Search

Interpersonal space (IPS) refers to the area surrounding the body in which we engage in social interactions while maintaining our comfort. Numerous previous studies have reported the psychological and physiological changes associated with the proximity of two people engaged in face-to-face interaction. Currently, there is limited knowledge about how the relative position between two socially intimate individuals affects their psychological and physiological states. This research measured the subjective discomfort and electrocardiographic responses of participants when standing static at various relative positions. The highest discomfort, lowest heart rate, and highest heart rate variability (HRV; parasympathetic activity index) were observed when the friend stood in the face-to-face position. Interestingly, heart rate also decreased when the friend stood on the right side, although HRV did not change. We interpreted the results as suggesting that the presence of a familiar person elicits the electrocardiographic responses associated with an increase in parasympathetic activity., (© 2024. The Author(s).)

Background: The present study examined age differences in and the relationship between two indices of cognitive reappraisal and expressive suppression: the degree of emotion regulation and the habitual use of emotion-regulation strategies., Method: In total, 101 younger and 99 older participants were included in this study. The degree of emotion regulation was measured using an experimental task in which participants were presented with negative or positive pictures and required to regulate their emotions. Habitual use of emotion regulation strategies was measured using an emotion regulation questionnaire., Results: The results showed that younger adults regulated their emotions to a greater extent than older adults in both reappraisal and suppression. Younger adults were more likely to use reappraisal than were older adults, although there were no age differences in the use of suppression. No significant correlations were found between the degree of emotion regulation and the habitual use of emotion regulation strategies., Conclusion: These results suggest that age differences in emotion regulation depend on the regulation strategy and that the degree of emotion regulation and habitual use of emotion regulation strategies are independent and quite different indicators in nature.

High-intensity interval training has attracted considerable attention as a time-efficient strategy for inducing physiological adaptations, but the underlying mechanisms have yet to be elucidated. By using metabolomics techniques, we investigated changes in the metabolic network responses in Thoroughbred horses to high-intensity interval exercise performed with two distinct (15 min or 2 min) rest intervals. The peak plasma lactate level was higher during high-intensity exercise with a 2 min rest duration than that with a 15 min rest duration (24.5±6.8 versus 13.3±2.7 mmol l-1). The arterial oxygen saturation was lower at the end of all exercise sessions with a 2 min rest duration than that with a 15 min rest duration. Metabolomic analysis of skeletal muscle revealed marked changes in metabolite concentrations in the first and third bouts of the 15 min rest interval conditions. In contrast, there were no metabolite concentrations or pathways that significantly changed during the third bout of exercise performed with a 2 min rest interval. Our findings suggest that the activity of each energy production system is not necessarily reflected by apparent changes in metabolite concentrations, potentially due in part to a better match between metabolite flux into and out of the pathway and cycle, as well as between metabolite production and disposal. This study provides evidence that changes in metabolite concentrations vary greatly depending on the number of repetitions and the length of rest periods between exercises, even if the exercises themselves are identical., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Extranodal NK/T-cell lymphoma (ENKTL), nasal type, is often seen in the head and neck region, but there have been rare instances of this disease with initial presentation as a lesion in the oral mucosa. The patient, a woman in her seventh decade of life, presented with an ulcer in the maxillary gingiva, and scraping cytology and biopsy were performed. Cytological specimens showed solitary or small aggregating cells with marked atypia in a necrotic background. Tumor cells were detected that had various nuclear shapes and azure granules in the cytoplasm. Biopsy showed that the tumor cells had diffusely infiltrated or interdigitated into the subepithelium. Immunohistochemistry revealed that the tumor cells had T- and NK cell phenotypes and were Epstein-Barr virus-encoded small RNA (EBER) positive, leading to a diagnosis of ENKTL. Thus, when nonepithelial tumor cells in a necrotic background and prominent atypia are found, as in this case, it is important to carefully observe for azurophil granules in the cytoplasm for differential diagnosis considerations., (© 2023 Wiley Periodicals LLC.)

Stimulator of interferon genes (STING) is critical for the type I interferon response to pathogen- or self-derived DNA in the cytosol. STING may function as a scaffold to activate TANK-binding kinase 1 (TBK1), but direct cellular evidence remains lacking. Here we show, using single-molecule imaging of STING with enhanced time resolutions down to 5 ms, that STING becomes clustered at the trans-Golgi network (about 20 STING molecules per cluster). The clustering requires STING palmitoylation and the Golgi lipid order defined by cholesterol. Single-molecule imaging of TBK1 reveals that STING clustering enhances the association with TBK1. We thus provide quantitative proof-of-principle for the signaling STING scaffold, reveal the mechanistic role of STING palmitoylation in the STING activation, and resolve the long-standing question of the requirement of STING translocation for triggering the innate immune signaling., (© 2024. The Author(s).)

This study aimed to measure the effects of trehalose (Tre) supplementation on the growth, intestinal morphology, gut bacteria, and footpad dermatitis (FPD) of broiler chickens reared at different stocking densities (SD). Four hundred newly hatched Ross 308 male chicks were randomly allocated to four groups of eight, following a 2 × 2 factorial arrangement in a randomized complete block design using two SDs (normal, 11; high, 14 birds/m 2 ) and two diets: basal with and without 0.5% Tre. Tre supplementation was provided during the starter/grower phase, but not the finisher phase. Data were analyzed using a two-way analysis of variance. We observed no significant effects of SD or Tre, individually or combined, on body weight gain (BWG), feed intake (FI), and feed conversion ratio (FCR) during the starter/grower period. However, high SD decreased both BWG ( P < 0.001) and FI ( P < 0.05), and increased FCR ( P < 0.001), during the finisher period. Whereas Tre reduced FCR ( P < 0.05) as a main effect, no combined effect was observed on FCR. Over the total period, high SD negatively affected BWG and FCR ( P < 0.001), and Tre significantly reduced FCR, with its effect unaffected by SD. No significant effects of SD or Tre were observed on jejunal morphology. The ileal abundance of Clostridium perfringens ( P > 0.05) was not affected by high SD but was significantly reduced by Tre. Neither high SD nor Tre altered Lactobacillus spp. counts; however, high SD increased FPD lesion scores, whereas Tre had no effect. The study showed that Tre supplementation during the starter/grower period improved FCR during the finisher period, possibly by decreasing the abundance of C. perfringens in broiler chickens., Competing Interests: Conflicts of interest: The authors declare that there are no conflict of interests., (2024 Japan Poultry Science Association.)

Recent developments in targeted protein degradation have provided great opportunities to eliminating extracellular protein targets using potential therapies with unique mechanisms of action and pharmacology. Among them, Lysosome-Targeting Chimeras (LYTACs) acting through mannose 6-phosphate receptor (M6PR) have been shown to facilitate degradation of several soluble and membrane-associated proteins in lysosomes with high efficiency. Herein we have developed a novel site-specific antibody conjugation approach to generate antibody mannose 6-phosphate (M6P) conjugates. The method uses a high affinity synthetic M6P glycan, bisM6P, that is coupled to an Fc-engineered antibody NNAS. This mutant without any effector function was generated by switching the native glycosylation site from position 297 to 298 converting non-sialylated structures to highly sialylated N-glycans. The sialic acid of the glycans attached to Asn298 in the engineered antibody was selectively conjugated to bisM6P without chemoenzymatic modification, which is often used for site-specific antibody conjugation through glycans. The conjugate is mainly homogeneous by analysis using mass spectrometry, typically with one or two glycans coupled. The M6P-conjugated antibody against a protein of interest (POI) efficiently internalized targeted soluble proteins, such as human tumor necrosis factor (TNF), in both cancer cell lines and human immune cells, through the endo-lysosomal pathway as demonstrated by confocal microscopy and flow cytometry. TNF in cell culture media was significantly depleted after the cells were incubated with the M6P-conjugated antibody. TNF internalization is mediated through M6PR, and it is correlated well with cell surface expression of cation-independent M6PR (CI-MPR) in immune cells. A significant amount of CI-MPR remains on the cell surface, while internalized TNF is degraded in lysosomes. Thus, the antibody-M6P conjugate is highly efficient in inducing internalization and subsequent lysosome-mediated protein degradation. Our platform provides a unique method for producing biologics-based degraders that may be used to treat diseases through event-driven pharmacology, thereby addressing unmet medical needs.

