remain unclear. This study examined the efficacy of ramelteon, suvorexant, and lemborexant in preventing post-stroke delirium symptoms in patients with stroke., Methods: A retrospective survey of medical records was conducted for patients with stroke aged > 75 years at Kyoto University Hospital from October 2021 to March 2023. Patients who received ramelteon, suvorexant, or lemborexant on admission and the following day were classified into the consecutive administration group, whereas those who did not were classified into the non-consecutive administration group. The primary outcome was an increase in the number of positive items in the delirium screening tool over 7 days., Results: Of the 104 patients, 33 and 71 were in the consecutive and non-consecutive administration groups, respectively. Fewer patients in the consecutive administration group had an increase in the number of positive items than in the other group (6% vs. 21%). Patients in the consecutive administration group significantly less often had an increase in the number of positive items in the delirium screening tool (P = 0.05; hazard ratio, 0.27; 95% confidence interval, 0.10-0.75)., Conclusions: This study revealed that early administration of a melatonin receptor agonist or orexin receptor antagonists may effectively prevent post-stroke delirium in older patients., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in accordance with the Ethical Guidelines for Life Science and Medical Reseach Involving Human Subjects, and was reviewed by the Ethics Committee of the Kyoto University Graduate School and Faculty of Medicine (approval number, R0545-2). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is deeply involved in the development and higher function of the nervous system, including learning and memory. By contrast, a reduction in BDNF levels is associated with various neurological disorders such as dementia and depression. Therefore, the inducers of Bdnf expression might be valuable in ameliorating or protecting against a decline in brain functions. We previously reported that, through high-throughput screening to identify inducers of Bdnf expression in Bdnf-luciferase transgenic mice, several herbal extracts induced Bdnf expression in cortical neurons. In the present study, we found that Panax notoginseng root extract (PNRE) potently induced Bdnf expression in primary cultured cortical neurons primarily via the L-type voltage-dependent Ca 2+ channel (L-VDCC) and calcineurin. PNRE promoted nuclear translocation of cAMP-responsive element-binding protein-regulated transcription coactivator 1 (CRTC1). These findings suggest that PNRE activates the L-VDCC/calcineurin/CRTC1 axis, which is the primary signaling pathway involved in the neuronal activity-dependent expression of Bdnf. Moreover, we demonstrated that PNRE increased the dendritic complexity of cortical neurons in vitro. Thus, by upregulating Bdnf expression, PNRE is a potential candidate for improving cognitive impairment seen in several kinds of dementia.

Endovascular aneurysm repair (EVAR) is commonly utilized for iliac artery aneurysms (IAA), yet some cases necessitate additional intervention due to aneurysm re-expansion. We report two cases: a 68-year-old male with a left internal IAA (IIAA) and an 80-year-old female with both a left common iliac artery aneurysm (CIAA) and IIAA, who underwent aneurysmorrhaphy following initial EVAR. Both procedures were successful, significantly reducing aneurysm size without immediate complications. The use of laparoscopy in aneurysmorrhaphy enhances oversight of inflow vessels and facilitates suturing in deep pelvic areas. Our cases indicate that incorporating laparoscopy can substantially improve surgical outcomes., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

We report a case of a 44-year-old male who underwent an electrophysiological study for symptomatic supraventricular tachycardia (SVT) with wide QRS complex. The SVT was diagnosed as an antidromic atrioventricular reentrant tachycardia (AVRT) via antegrade conduction of left-sided accessory pathway (AP). However, the QRS morphology changed during the SVT, and then the SVT was terminated spontaneously. The mapping of AP was performed during sinus rhythm, and the radiofrequency application successfully eliminated the AP, which rendered tachycardias non-inducible. This was a rare case of antidromic AVRT during which the QRS morphology changed., (© 2024 Wiley Periodicals LLC.)

The structure of iriomoteolide-1a, a marine macrolide with potent cytotoxic activity against human cancer cells, has been under scrutiny for more than a decade since the first total synthesis of the proposed structure was achieved by Horne. Here we disclose the correct structure of iriomoteolide-1a. Given a huge number of possible stereoisomers, we adopted an integrated strategy toward the structure elucidation of iriomoteolide-1a: (1) NMR spectroscopic analysis/molecular mechanics-based conformational analysis for configurational reassignment of the macrolactone domain; (2) model synthesis for validating the reassigned configuration of the macrolactone domain; (3) GIAO NMR calculation/DP4+ analysis of side chain stereoisomers; and (4) total synthesis of the most likely structure. Moreover, the correct structure of iriomoteolide-1b, a natural congener, was also determined by an integration of NMR spectroscopic analysis, GIAO NMR calculation/DP4+ analysis, and total synthesis.