Automatic imitation, in which one person's movement is affected by the observation of another person's movements, has been widely reported. However, it remains unclear how automatic imitation changes over a wide age range, particularly during childhood. In this study, we examined the differences in the tendency for automatic imitation between adults and children and the cross-sectional age-related changes in children aged 5-12 years, using a stimulus-response conflict paradigm. In this task, participants perform a choice-reactive finger movement corresponding to a given response stimulus while observing another participant's compatible or incompatible movement stimuli. The tendency for automatic imitation was assessed based on the reaction time, correct rate, and inverse efficiency score. The results showed that the degree of automatic imitation was weak until the children were 7 years old. Interestingly, our results show that the tendency for automatic imitation during childhood changed to an inverted U-shape, indicating nonlinear changes in automatic imitation during childhood. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The human adrenal cortex secretes aldosterone and cortisol as major corticosteroids. For their production, CYP11B2 and CYP11B1 catalyze the last steps in the syntheses of aldosterone and cortisol, respectively. In our previous study, CYP11B2 was the first successfully purified from rat adrenals and human clinical samples and then was proved to be aldosterone synthase. We demonstrated the immunohistochemistry for CYP11B2 of both rats and humans and applied it clinically to visualize the functional histology of aldosterone-producing adenoma (APA) causing primary aldosteronism (PA). We discovered aldosterone-producing cell clusters (APCCs) and possible APCC-to-APA transitional lesions (pAATLs) and further visualized aldosterone-producing lesions for rare forms of PA including familial hyperaldosteronism type 3 and novel non-familial juvenile PA. Here we review the history of our research on aldosterone-producing lesions.

Sulfur vacancy on an MoS 2 basal plane plays a crucial role in device performance and catalytic activity; thus, an understanding of the electronic states of sulfur vacancies is still an important issue. We investigate the electronic states on an MoS 2 basal plane by ambient-pressure X-ray photoelectron spectroscopy (AP-XPS) and density functional theory calculations while heating the system in hydrogen. The AP-XPS results show a decrease in the intensity ratio of S 2p to Mo 3d, indicating that sulfur vacancies are formed. Furthermore, low-energy components are observed in Mo 3d and S 2p spectra. To understand the changes in the electronic states induced by sulfur vacancy formation at the atomic scale, we calculate the core-level binding energies for the model vacancy surfaces. The calculated shifts for Mo 3d and S 2p with the formation of sulfur vacancy are consistent with the experimentally observed binding energy shifts. Mulliken charge analysis indicates that this is caused by an increase in the electronic density associated with the Mo and S atoms around the sulfur vacancy as compared to the pristine surface. The present investigation provides a guideline for sulfur vacancy engineering., (© 2023 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Insulin is used as a therapeutic agent in patients with diabetes, and cutaneous lipohypertrophy (LH) and localized insulin-derived amyloidosis (LIDA) are well-known adverse effects associated with insulin injections. The clinical implications, management, assessment methods, and pathological differentiation of LH and LIDA have been recently updated. This review was to update our knowledge of the pathological differentiation, effects of insulin absorption, hypoglycemic events, and recent assessment methods for LH and LIDA. A scoping review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Reviews guidelines. Original studies and case reports in English were also included. PubMed and Scopus databases were searched for keywords to identify papers published up to January 2022. A total of 113 studies were identified through a database search, and 31 were eligible for inclusion in this scoping review. In the 31 studies included in this review, patients with type 2 diabetes had high frequencies of LH and LIDA. LH outcome parameters were assessed using pathological findings and imaging. LIDA is mainly determined by pathological methods, such as hematoxylin and eosin and Congo red staining. Several in vitro and in vivo LIDA models of LIDA have been developed. These results suggest that pathological analysis is required to identify LH and LIDA. It is important to consider LIDA, as it likely influences insulin adsorption and glycemic control. Although several studies have evaluated the LIDA process, little is known about the mechanisms underlying the development of adverse effects associated with insulin injections., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Chronic Diseases and Translational Medicine published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.)

Yes-associated protein (YAP) is a transcriptional coactivator that is essential for the malignancy of various cancers. We have previously shown that YAP activity is positively regulated by phosphatidylserine (PS) in recycling endosomes (REs). However, the mechanism by which YAP is activated by PS in REs remains unknown. In the present study, we examined a group of protein phosphatases (11 phosphatases) that we had identified previously as PS-proximity protein candidates. Knockdown experiments of these phosphatases suggested that PPP1R12A, a regulatory subunit of the myosin phosphatase complex, was essential for YAP-dependent proliferation of triple-negative breast cancer MDA-MB-231 cells. Knockdown of PPP1R12A increased the level of phosphorylated YAP, reduced that of YAP in the nucleus, and suppressed the transcription of CTGF (a YAP-regulated gene), reinforcing the role of PPP1R12A in YAP activation. ATP8A1 is a PS-flippase that concentrates PS in the cytosolic leaflet of the RE membrane and positively regulates YAP signalling. In subcellular fractionation experiments using cell lysates, PPP1R12A in control cells was recovered exclusively in the microsomal fraction. In contrast, a fraction of PPP1R12A in ATP8A1-depleted cells was recovered in the cytosolic fraction. Cohort data available from the Cancer Genome Atlas showed that high expression of PPP1R12A, PP1B encoding the catalytic subunit of the myosin phosphatase complex, or ATP8A1 correlated with poor prognosis in breast cancer patients. These results suggest that the "ATP8A1-PS-YAP phosphatase" axis in REs facilitates YAP activation and thus cell proliferation., (© 2023. The Author(s).)

Introduction: The purpose of this study was to determine whether acute high-intensity interval exercise or sprint interval exercise induces greater physiological and skeletal muscle responses compared to moderate-intensity continuous exercise in horses., Methods: In a randomized crossover design, eight trained Thoroughbred horses performed three treadmill exercise protocols consisting of moderate-intensity continuous exercise (6 min at 70% VO 2 max; MICT), high-intensity interval exercise (6 × 30 s at 100% VO 2 max; HIIT), and sprint interval exercise (6 × 15 s at 120% VO 2 max; SIT). Arterial blood samples were collected to measure blood gas variables and plasma lactate concentration. Biopsy samples were obtained from the gluteus medius muscle before, immediately after, 4 h, and 24 h after exercise for biochemical analysis, western blotting and real-time RT-PCR. Effects of time and exercise protocol were analyzed using mixed models ( p  < 0.05)., Results: Heart rate and plasma lactate concentration at the end of exercise were higher in HIIT and SIT than those in MICT (heart rate, HIIT vs. MICT, p = 0.0005; SIT vs. MICT, p = 0.0015; lactate, HIIT vs. MICT, p = 0.0014; SIT vs. MICT, p = 0.0003). Arterial O 2 saturation and arterial pH in HIIT and SIT were lower compared with MICT (SaO 2 , HIIT vs. MICT, p = 0.0035; SIT vs. MICT, p = 0.0265; pH, HIIT vs. MICT, p = 0.0011; SIT vs. MICT, p = 0.0023). Muscle glycogen content decreased significantly in HIIT ( p = 0.0004) and SIT ( p = 0.0016) immediately after exercise, but not in MICT ( p = 0.19). Phosphorylation of AMP-activated protein kinase (AMPK) in HIIT showed a significant increase immediately after exercise ( p = 0.014), but the increase was not significant in MICT ( p = 0.13) and SIT ( p = 0.39). At 4 h after exercise, peroxisome proliferator-activated receptor γ co-activator-1α mRNA increased in HIIT ( p = 0.0027) and SIT ( p = 0.0019) and vascular endothelial growth factor mRNA increased in SIT ( p = 0.0002)., Discussion: Despite an equal run distance, HIIT and SIT cause more severe arterial hypoxemia and lactic acidosis compared with MICT. In addition, HIIT activates the AMPK signaling cascade, and HIIT and SIT elevate mitochondrial biogenesis and angiogenesis, whereas MICT did not induce any significant changes to these signaling pathways., Competing Interests: KM, OH, YT, and YE are employees of the Japan Racing Association. The remaining 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 © 2023 Mukai, Ohmura, Takahashi, Ebisuda, Yoneda and Miyata.)

Purpose: Pancreatic cancer (PC) has one of the worst prognoses among all solid cancers. Hospital volume has been shown to be significantly associated with outcomes in patients with PC undergoing surgery. Nonetheless, the association between hospital volume and prognosis in patients with metastatic PC remains unclear. This study aimed to examine the association between hospital volume and prognosis in patients with metastatic PC using large-scale population-based cancer registry data., Methods: This retrospective observational study was conducted using data from the Osaka Cancer Registry database. Data of patients with metastatic PC over 10 years (2009-2018) were obtained. Hospitals were categorized into high-volume hospitals (HVHs; ≥ 240 patients diagnosed with PC for 10 years), middle-volume hospitals (MVHs; 120-239 patients diagnosed with PC for 10 years), and low-volume hospitals (LVHs; < 120 patients diagnosed with PC for 10 years). Multivariate analysis was performed to identify factors associated with overall survival (OS)., Results: The analysis included 8,929 patients with metastatic PC. Median OS was significantly more favorable in HVHs than in MVHs and LVHs. Multivariate analysis adjusted for hospital volume, age, primary tumor site, year of diagnosis, chemotherapy, and radiotherapy revealed that hospital volume was an independent factor associated with OS (HVHs vs. MVHs: hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03-1.16; P = 0.003, HVHs vs. LVHs: HR, 1.20; 95% CI, 1.13-1.27; P < 0.001)., Conclusion: Hospital volume is an independent prognostic factor in patients with metastatic PC, suggesting an association between hospital volume and treatment outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To verify the anterior capsule opacification (ACO) and contraction (ACC) of the ZCB00V intraocular lens (IOL), made of the same material as the AR40e with a high ACC rate., Study Design: Retrospective cohort study., Methods: We evaluated 35 patients at 1 week, 1, 3 and 6 months post phacoemulsification with either a ZCB00V (n = 35) or FY-60AD (n = 34) IOL implantation. The ACC rate was calculated using retroillumination images of the anterior segment, and the ACO was measured using anterior segment photographs and image analysis software. The contact grade between the IOL and anterior capsule was estimated from the Pentacam ® images., Results: The postoperative ACC rates (mean ± standard deviation) at 3 months were 1.03%±2.54% for the ZCB00V and, and 7.12%±9.47% for the FY-60AD. The ZCB00V-implanted eyes showed a significantly lower postoperative ACC at 1 week, 3 months, and 6 months (P < 0.01). On the other hand, the FY-60AD-implanted eyes had more pronounced ACO, and a significantly larger area of opacification (62.24%±21.32% vs. 16.90%±8.34%; P = 0.0005). Pentacam ® analysis revealed a space between the anterior capsule and IOL surface in the ZCB00V-implanted eyes, whereas the anterior capsule firmly adhered to the IOL surface in the FY-60AD-implanted eyes., Conclusion: The ACC and ACO were significantly lower in eyes with ZCB00V IOLs compared to those with the FY-60AD. The anterior segment image analysis revealed that the elevated anterior rim of the ZCB00V IOL prevented adhesion between the anterior capsule and IOL optic surface, suggesting an open capsule effect., (© 2023. Japanese Ophthalmological Society.)

The antibiotic lincomycin binds to the 23S ribosomal RNA peptidyl transferase loop region to inhibit protein synthesis. However, lincomycin can also stimulate the growth and secondary metabolism of actinomycetes in a concentration-dependent manner. In Streptomyces coelicolor A3(2), lincomycin stimulates the production of the blue-pigmented antibiotic actinorhodin at concentrations below the minimum inhibitory concentration. To better understand the molecular mechanism underlying these concentration-dependent positive effects, this study investigated how the target molecule, the ribosome, undergoes dynamic changes in the presence of lincomycin and explored the ribosome-related factors involved. Lincomycin, at a concentration that stimulates actinorhodin production of S. coelicolor A3(2), could restore temporarily arrested ribosome function by utilizing ribosome-related proteins and translation factors, presumably under the control of the transcription factor WblC protein that confers intrinsic resistance to multiple translation-inhibiting antibiotics, to eventually produce stable and active ribosomes even during the late growth phase. This qualitatively and quantitatively positive ribosome alteration can be advantageous for producing actinorhodin biosynthetic enzymes. A series of gene expression and biochemical analyses revealed that lincomycin at the concentration that induces ribosomal stabilization in S. coelicolor A3(2) could influence the localization of the 20S proteasome-related proteins, resulting in reduced proteasome activity. These findings suggest that the functional analysis of 20S proteasome represents a potential pivotal challenge for understanding the molecular mechanism of ribosome stabilization induced by lincomycin. Therefore, as lincomycin can dynamically alter its target molecule, the ribosome, we discuss the future issues and prospects for an increased understanding of the concentration-dependent properties of antibiotics. IMPORTANCE Antibiotics were originally defined as chemical compounds produced by a microbe that inhibits the growth of other microbes. However, an unexplained effect of this is that a low concentration of antibiotics, such as those below the minimum inhibitory concentration, can positively affect microbial growth and metabolism. The secondary metabolic activation of streptomycetes in the presence of the translation-inhibiting antibiotic lincomycin illustrates the concentration-dependent positive effect of the antibiotic. The significance of this study is that the phenomenological interpretation of the molecular mechanism of the concentration-dependent positive effect of lincomycin in Streptomyces coelicolor A3(2) has provided novel insight into the possible role of antibiotics in making their target molecules stable and active with the assistance of various related factors that benefit their function. Further exploration of this idea would lead to an essential understanding of antibiotics, including why actinomycetes make them and their role in nature., Competing Interests: The authors declare no conflict of interest.

As the global marketplace for lithium-ion batteries (LIBs) proliferates, technologies for efficient and environmentally friendly recycling, i.e., direct recycling, of spent LIBs are urgently required. In this contribution, we elucidated the mechanisms underlying the degradation that occurs during the cycling of a Li/LiNi 0.6 Co 0.2 Mn 0.2 O 2 (NCM622) cell. The results provided fundamental insights into the optimum procedures for direct recycling using a recently developed, state-of-the-art positive electrode material. Capacity fade in NCM622 was induced by cycling at high voltages above 4.6 V vs Li + /Li, during which the rhombohedral symmetry approached cubic symmetry. The selective line broadening and peak shifts that appeared in the X-ray diffraction patterns after cycling indicated the formation of stacking faults along the c h -axis. In addition, high-resolution transmission electron microscopy clarified that rock-salt domains were located on the NCM622 surface before and after cycling. These structural analyses confirmed that the NCM622 particles degrade not at their surfaces but rather in the bulk, contradicting previous reports where degradation during cycling is mainly caused by rock-salt domains on the surface. Material regeneration processes involving the restoration of the original stacking sequence are essential for effective direct recycling., Competing Interests: The author declares no competing financial interest., (© 2023 The Author. Published by American Chemical Society.)