Background: Helicobacter pylori ( H. pylori ) eradication treatment for primary gastric mucosa-associated lymphoid tissue (MALT) lymphoma has already been established. However, t (11;18) (q21;q21)/ API2-MALT1 translocation-positive lesions are a type of primary gastric MALT lymphoma in which a response to eradication treatment is difficult to achieve. In addition, trisomy 18 may be associated with diffuse large B-cell lymphoma (DLBCL) transformation of gastric MALT lymphoma., Case Summary: A 66-year-old man was diagnosed with MALT lymphoma in the ascending colon by colonoscopy and biopsy. Two years later, esophagogastroduodenoscopy revealed chronic atrophic gastritis that was positive for H. pylori , and eradication treatment was administered. Two years and nine months later (at the age of 70), a new ulcerative lesion suggestive of MALT lymphoma appeared in the gastric body, and six months later, a similar lesion was also found in the fundus. One year later (4 years and 3 months after H. pylori eradication), at the age of 72, the lesion in the gastric body had become deeper and had propagated. A biopsy revealed a pathological diagnosis of DLBCL. Both MALT lymphoma lesions in the ascending colon and DLBCL lesions in the stomach were positive for the t (11;18) (q21;q21)/ API2-MALT1 translocation, and trisomy 18q21 was also detected. After 6 courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy, all of the above lesions disappeared [complete remission (CR)], and CR has been maintained for more than 3 years. In addition, both the colonic and gastric lesions were proven to have the same clonality., Conclusion: Because the patient had a MALT1 translocation with trisomy 18q21, it was thought that this gastric MALT lymphoma developed independently of H. pylori infection and progressed., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: The maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene ATG16L1 have been implicated in susceptibility and severity of Crohn's disease (CD). Individuals carrying the risk ATG16L1 T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8 + T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses., Results and Discussion: However, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, Tlr7 -/- mice have a significant increase in large intestinal lamina propria (LP) granzyme B + tissue-resident memory CD8 + T (T RM ) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of Atg16l1 in myeloid ( Atg16l1 ΔLyz2 ) or dendritic cells ( Atg16l1 ΔCd11c ) leads to a similar increase of LP T RM . Furthermore, Tlr7 -/- and Atg16l1 ΔCd11c mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of Atg16l1 ΔCd11c mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP T RM and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7., Conclusion: In conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with ATG16L1 risk variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hamade, Tsuda, Oshima, Stamps, Wong, Stamps, Thomas, Salumbides, Jin, Nunnelee, Dhall, Targan and Michelsen.)

ICE KKS102 Tn 4677 carries a bph operon for the mineralization of polychlorinated biphenyls (PCBs)/biphenyl and belongs to the Tn 4371 ICE (integrative and conjugative element) family. In this study, we investigated the role of the traR gene in ICE transfer. The traR gene encodes a LysR-type transcriptional regulator, which is conserved in sequence, positioning, and directional orientation among Tn 4371 family ICEs. The traR belongs to the bph operon, and its overexpression on solid medium resulted in modest upregulation of traG (threefold), marked upregulation of xis (80-fold), enhanced ICE excision and, most notably, ICE transfer frequency. We propose the evolutional roles of traR , which upon insertion to its current position, might have connected the cargo gene activation and ICE transfer. This property of ICE, i.e., undergoing transfer under environmental conditions that lead to cargo gene activation, would instantly confer fitness advantages to bacteria newly acquiring this ICE, thereby resulting in efficient dissemination of the Tn 4371 family ICEs.IMPORTANCEOnly ICE KKS102 Tn 4677 is proven to transfer among the widely disseminating Tn 4371 family integrative and conjugative elements (ICEs) from β and γ-proteobacteria. We showed that the traR gene in ICE KKS102 Tn 4677 , which is conserved in the ICE family with fixed location and direction, is co-transcribed with the cargo gene and activates ICE transfer. We propose that capturing of traR by an ancestral ICE to the current position established the Tn 4371 family of ICEs. Our findings provide insights into the evolutionary processes that led to the widespread distribution of the Tn 4371 family of ICEs across bacterial species., Competing Interests: The authors declare no conflict of interest.