Invadopodia are protrusive structures that mediate the extracellular matrix (ECM) degradation required for tumor invasion and metastasis. Rho small GTPases regulate invadopodia formation, but the molecular mechanisms of how Rho small GTPase activities are regulated at the invadopodia remain unclear. Here we have identified FilGAP, a GTPase-activating protein (GAP) for Rac1, as a negative regulator of invadopodia formation in tumor cells. Depletion of FilGAP in breast cancer cells increased ECM degradation and conversely, overexpression of FilGAP decreased it. FilGAP depletion promoted the formation of invadopodia with ECM degradation. In addition, FilGAP depletion and Rac1 overexpression increased the emergence of invadopodia induced by epidermal growth factor, whereas FilGAP overexpression suppressed it. Overexpression of GAP-deficient FilGAP mutant enhanced invadopodia emergence as well as FilGAP depletion. The pleckstrin-homology (PH) domain of FilGAP binds phosphatidylinositol 3,4-bisphosphate [PI(3,4)P 2 ], which is distributed on membranes of the invadopodia. FilGAP localized to invadopodia in breast cancer cells on the ECM, but FilGAP mutant lacking PI(3,4)P 2 -binding showed low localization. Similarly, the decrease of PI(3,4)P 2 production reduced the FilGAP localization. Our results suggest that FilGAP localizes to invadopodia through its PH domain binding to PI(3,4)P 2 and down-regulates invadopodia formation by inactivating Rac1, inhibiting ECM degradation in invasive tumor cells.Key words: invadopodia, breast carcinoma, Rac1, FilGAP, PI(3,4)P 2 .

YcjT is a kojibiose phosphorylase found in Escherichia coli. We found that sucrose was a good acceptor of YcjT in reverse phosphorolysis using β-d-glucose 1-phosphate as a donor. The product was identified as β-d-fructofuranosyl α-d-glucopyranosyl-(1→2)-α-d-glucopyranoside. This sugar was also synthesized from sucrose and maltose using YcjT and maltose phosphorylase and promoted the growth of the probiotic Bifidobacterium breve., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism by which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3-/- mice was shown to depend on Toll-like receptor 7 (TLR7), which senses a combination of nucleosides and oligoribonucleotides (ORNs). TLR7 increased phagocyte numbers by driving the proliferation of Ly6Chi immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3-/- mice. Downstream of TLR7, FcRγ and DAP10 were required for monocyte proliferation. Histiocytosis is accompanied by inflammation in SLC29A3 disorders. However, TLR7 in nucleoside-laden splenic monocytes failed to activate inflammatory responses. Enhanced production of proinflammatory cytokines was observed only after stimulation with ssRNAs, which would increase lysosomal ORNs. Patient-derived monocytes harboring the G208R SLC29A3 mutation showed enhanced survival and proliferation in a TLR8-antagonist-sensitive manner. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders., (© 2023 Shibata et al.)

We investigated the effects of oral administration of β-cryptoxanthin (β-CRX), a precursor of vitamin A synthesis, on the transcriptomes of peripheral neutrophils and liver tissue in post-weaned Holstein calves with immature immunity. A single oral administration of β-CRX (0.2 mg/kg body weight) was performed in eight Holstein calves (4.0 ± 0.8 months of age; 117 ± 10 kg) on Day 0. Peripheral neutrophils (n = 4) and liver tissue (n = 4) were collected on Days 0 and 7. Neutrophils were isolated by density gradient centrifugation and treated with the TRIzol reagent. mRNA expression profiles were examined by microarray and differentially expressed genes were investigated using the Ingenuity Pathway Analysis software. The differentially expressed candidate genes identified in neutrophils (COL3A1, DCN, and CCL2) and liver tissue (ACTA1) were involved in enhanced bacterial killing and maintenance of cellular homoeostasis respectively. The changes in the expression of six of the eight common genes encoding enzymes (ADH5 and SQLE) and transcription regulators (RARRES1, COBLL1, RTKN, and HES1) were in the same direction in neutrophils and liver tissue. ADH5 and SQLE are involved in the maintenance of cellular homoeostasis by increasing the availability of substrates, and RARRES1, COBLL1, RTKN, and HES1 are associated with the suppression of apoptosis and carcinogenesis. An in silico analysis revealed that MYC, which is related to the regulation of cellular differentiation and apoptosis, was the most significant upstream regulator in neutrophils and liver tissue. Transcription regulators such as CDKN2A (cell growth suppressor) and SP1 (cell apoptosis enhancer) were significantly inhibited and activated, respectively, in neutrophils and liver tissue. These results suggest that oral administration of β-CRX promotes the expression of candidate genes related to bactericidal ability and regulation of cellular processes in peripheral neutrophils and liver cells in response to the immune-enhancing function of β-CRX in post-weaned Holstein calves., (© 2023 The Authors. Journal of Animal Physiology and Animal Nutrition published by Wiley-VCH GmbH.)

Heat acclimatization or acclimation training in horses is practiced to reduce physiological strain and improve exercise performance in the heat, which can involve metabolic improvement in skeletal muscle. However, there is limited information concerning the acute signaling responses of equine skeletal muscle after exercise in a hot environment. The purpose of this study was to investigate the hypothesis that exercise in hot conditions induces greater changes in heat shock proteins and mitochondrial-related signaling in equine skeletal muscle compared with exercise in cool conditions. Fifteen trained Thoroughbred horses [4.6 ± 0.4 (mean ± SE) years old; 503 ± 14 kg] were assigned to perform a treadmill exercise test in cool conditions [ COOL ; Wet Bulb Globe Temperature (WBGT), 12.5°C; n  = 8] or hot conditions ( HOT ; WBGT, 29.5°C; n  = 7) consisting of walking at 1.7 m/s for 1 min, trotting at 4 m/s for 5 min, and cantering at 7 m/s for 2 min and at 90% of V O 2max for 2 min, followed by walking at 1.7 m/s for 20 min. Heart rate during exercise and plasma lactate concentration immediately after exercise were measured. Biopsy samples were obtained from the middle gluteal muscle before and at 4 h after exercise, and relative quantitative analysis of mRNA expression using real-time RT-PCR was performed. Data were analyzed with using mixed models. There were no significant differences between the two groups in peak heart rate ( COOL , 213 ± 3 bpm; HOT , 214 ± 4 bpm; p  = 0.782) and plasma lactate concentration ( COOL , 13.1 ± 1.4 mmoL/L; HOT , 17.5 ± 1.7 mmoL/L; p  = 0.060), while HSP-70 ( COOL , 1.9-fold, p  = 0.207; HOT , 2.4-fold, p  = 0.045), PGC-1α ( COOL , 3.8-fold, p  = 0.424; HOT , 8.4-fold, p  = 0.010), HIF-1α ( COOL , 1.6-fold, p  = 0.315; HOT , 2.2-fold, p  = 0.018) and PDK4 ( COOL , 7.6-fold, p  = 0.412; HOT , 14.1-fold, p  = 0.047) mRNA increased significantly only in HOT at 4 h after exercise. These data indicate that acute exercise in a hot environment facilitates protective response to heat stress (HSP-70), mitochondrial biogenesis (PGC-1α and HIF-1α) and fatty acid oxidation (PDK4)., Competing Interests: YE, KM, YT, TY, and HO are employees of the Japan Racing Association. The remaining 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 © 2023 Ebisuda, Mukai, Takahashi, Yoshida, Kawano, Matsuhashi, Miyata, Kuwahara and Ohmura.)

Background: The effectiveness of chemotherapy in older adult patients with biliary tract cancer (BTC) remains to be established, despite the fact that the majority of patients diagnosed with BTC tend to be aged ≥ 70 years. In this study, we used three databases to examine the effectiveness of chemotherapy in a large patient population aged ≥ 70 years with metastatic BTC., Methods: Using a large Japanese database that combined three data sources (Osaka Cancer Registry, Japan's Diagnosis Procedure Combination, the hospital-based cancer registry database), we extracted the data from patients pathologically diagnosed with metastatic BTC, between January 1, 2013, and December 31, 2015, in 30 designated cancer care hospitals (DCCHs). A cohort of patients with comparable backgrounds was identified using propensity score matching. The log-rank test was used to examine how chemotherapy affected overall survival (OS)., Results: Among 2,622 registered patients with BTC in 30 DCCHs, 207 older adult patients aged > 70 years with metastatic BTC were selected. Chemotherapy significantly improved the prognosis of older adult patients, according to propensity score matching (chemotherapy, 6.4 months vs. best supportive care, 1.8 months, P value < 0.001). The number of patients receiving chemotherapy tends to decrease with age. Gemcitabine plus cisplatin (GC) and gemcitabine plus S-1 (oral fluoropyrimidine) (GS) combination therapy were frequently performed in the chemotherapy group for patients under 80 years of age (70-74 years, 61.7%; 75-79 years, 62.8%). In contrast, monotherapy including GEM and S-1 was more frequently performed in age groups over 80 years (80-84 years, 56.2%; 85-89 years, 77.7%; ≥90 years, 100%). In the chemotherapy group among older adult patients aged < 85 years, the median OS was significantly longer according to age-group analysis of the 5-year age range following propensity score matching., Conclusions: In older adult patients with metastatic BTC who received chemotherapy, prolonged survival was observed. Chemotherapy may be a viable option for patients with metastatic BTC who are aged < 85 years., (© 2023. The Author(s).)

Esophagogastroduodenoscopy in a 58-year-old man revealed a protruding lesion measuring 6 mm in diameter in the fornix. An endoscopic biopsy of the lesion indicated well-differentiated adenocarcinoma. The lesion was resected by polypectomy. According to the Japanese histologic diagnostic criteria, we made a final diagnosis of early gastric cancer (U, Gre, 6×6 mm, Type 0-I, tub1, pT1a (M), pUl0, Ly0, V0, pHM0, pVM0). A retrospective review of the endoscopic images showed that this lesion had already been present in the images taken 16 years ago. The size and morphology of the lesion were the same as those of the first detected lesion.

Background: A close association between obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents has been investigated in previous studies. However, few studies examined the relationship between lifetime comorbidity of ADHD and OCD in adults. Therefore, we sought to investigate the clinical and psychopathological features related to comorbid ADHD in Japanese adult patients with OCD., Methods: We assessed lifetime comorbidity of ADHD in 93 adult Japanese patients with OCD. Additionally, we used the Japanese version of Conners' Adult ADHD Rating Scales to assess the characteristics and severity of ADHD in each participant. According to the results, we excluded OCD patients that did not have ADHD but who exhibited elevated levels of ADHD traits. We compared OCD patients with ADHD (ADHD+ group) and those without ADHD or its trait (ADHD- group) in terms of background profiles and clinical features, such as OCD symptomatology and psychometric test results. Additionally, the 6-month treatment outcome was compared prospectively between groups., Results: Of the 93 OCD participants, the prevalence of lifetime comorbidity of ADHD was estimated as 16.1%. Compared with the ADHD- group, participants in the ADHD+ group had an earlier age of onset of OCD, higher frequencies of hoarding symptoms, higher levels of depressive and anxiety symptoms and lower quality of life, more elevated levels of impulsivity, and higher rates of substance or behavioral addiction and major depression. Finally, the mean improvement rate on the Yale-Brown Obsessive Compulsive Scale after 6 months of standardized OCD treatment in the ADHD+ group (16.1%) was significantly lower than that in the ADHD- group (44.6%)., Conclusion: The lifetime comorbidity of ADHD is likely to exert a significant effect on clinical features and treatment outcome in adult patients with OCD. It is important to consider that underlying ADHD pathology may function as a facilitator for increased severity of global clinical features and treatment refractory conditions in OCD patients. Further studies are required to examine treatment strategies for such patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Image-based deep learning (IBDL) is an advanced technique for predicting the surface irradiation conditions of laser surface processing technology. In pulsed-laser surface processing techniques, the number of superimposed laser shots is one of the fundamental and essential parameters that should be optimized for each material. Our primary research aims to build an adequate dataset using laser-irradiated surface images and to successfully predict the number of superimposed shots using the pre-trained deep convolutional neural network (CNN) models. First, the laser shot experiments were performed on copper targets using a nanosecond YAG laser with a wavelength of 532 nm. Then, the training data were obtained with the different superimposed shots of 1 to 1024 in powers of 2. After that, we used several pre-trained deep CNN models to predict the number of superimposed laser shots. Based on the dataset with 1936 images, VGG16 shows a high validation accuracy, higher sensitivity, and more than 99% precision than other deep CNN models. Utilizing the VGG16 model with high sensitivity could positively impact the industries' time, efficiency, and overall production.

Although most patients with hepatitis C virus (HCV) infection have been cured since the introduction of direct-acting antiviral (DAA) treatments, whether patients with psychiatric disorders and chronic HCV infection receive benefits from DAA treatments remain unclear. The efficacy and safety of DAA treatment were compared between patients with and without psychiatric disorders. Data were retrospectively collected from medical records at the Suzuka General Hospital (Japan) between September 2014 and December 2021. The study was an observational, single-center study. Fisher's exact test, Mann-Whitney U test and Friedman's test were used for the comparisons between groups. Patients with HCV infection who had been started on DAA treatments were included. In total, 15 HCV cases with psychiatric disorders (P) and 209 HCV cases with nonpsychiatric disorders (NP) were started on DAA treatments for HCV infection. Patients in group P were younger (55±13.9 years) compared with those in group NP (68±13.0 years). A total of 12 patients (80%) in group P achieved and 188 patients (90%) in group NP achieved sustained virologic response (SVR), with no significant difference between the two groups. The remaining three patients in group P who did not achieve SVR included two drop-out cases. Regarding the laboratory data at the end of DAA treatments and SVR, there were no significant differences between the two groups. There were no cases of discontinuation or reduction of medication due to psychiatric disorders during DAA treatment. DAA treatment for HCV infection is effective, tolerable and safe for psychiatric patients, as well as patients without psychiatric disorders. Psychiatric patients with HCV infection should undergo DAA treatment to prevent progression to liver failure and/or cancer., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Importance: Precision oncology using comprehensive genomic profiling (CGP) by next-generation sequencing is aimed at companion diagnosis and genomic profiling. The clinical utility of CGP before the standard of care (SOC) is still not resolved, and more evidence is needed., Objective: To investigate the clinical utility of next-generation CGP (FoundationOne CDx [F1CDx]) in patients with previously untreated metastatic or recurrent solid tumors., Design, Setting, and Participants: This multicenter, prospective, observational cohort study enrolled patients with previously untreated advanced solid tumors between May 18, 2021, and February 16, 2022, with follow-up through August 16, 2022. The study was conducted at 6 hospitals in Japan. Eligible patients were aged 20 years or older and had Eastern Cooperative Oncology Group performance status of 0 to 1 with previously untreated metastatic or recurrent cancers in the gastrointestinal or biliary tract; pancreas, lung, breast, uterus, or ovary; and malignant melanoma., Exposure: Comprehensive genomic profiling testing before SOC for advanced solid tumors., Main Outcomes and Measures: Proportion of patients with actionable or druggable genomic alterations and molecular-based recommended therapy (MBRT)., Results: A total of 183 patients met the inclusion criteria and 180 patients (92 men [51.1%]) with a median age of 64 years (range, 23-88 years) subsequently underwent CGP (lung [n = 28], colon/small intestine [n = 27], pancreas [n = 27], breast [n = 25], biliary tract [n = 20], gastric [n = 19], uterus [n = 12], esophagus [n = 10], ovary [n = 6], and skin melanoma [n = 6]). Data from 172 patients were available for end point analyses. Actionable alterations were found in 172 patients (100.0%; 95% CI, 97.9%-100.0%) and druggable alternations were identified in 109 patients (63.4%; 95% CI, 55.7%-70.6%). The molecular tumor board identified MBRT for 105 patients (61.0%; 95% CI, 53.3%-68.4%). Genomic alterations included in the companion diagnostics list of the CGP test were found in 49 patients (28.5%; 95% CI, 21.9%-35.9%) in a tumor-agnostic setting. After a median follow-up of 7.9 months (range, 0.5-13.2 months), 34 patients (19.8%; 95% CI, 14.1%-26.5%) received MBRT., Conclusions and Relevance: The findings of this study suggest that CGP testing before SOC for patients with advanced solid tumors may be clinically beneficial to guide the subsequent anticancer therapies, including molecularly matched treatments.