Aims: Catheter ablation (CA) of atrial fibrillation (AF) improves left ventricular ejection fraction (LVEF) in patients with heart failure with reduced ejection fraction (HFrEF). The impact of ST-segment depression before CA on LVEF recovery and clinical outcomes remains unknown. In the present study, we aimed to investigate the relationship between ST-segment depression during AF rhythm before CA and improvement in the LVEF and clinical outcomes in persistent atrial fibrillation (PerAF) patients with HFrEF., Methods and Results: The present study included 122 PerAF patients (male; 98 patients, 80%, mean age: 69 [56, 76] years) from the Osaka Rosai Atrial Fibrillation ablation (ORAF) registry who had LVEF < 50% and underwent an initial ablation. The patients who underwent percutaneous coronary intervention or coronary artery bypass grafting within the past 1 month were not included in the enrolled patients. We assigned the patients based on the presence of ST-segment depression before CA during AF rhythm and evaluated improvement in the LVEF (LVEF ≥ 15%) 1 year after CA and the relationship between ST-segment depression and heart failure (HF) hospitalization/major adverse cardiovascular events (MACE), which are defined as a composite of HF hospitalization, cardiovascular death, hospitalization due to coronary artery disease, ventricular arrhythmia requiring hospitalization and stroke. The percentage of patients with improvement in the LVEF 1 year after CA was significantly lower in the patients with ST-segment depression than those without (58.6% vs. 79.7%, P = 0.012). Multiple regression analysis showed ST-segment depression was independently and significantly associated with improvement in the LVEF 1 year after CA (HR: 0.35; 95% CI: 0.129-0.928, P = 0.035). Kaplan-Meier analysis showed that the patients with ST-segment depression significantly had higher risk of HF hospitalization and MACE than those without (log rank P = 0.022 and log rank P = 0.002, respectively). Multivariable Cox proportional hazards analysis showed that ST-segment depression was independently and significantly associated with a higher risk of MACE (HR: 2.82; 95% CI: 1.210-6.584, P = 0.016)., Conclusions: ST-segment depression before CA during AF rhythm was useful prognostic predictor of improvement in the LVEF and clinical outcomes including HF hospitalization and MACE in PerAF patients with HFrEF., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Residual non-pulmonary vein (PV) foci are significantly associated with atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). However, we previously reported among patients with non-PV foci induced only once, none experienced AF recurrence. Thus, we aimed to investigate the correlation between the residual induction number of non-PV foci and ablation outcome in paroxysmal AF patients., Methods and Results: We investigated 55 paroxysmal AF patients with residual non-PV foci after PVI and ablation of non-PV-foci. Study patients were classified into the residual one-time induction of non-PV foci (residual OTI-nPVF) group (n = 23) and residual repeatedly induced non-PV foci (residual RI-nPVF) group (n = 32). Furthermore, the residual RI-nPVF group was divided into the low inducibility group (n = 10) and high inducibility group (n = 22) according to the presence or absence of non-PV foci provoked by two sets of drug induction tests (non-PV foci inducibility). In addition, the latter was divided into the ablation group (n = 14) or observation group (n = 8). The 2-year AF recurrence-free rate in the residual RI-nPVF group was significantly lower compared to the residual OTI-nPVF group (53% vs. 90%, p = 0.018). There was no significant difference of the 2-year AF recurrence-free rates in the inducibility of non-PV foci (p = 0.913) and the presence or absence of ablation (p = 0.812) in the residual RI-nPVF group., Conclusions: Among paroxysmal AF patients, the presence of residual RI-nPVF was associated with higher AF recurrence compared to residual OTI-nPVF. Furthermore, within residual RI-nPVF subgroup, non-PV foci inducibility or ablation of some residual RI-nPVF did not affect ablation outcome., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

High-throughput phenotyping serves as a framework to reduce chronological costs and accelerate breeding cycles. In this study, we developed models to estimate the phenotypes of biomass-related traits in soybean ( Glycine max ) using unmanned aerial vehicle (UAV) remote sensing and deep learning models. In 2018, a field experiment was conducted using 198 soybean germplasm accessions with known whole-genome sequences under 2 irrigation conditions: drought and control. We used a convolutional neural network (CNN) as a model to estimate the phenotypic values of 5 conventional biomass-related traits: dry weight, main stem length, numbers of nodes and branches, and plant height. We utilized manually measured phenotypes of conventional traits along with RGB images and digital surface models from UAV remote sensing to train our CNN models. The accuracy of the developed models was assessed through 10-fold cross-validation, which demonstrated their ability to accurately estimate the phenotypes of all conventional traits simultaneously. Deep learning enabled us to extract features that exhibited strong correlations with the output (i.e., phenotypes of the target traits) and accurately estimate the values of the features from the input data. We considered the extracted low-dimensional features as phenotypes in the latent space and attempted to annotate them based on the phenotypes of conventional traits. Furthermore, we validated whether these low-dimensional latent features were genetically controlled by assessing the accuracy of genomic predictions. The results revealed the potential utility of these low-dimensional latent features in actual breeding scenarios., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Mashiro Okada et al.)