Background: Local resection, including endoscopic resection, is recommended for rectal neuroendocrine tumors (NETs) < 15 mm in patients without risk factors for metastasis, though the short- and long-term outcomes are unclear., Aims: This study investigates the efficacy of endoscopic resection for rectal NETs < 15 mm., Methods: The short- and long-term outcomes of patients with rectal NETs < 15 mm who underwent endoscopic resection and the outcomes of each endoscopic technique were analyzed. The tumors were stratified as < 10 mm (small-size group, SSG) and 10-14 mm (intermediate-size group, IMG)., Results: Overall, 139 lesions (SSG, n = 118; IMG, n = 21) were analyzed. All tumors were classified as G1 (n = 135) or G2 (n = 4) according to the 2019 World Health Organization grading criteria. The complete resection rate was not different between the groups (P = 0.151). Endoscopic submucosal dissection (ESD) and endoscopic submucosal resection with a ligation device (ESMR-L) achieved complete resection rates > 90% in the SSG. The ESMR-L procedure time (P < 0.001) and hospitalized period (P < 0.001) were significantly shorter than those of ESD. ESD achieved a complete resection rate of 80.0% in the IMG. The tumor size did not affect the overall survival or rate of lymph node/distant metastases., Conclusions: Endoscopic resection is a feasible and effective treatment for patients with rectal NETs < 15 mm without the risk factors of metastasis. ESMR-L and ESD are optimal techniques for resecting tumors smaller than 10 mm and 10-14 mm, respectively., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Unilateral axillary lymphadenopathy is known to occur after coronavirus disease (COVID-19) vaccination. Post-vaccination lymphadenopathy may mimic the metastatic lymph nodes in breast cancer, and it is challenging to distinguish between them. This study investigated whether the localization of axillary lymphadenopathy on magnetic resonance imaging (MRI) could be used to distinguish reactive lymphadenopathy after COVID-19 vaccines from metastatic nodes., Materials and Methods: We retrospectively examined preoperative MRI images of 684 axillae in 342 patients who underwent breast cancer surgery from June to October 2021. Lymphadenopathy was defined as cortical thickening or short axis ≥ 5 mm. The axilla was divided into ventral and dorsal parts on the axial plane using a perpendicular line extending from the most anterior margin of the muscle group, including the deltoid, latissimus dorsi, or teres major muscles, relative to a line along the lateral chest wall. We recorded the presence or absence of axillary lymphadenopathy in each area and the number of visible lymph nodes., Results: Of 80 axillae, 41 and 39 were included in the vaccine and metastasis groups, respectively. The median time from the last vaccination to MRI was 19 days in the vaccine group. The number of visible axillary lymph nodes was significantly higher in the vaccine group (median, 15 nodes) than in the metastasis group (7 nodes) (P < 0.001). Dorsal lymphadenopathy was observed in 16 (39.0%) and two (5.1%) axillae in the vaccine and metastasis groups, respectively (P < 0.001). If the presence of both ventral and dorsal lymphadenopathy is considered indicative of vaccine-induced reaction, this finding has a sensitivity of 34.1%, specificity of 97.4%, and positive and negative predictive values of 93.3％ and 58.5%, respectively., Conclusion: The presence of deep axillary lymphadenopathy may be an important factor for distinguishing post-vaccination lymphadenopathy from metastasis. The number of axillary lymph nodes may also help., (© 2023. The Author(s).)

Background: Cytology is a fast and simple modality for identifying malignancies and tumor histology. In this study, we analyzed the sensitivity of cytology for liver tumor biopsy and evaluated its potential for prompt clinical diagnosis., Methods: This retrospective study included patients who had concurrently undergone conventional cytology, on-site cytology, and histopathology for ultrasound-guided liver tumor biopsies. In the case of malignant tumors, malignancy was first diagnosed, then preliminary clinical diagnosis was established using histology based on cytology and clinical information, followed by histopathological diagnosis. Sensitivity of malignancy detection was evaluated by comparison with histopathological diagnosis., Results: Of the 191 tumors, 164 (85.9%) were malignant. The sensitivity of conventional cytology for malignancy detection was 97.6%. The sensitivity of non-hepatocellular carcinoma (non-HCC) (99.3%) detection was higher than that of the HCCs (87.5%; p = 0.001). The sensitivity of on-site cytology for malignancy detection was as high as that of conventional cytology. Similar to conventional cytology, the sensitivity of on-site cytology for non-HCC detection (99.3%) was higher than that for HCCs (79.2%; p < 0.001). In most cases of non-HCC tumors (126/140, 90.0%), accurate preliminary clinical diagnoses were obtained by combining on-site cytology with clinical information., Conclusion: Cytology of liver tumor biopsy has high sensitivity for malignancy, especially in non-HCC tumors. On-site cytology can contribute to the prompt clinical diagnosis of non-HCC tumors when combined with clinical information. This approach may be a reassuring modality for patients with severely advanced cancers requiring prompt clinical diagnosis and quick initiation of treatment owing to their deteriorating health., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aims: In patients with aortic stenosis (AS), the coronary flow reserve decreases even in the absence of epicardial coronary artery stenosis. Systolic coronary flow reversal (SFR) reflecting reduced coronary microcirculation, often seen in patients with severe AS, has a potential negative impact on the pathogenesis of cardiac dysfunction. However, there are limited data on the relationship between the severity of AS and SFR, as well as on the benefits of transcatheter aortic valve implantation (TAVI). The aim of this study was to evaluate the relationship between the severity of AS and efficacy of TAVI in improving SFR., Methods and Results: Consecutive patients with AS who had undergone TAVI using transoesophageal echocardiography (TEE) from November 2020 to February 2022 were prospectively enrolled. Coronary flow in the left anterior descending artery as well as the aortic valve peak velocities, and the mean aortic valve pressure gradients (AVPGs), indicating the severity of AS, were measured using intraprocedural TEE before and after TAVI. The following parameters were measured as coronary flow: systolic and diastolic peak velocity (cm/s) and systolic and diastolic velocity-time integral (VTI) (cm). SFR was defined as the presence of a reversal coronary flow component in systole. The enrolled patients were classified into two groups according to the presence or absence of SFR before TAVI. A total of 25 patients were included: 13 had SFR and 12 who had no SFR, before TAVI. Patients with SFR had significantly higher aortic valve peak velocities (451.1 ± 45.9 vs. 372.1 ± 52.1 cm/s; P < 0.001) and mean AVPGs (49.2 ± 14.5 vs. 30.3 ± 11.6 mmHg; P = 0.002) than those without. The optimal binary cut-off aortic valve peak velocity values and the mean AVPG associated with the presence of SFR before TAVI were >410.0 cm/s (specificity, 75.0%; sensitivity, 92.3%) and >37.4 mmHg (specificity, 83.3%; sensitivity, 92.3%), respectively. After TAVI, SFR immediately disappeared in 11 of 13 patients with SFR (84.6%). Overall, the systolic coronary VTI significantly increased after TAVI (2.0 ± 4.7 vs. 6.4 ± 3.2 cm, P < 0.001), and this increase was greater in patients with SFR than in those without SFR before TAVI (interaction P = 0.035)., Conclusions: SFR was found to be associated with the severity of AS and with a greater increase in systolic coronary flow immediately after TAVI., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Lipolanthine is a subclass of lanthipeptide that has the modification of lipid moiety at the N-terminus. A cryptic biosynthetic gene cluster comprising four genes (sinA, sinKC, sinD, and sinE) involved in the biosynthesis of lipolanthine was identified in the genome of an actinobacterium Sinosporangium siamense. Heterologous coexpression of a precursor peptide coding gene sinA and lanthipeptide synthetase coding gene sinKC in the host Escherichia coli strain BL21(DE3) resulted in the synthesis of a new lanthipeptide, sinosporapeptin. It contained unusual amino acids, including one labionin and two dehydrobutyrine residues, as determined using NMR and MS analyses. Another coexpression experiment with two additional genes of decarboxylase (sinD) and N-acetyl transferase (sinE) resulted in the production of a lipolanthine-like modified sinosporapeptin., (© 2023. The Author(s), under exclusive licence to Microbiological Society of Korea.)

Given that Thoroughbred horses' canter is an asymmetric gait, not only speed but also leading or trailing limbs could affect muscle activities. However, the muscle activity during a canter remains poorly understood. Hence, we aimed to investigate speed and lead-side (leading or trailing) effects on surface electromyography (sEMG) during a canter. The sEMG data were recorded from left Musculus brachiocephalicus (Br), M. infraspinatus (Inf), long head of M. triceps brachii (TB), M. gluteus medius (GM), M. semitendinosus (ST), and M. flexor digitorum longus of seven Thoroughbreds with hoof-strain gauges at the left hooves. Horses cantered on a flat treadmill at 7, 10, and 13 m/s for 25 s each without lead change. Subsequently, the horses trotted for 3 min and cantered at the same speed and duration in the opposite lead side ("leading" at the left lead and "trailing" at the right lead). The order of the lead side and speed was randomized. The mean of 10 consecutive stride durations, duty factors, integrated-EMG values (iEMG) for a stride, and muscle onset and offset timing were compared using a generalized mixed model (P < 0.05). Stride durations and duty factors significantly decreased with speed regardless of the lead side. In all muscles, iEMG at 13 m/s significantly increased compared with 7 m/s (ranging from +15% to +134%). The lead-side effect was noted in the iEMG of Br (leading > trailing, +47%), Inf (leading > trailing, +19%), GM (leading < trailing, +20%), and ST (leading < trailing, +19%). In TB, GM, and ST, muscle onset in trailing was earlier than the leading, while offset in the leading was earlier in Br. In conclusion, different muscles have different responses to speed and lead side; thus, both the lead side and running speed should be considered during training and/or rehabilitation including canter or gallop., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Takahashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), but currently available treatments do not improve kidney function or prevent the initiation of dialysis/kidney replacement therapy. A previous study demonstrated that bardoxolone methyl improves the estimated glomerular filtration rate (eGFR), but the study was prematurely terminated because of an imbalance in heart failure between treatment groups. The subsequent phase 2 TSUBAKI study demonstrated no incidence of heart failure and an improved eGFR and GFR as determined by inulin clearance in DKD patients., Methods: This randomized, double-blind, placebo-controlled multicentre phase 3 study was designed to assess the efficacy and safety of bardoxolone methyl in DKD patients with an eGFR ≥15.0-<60.0 ml/min/1.73 m2 and a urinary albumin:creatinine ratio (UACR) ≤3500 mg/g but without risk factors for heart failure. The primary endpoint is the time to onset of a ≥30% decrease in the eGFR or ESKD. Randomized patients (1:1) have been under treatment with once-daily oral bardoxolone methyl (5, 10 or 15 mg by intrapatient dose adjustment) or placebo for at least 3 years., Results: The mean age of the 1013 patients is 65.9 years, 21.5% are female, the mean eGFR is 37.84 ml/min/1.73 m2 and the median UACR is 351.80 mg/g., Conclusions: Appropriate patients are enrolled in this study. This study will investigate the long-term efficacy and safety of bardoxolone methyl in DKD patients covering a wider range of eGFR (≥15.0-<60.0 ml/min/1.73 m2) and albuminuria (≤3500 mg/g) compared with previous studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

We investigated the risk factors for epistaxis in Japanese flat races over a 20-year period. The veterinary records of horses identified as having epistaxis by endoscopy on the race day, and the official racing records of all flat races from April to September between 2001 and 2020, were reviewed. The racecourses ( n = 10), surface type, surface condition, race class, race distance, race year, sex, age, two training centers, ambient temperature, and body weight on race days were assessed using multivariable logistic regression ( p < 0.05). Of 475,709 race starts, 616 (1.30 cases per 1000 starts; 95% confidence interval [CI], 1.20-1.40) included an epistaxis event. Nine variables were significantly associated with epistaxis. Seven of the variables have been reported in previous studies: lower ambient temperature, soft surface conditions, shorter racing distances (≤1400 m), increasing age, females and geldings compared to males, training center, and race year. However, two novel variables were identified as significantly associated with epistaxis, increasing body weight per 20 kg ( p < 0.001, odds ratio [OR], 1.33; 95% CI, 1.25-1.41) and the racecourses that the horses were running at ( p < 0.001, especially Sapporo [OR; 4.74, 95% CI, 3.07-7.31], Hakodate [OR, 4.66; 95% CI, 3.05-7.11], and Kokura [OR, 4.14; 95% CI, 2.65-6.48] compared to the reference racecourse [Kyoto]). These results can facilitate developing interventions to reduce epistaxis in flat racing.

A series of Li 4/3-2 x /3 Zn x Ti 5/3- x /3 O 4 (LZTO) with 0 ≤ x ≤ 0.5 have received considerable interest as a negative electrode material for long-cycle-life lithium-ion batteries. However, their dynamic structural transformations under operating conditions have remained unknown, making an in-depth understanding essential for further improving the electrochemical performance. We, thus, performed almost simultaneous operando X-ray diffraction (XRD) and X-ray absorption spectroscopy (XAS) studies on x = 0.125, 0.375, and 0.5. The x = 0.5 sample, Li 2 ZnTi 3 O 8 , indicated differences in the cubic lattice parameter between the discharge and charge reactions ( δa c s), corresponding to the reversible movement of Zn 2+ ions between the tetrahedral and octahedral sites. δa c was also observed for x = 0.125 and 0.375, although the capacity region exhibiting δa c decreased with a decrease in x . For all of the samples, there is no significant difference in the nearest-neighbor distance of the Ti-O bond ( d Ti-O ) between the discharge and charge reactions. We also demonstrated different structural transformations between the micro- (XRD) and atomic (XAS) scales. In the case for x = 0.5, for instance, the maximum microscale change in a c was within +0.29(3)%, whereas at the atomic scale, d Ti-O changed by up to +4.8(3)%. Combined with our previous results for ex situ XRD and operando XRD/XAS measurements on other x compositions, the whole structural nature of LZTO, such as correspondence between a c and d Ti-O , origins for voltage hysteresis, and zero-strain reaction mechanisms, has been unveiled.

Background: Predicting the risk of malignant transformation in pancreatic cyst patients is challenging., Aim: We retrospectively investigated the risk factors for malignant transformation in pancreatic cyst patients., Methods: Patients with pancreatic cysts diagnosed using imaging tests were followed from November 2008 to December 2021. A significant change was defined as the additional development of high-risk stigmata (HRS), worrisome features (WFs), or pancreatic cancer during monitoring., Results: In total, 479 patients were analyzed, with a median observation period of 50 months. Forty-four patients (9.2%) showed significant changes, and eight (1.7%) developed pancreatic cancer. The univariate analysis showed that the cyst diameter at diagnosis (≥ 14 mm), main pancreatic duct (MPD) diameter at diagnosis (≥ 3 mm), presence of multilocular cysts, and an inconsistent MPD caliber were significant predictive factors for a significant change. One point was assigned for each significant factor. We grouped the patients into three groups: the low-risk group (total score 0), medium-risk group (score 1-2), and high-risk group (score 3-4). The high-risk group had a higher risk of a significant change than the medium- and low-risk groups (age-adjusted HRs for the medium-risk and high-risk groups were 3.0 and 5.2 compared with the low-risk group)., Conclusion: Stratification based on risk factors may help predict the development of significant changes in pancreatic cyst patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The adsorption isotherms, kinetics, and thermodynamics of fluoride ions (F - ) on FeOOH powders in water were investigated to obtain fundamental information on FeOOH powders, which are used as F - adsorbents in drinking and industrial water, and industrial wastewater. FeOOH powders were prepared as precipitates by mixing aqueous FeCl 3 and NaOH solutions (1:3 mol/mol) in the presence of 2,2,6,6,-tetramethylpiperidine-1-oxyl radical (TEMPO)-oxidized cellulose nanofibrils (TOCNs), carboxymethylcellulose (CMC), or TEMPO-oxidized cellulose (TOC) fibers (without nanofibrillation), and subsequent drying and pulverizing. The FeOOH:TOCN, FeOOH:CMC, and FeOOH:TOC dry mass ratios were controlled at 87:13. The amount of F - adsorbed by the FeOOH/TOCN powder per FeOOH mass was higher than those adsorbed by FeOOH, FeOOH/CMC, or FeOOH/TOC. The F - adsorption isotherms on the FeOOH-containing powders showed higher correlation coefficients with the Langmuir model than with the Freundlich model. This indicates that F - adsorbed on FeOOH initially formed a monolayer, predominantly via physical adsorption. Pseudo-second-order kinetics fitted well to the time-dependent F - adsorption behaviors on the FeOOH-containing powders. Thermodynamic analysis of F - adsorption on the FeOOH-containing powders showed that the ΔG values were negative, which indicates that F - adsorption on the FeOOH-containing powders proceeded spontaneously in water. The negative ΔG value for FeOOH/TOCN was higher than those for FeOOH, FeOOH/CMC, and FeOOH/TOC at the same temperature. This shows that the FeOOH/TOCN powder can be used as an excellent and efficient F - adsorbent in water., (© 2023. The Author(s).)