Background: Esophageal cancer is one of the most common types of cancer in Japan. Herein, we report the efficacy and safety of E7389-LF plus the immune checkpoint inhibitor, nivolumab, from the esophageal cancer cohort of the phase 2 part of Study 120., Methods: Eligible patients received E7389-LF 2.1 mg/m 2 plus nivolumab 360 mg intravenously Q3W. The primary objective was to evaluate the objective response rate (ORR); other objectives included safety, progression-free survival (PFS), and overall survival (OS)., Results: Of the 35 Japanese patients enrolled, 7 (20.0%) had a partial response as their best overall response, and 14 (40.0%) had stable disease. The ORR was 20.0% (95% CI 8.4-36.9). The duration of response was 5.6 months (95% CI 1.7-not estimable [NE]). The median PFS was 2.81 months (95% CI 1.31-4.17). The median OS was not reached (95% CI 6.54 months-NE). The most common treatment-emergent adverse events were neutropenia (65.7%), pyrexia (60.0%), and leukopenia (57.1%). Select plasma endothelial cell markers levels increased from day 1 of cycle 1 and changes were pronounced between days 8-15 of each cycle., Conclusions: E7389-LF plus nivolumab showed antitumor activity in patients with unresectable and pretreated esophageal cancer and should be evaluated further in a broader population., Clinical Trial Registration: NCT04078295., (© 2024. The Author(s).)

In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population., (© 2024 The Author(s). Microbiology and Immunology published by The Societies and John Wiley & Sons Australia, Ltd.)

Background: Creation of an arteriovenous fistula (AVF) as vascular access is a basic operation that should be learned by all surgeons involved in renal failure treatment. AVF creation is often challenging for inexperienced young surgeons because it requires comprehensive surgical techniques. For such young surgeons, we introduced cadaveric surgical training (CST) for AVF creation using fresh-frozen cadavers (FFCs). This study was performed to identify the differences in AVF surgical techniques between FFCs and living bodies and to examine the impact of CST on young surgeons., Methods: Twelve CST sessions were performed for AVF creation at the Clinical Anatomy Education and Research Center of Tokushima University Hospital from March 2021 to June 2022. Seven young surgeons (1st- and 2nd-year) performed the operation, and two surgeons (10th- and 11th-year) supervised it. We conducted an anonymous questionnaire survey using a 5-point Likert scale to examine the impact of CST on young surgeons., Results: Twelve CST sessions were performed on nine FFCs. All training sessions allowed completion of AVF creation with a median operative time of 78.5 min. Although veins and arteries were more difficult to identify than in a living body, other surgical operations could be performed in the same way as in a living body. All the respondents stated that it was good for them to experience CST. In addition, 86% of surgeons responded that CST improved their surgical techniques, and 71% of surgeons responded that they were less anxious about AVF creation., Conclusions: CST for AVF creation is useful for surgical education because it enables learning of surgical techniques that are almost equivalent to those in living bodies. In addition, this study suggested that CST not only contributes to the improvement of surgical skills of young surgeons but also promotes the reduction of anxiety and stress about AVF creation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Interstitial lung disease (ILD) is one of the most common fatal immune-related adverse events (irAEs). ILD development adversely affects the continuation of anticancer drug therapy, including immune checkpoint inhibitor (ICI) therapy and prognosis. There are no established useful clinical indicators for the early detection of ILD. Furthermore, the factors that lead the attending physician to suspect ICI-induced ILD (ICI-ILD) remain unclear. This study aimed to investigate the ICI-ILD detection based on subjective symptoms and their relationship with disease severity in patients receiving anti-PD-1/PD-L1 antibody., Methods: This was a retrospective observational study. We enrolled the patients who received anti-PD-1/PD-L1 antibody at Kyoto University Hospital between September 2014 and April 2021. Patients who developed ICI-ILD were stratified into two distinct groups based on factors that triggered the suspicion of ILD development. The "Subjective symptoms" group was defined as patients in whom ILD was detected based on subjective symptoms. Conversely, the "Routine examinations" group was defined as patients in whom ILD was suspected based on scheduled routine examinations. The severity of ILD in each group was assessed and its association with changes in the respiratory symptoms was examined., Results: Of 926 patients who received anti-PD-1/PD-L1 antibody, 51 patients (5.5%) developed ICI-ILD. The incidence of ICI-ILD in patients with lung cancer was significantly higher than that in patients with other cancers (P < 0.001). Among the patients with ICI-ILD, 27 patients (52.9%) were classified into the "Subjective symptoms" group. The "Subjective symptoms" group exhibited a significantly higher proportion of Grade 3-5 ICI-ILD cases than the "Routine examinations" group (76.2% vs. 23.8%, P = 0.010). At the last visit, before the suspected onset of ILD, 21 of the 27 patients (77.8%) had no symptoms or no change in the respiratory symptoms., Conclusion: Subjective symptoms triggered the suspicion of Grade 3-5 ICI-ILD. Enhanced monitoring and patient education could be essential for the early detection of ICI-ILD because ILD may develop rapidly. Our findings might help to manage ICI-ILD in clinical practice., (© 2024. The Author(s).)