Aim: Appropriate sample selection with a tumor fraction ≥20% without necrosis contamination is required for successful cancer genomic profiling (CGP). Rapid on-site evaluation (ROSE) is performed to assess adequate sampling., Method: This retrospective study included 54 patients who underwent CGP using liver tumor biopsy specimen with ROSE., Result: The sampling success rate (98.1%) was higher than the previously reported 77.5%-88.9%. ROSE was performed once in 51 patients and twice in three patients; for those undergoing ROSE twice, the first ROSE was negative for malignancy, or showed few tumor cells with necrotic cell contamination, while the second ROSE obtained from another location showed abundant malignant cells. In these patients, the CGP was successful using the second specimen, though the first sample did not meet the required criteria for CGP test., Conclusion: Performing ROSE during liver tumor biopsy may be useful for CGP test sampling because ROSE prevents sampling errors and contributes to adequate sampling., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The relationship between the menstrual cycle and the oral microbiome has not been clarified. The purpose of this study was to assess potential changes in the oral microbiome of healthy young adults using 16S rRNA-based sequencing. Eleven females (aged 23-36 years) with stable menstrual cycles and without any oral problems were recruited. Saliva samples were collected before brushing every morning during the menstrual period. Based on basal body temperatures, menstrual cycles were divided into four phases, namely the menstrual, follicular, early luteal, and late luteal phases. Our results showed that the follicular phase had a significantly higher abundance ratio of the Streptococcus genus than the early and late luteal phases, whereas the abundance ratios of the Prevotella 7 and Prevotella 6 genera were significantly lower in the follicular phase than those in the early and late luteal phases and that in the early luteal phase, respectively. Alpha diversity by the Simpson index was significantly lower in the follicular phase than that in the early luteal phase, and beta diversity showed significant differences among the four phases. Using the relative abundance data and copy numbers of the 16S rRNA genes in the samples, the bacterial amounts in the four phases were compared, and we observed that the follicular phase had significantly lower amounts of the Prevotella 7 and Prevotella 6 genera than the menstrual and early luteal phase, respectively. These results indicate reciprocal changes with the Streptococcus genus and Prevotella genera, particularly in the follicular phase. In the present study, we showed that the oral microbiome profiles are affected by the menstrual cycles of healthy young adult females., 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 © 2023 Yamazaki, Ogura, Minami, Ogai, Horiguchi, Okamoto and Mukai.)

Negative electrode materials with high thermal stability are a key strategy for improving the safety of lithium-ion batteries for electric vehicles without requiring built-in safety devices. To search for crucial clues into increasing the thermal stability of these materials, we performed differential scanning calorimetry (DSC) and in situ high-temperature (HT)-X-ray diffraction (XRD)/X-ray absorption (XAS) up to 450 °C with respect to a solid-solution compound of Li 4/3-2 x /3 Zn x Ti 5/3- x /3 O 4 with 0 ≤ x ≤ 0.5. The DSC profile of fully discharged x = 0.5 (Li 2 ZnTi 3 O 8 ) with a LiPF 6 -based electrolyte could be divided into three temperature ( T ) regions: (i) T ≤ 250 °C for Δ H accum i , (ii) 250 °C < T ≤ 350 °C for Δ H accum ii , and (iii) T > 350 °C for Δ H accum iii , where Δ H accum n is the accumulated change in enthalpy in region n . The HT-XRD/XAS analyses clarified that Δ H accum i and Δ H accum ii originated from the decomposition of solid electrolyte interphase (SEI) films and the formation of a LiF phase, respectively. Comparison of the DSC profiles with x = 0 (Li[Li 1/3 Ti 5/3 ]O 4 ) and graphite revealed the operating voltage, i.e., amount of SEI films, and stability of the crystal lattice play significant roles in the thermal stability of negative electrode materials. Indeed, the highest thermal stability was attained at x = 0.25 using this approach.

Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs., (© 2023. The Author(s).)

Stimulator of interferon genes (STING) is an ER-localized transmembrane protein and the receptor for 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which is a second messenger produced by cGAMP synthase (cGAS), a cytosolic double-stranded DNA sensor. The cGAS-STING pathway plays a critical role in the innate immune response to infection of a variety of DNA pathogens through the induction of the type I interferons. Pharmacological activation of STING is a promising therapeutic strategy for cancer, thus the development of potent and selective STING agonists has been pursued. Here we report that mouse STING can be activated by phenylarsine oxide (PAO), a membrane permeable trivalent arsenic compound that preferentially reacts with thiol group of cysteine residue (Cys). The activation of STING with PAO does not require cGAS or cGAMP. Mass spectrometric analysis of the peptides generated by trypsin and chymotrypsin digestion of STING identifies several PAO adducts, suggesting that PAO covalently binds to STING. Screening of STING variants with single Cys to serine residues (Ser) reveals that Cys88 and Cys291 are critical to the response to PAO. STING activation with PAO, as with cGAMP, requires the ER-to-Golgi traffic and palmitoylation of STING. Our results identify a non-nucleotide STING agonist that does not target the cGAMP-binding pocket, and demonstrate that Cys of STING can be a novel target for the development of STING agonist.Key words: STING agonist, cysteine modification, innate immunity, phenylarsine oxide.

Objective Pancreatic cystic lesions (PCLs) are known risk factors for pancreatic cancer. Therefore, this study explored the predictors identifying PCLs in a general population and developed a scoring system to help more efficiently diagnose these entities during medical checkups. Methods We reviewed 9,369 examinees of abdominal ultrasound (AUS) during medical checkups between January 2013 and November 2019. Predictors of PCLs were identified using a multivariate logistic regression analysis, and we constructed a scoring system based on these predictors. Results PCLs were detected in 118 (1.3%). Age 50-59 years old [odds ratio (OR) 2.52, 95% confidence interval (CI) 1.18-5.35], 60-69 years old (OR 3.91, 95% CI 1.86-8.26), and ≥70 years old (OR 10.5, 95% CI 5.03-21.7) as well as abdominal pain (OR 1.85, 95% CI 1.14-3.00), alcohol consumption (OR 1.72, 95% CI 1.03-2.89), a family history of pancreatic cancer (OR 2.41, 95% CI 1.09-5.34), and pre-diabetes or diabetes (OR 1.78, 95% CI 1.05-3.00) were predictors of PCLs. The following scores were assigned according to regression coefficients: age (50-59 years old, 1 point; 60-69 years old, 1.5 points; ≥70 years old, 2.5 points); abdominal pain, 1 point, alcohol consumption, 1 point; a family history of pancreatic cancer, 1 point; and pre-diabetes, 1 point. The PCL detection rate increased with the total score: 0.2% for total score 0 point, 5.4% for ≥4.0 points. The area under the curve of the scoring system was 0.75 (95% CI 0.70-0.79). Conclusion Our scoring system allows the risk of PCLs to be determined and may help more efficiently diagnose these entities.