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Chemical genetics is a multidisciplinary research method. In this study, it is used to screen compounds that promote aluminum-induced malate secretion in Arabidopsis thaliana. Inhibition of p38 mitogen-activated protein kinase (p38 MAPK; LY2228820) significantly increased the transcription of Arabidopsis thaliana aluminum-activated malate transporter 1 (AtALMT1) and sensitive to proton rhizotoxicity 1 (STOP1)-regulated genes, multidrug and toxic compound extrusion and aluminum sensitive 3, but not AtSTOP1 and the Al-biomarker genes At3g28510, At5g13320, suggesting that LY2228820 increased the early expression of STOP1-regulated genes without affecting AtSTOP1 expression. Inhibition of p38 MAPK (LY2228820) and Aurora A (MLN8237) increased aluminum-activated malate transport via AtALMT1, suggesting that both MLN8237 and LY2228820 interfere with AtALMT1 activity. An increase in root elongation was also observed in Arabidopsis after applying compounds LY2228820 and MLN8237. Thus, both LY2228820 and MLN8237 may play important roles in alleviating the inhibitory effects of aluminum on roots., (© 2024. The Author(s) under exclusive licence to The Botanical Society of Japan.)

Lysine-specific demethylase 1 (LSD1/KDM1A) is a pivotal epigenetic enzyme that contributes to several malignancies including malignant glioma. LSD1 is a flavin adenine dinucleotide dependent histone demethylase that specifically targets histone H3 lysine (K) 4 mono- (me1) and di-methylation (me2) and H3K9me1/2 for demethylation. Herein we report the development of an LSD inhibitor, S2172, which efficiently penetrates the blood-brain barrier. S2172 effectively suppresses LSD1 enzymatic activity, resulting in the depletion of cell growth both in vitro in glioma stem cells (GSCs) (mean half-maximal inhibitory concentration (IC 50 ) of 13.8 μM) and in vivo in a GSC orthotopic xenograft mouse model. Treatment with S2172 robustly reduced the expression of the stemness-related genes MYC and Nestin in GSC cells. Consistent with this, chromatin immunoprecipitation-sequencing revealed a significant S2172-dependent alteration in H3K4me2/H3K4me3 status. Furthermore, we identified 284 newly acquired H3K4me2 peak regions after S2172 treatment, which were encompassed within super-enhancer regions. The altered H3K4me2/H3K4me3 status induced by S2172 treatment affected the expression of genes related to tumorigenesis. Our data suggest that targeting LSD1 with S2172 could provide a promising treatment option for glioblastomas, particularly due to targeting of GSC populations., (© 2024. The Author(s).)

Aluminium (Al 3+ ) toxicity in acidic soils poses a significant challenge for crop cultivation and reduces crop productivity. The primary defense mechanism against Al 3+ toxicity involves the activation of organic acid secretion. In this study, responses of 9 Vigna mungo cultivars to Al 3+ toxicity were investigated, with a particular emphasis on the root system and crucial genes involved in Al 3+ tolerance using molecular cloning and expression analysis. Sensitive blackgram-KM2 cultivars exposed to 100-µM Al 3+ toxicity for 72 h exhibited a root-growth inhibition of approximately 66.17%. Significant loss of membrane integrity and structural deformative roots were found to be the primary symptoms of Al 3+ toxicity in blackgram. MATE (Multidrug and Toxic Compound Extrusion) and ALS3 (Aluminium Sensitive 3) genes were successfully cloned from a sensitive blackgram cv KM2 with phylogenetic analysis revealing their evolutionary relationship to Vigna radiata and Glycine max. The MATE gene is mainly localized in the plasma membrane, and highly expressed under Al 3+ , thus suggesting its role in transports of citrate-Al 3+ complexes, and detoxifying Al 3+ within plant cells. In addition, ALS3 was also induced under Al 3+ toxicity, which codes the UDP-glucose transporter and is required for the maintenance of ions homeostasis. In summary, this study highlights the understanding of Al 3+ toxicity and underlying molecular mechanisms linked to the efflux of organic acid in blackgram, ultimately aiding the framework for the development of strategies to enhance the resilience of blackgram and other pulse crops in Al-rich soils., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC 50  = 0.024 μM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y.N., T. Su., N.H., R.N., M.Y., A.I., and F.S. are listed as inventors on a PCT international patent application (WO/2021/106988) that covers compound 7i, a compound studied in this paper. The remaining authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: The utilization of long-term effect of internet of things (IoT) on glycemic control is controversial. This trial aimed to examine the effect of an IoT-based approach for type 2 diabetes., Materials and Methods: This randomized controlled trial enrolled 1,159 adults aged 20-74 years with type 2 diabetes with a HbA1c of 6.0-8.9% (42-74 mmol/mol), who were using a smartphone on a daily basis were randomly assigned to either the IoT-based approach group (ITG) or the control group (CTG). The ITG were supervised to utilize an IoT automated system that demonstrates a summary of lifelogging data (weight, blood pressure, and physical activities) and provides feedback messages that promote behavioral changes in both diet and exercise. The primary end point was a HbA1c change over 52 weeks., Results: Among the patients, 581 were assigned to the ITG and 578 were in the CTG. The changes in HbA1c from baseline to the final measurement at 52 weeks [mean (standard deviation)] were -0.000 (0.6225)% in ITG and - 0.006 (0.6449)% in CTG, respectively (P = 0.8766). In the per protocol set, including ITG using the IoT system almost daily and CTG, excluding those using the application almost daily, the difference in HbA1c from baseline to 52 weeks were -0.098 (0.579)% and 0.027 (0.571)%, respectively (P = 0.0201). We observed no significant difference in the adverse event profile between the groups., Conclusions: The IoT-based approach did not reduce HbA1c in patients with type 2 diabetes. IoT-based intervention using data on the daily glycemic control and HbA1c level may be required to improve glycemic control., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objectives: The Cancer Control Act requires the maintenance of regional cooperation pathways (RCP) for cancer treatment. In 2008, we started RCP for early detection of new gastric cancer after endoscopic submucosal dissection (ESD). In gastric cancer treatment, RCP after surgical resection had been widely used, but little is known about RCP after ESD. This study aimed to evaluate the effectiveness of RCP after ESD., Methods: This study included 465 patients on whom our RCP was implemented from 2008 to 2018. A regional family physician performed surveillance endoscopy at 3 months and 1 year after ESD and annually thereafter. We retrospectively evaluated the cumulative incidence and treatment outcomes of new gastric cancer and compared them with previous reports., Results: During a median follow-up period of 70.5 months (3-120 months), 58 patients developed new gastric cancers, and metachronous gastric cancer was detected in 55 patients more than 1 year after ESD. The 5-year cumulative incidence rate was 9.8%. Three patients did not want treatment. Among the remaining 55 patients, the initial treatment was ESD in 51 and surgical resection in 4. Eventually, 50 patients (48 in the ESD group and 2 in the surgical resection group) fulfilled the pathologic criteria for curative ESD. There were no deaths due to gastric cancer., Conclusion: Our study was the first to reveal the incidence of new gastric cancer after ESD using RCP. Most lesions were cured with ESD, and no patients died of gastric cancer. Therefore, we consider RCPs to be an option for surveillance after ESD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cholesteatoma is a benign tumor of the middle ear. Tympanoplasty is performed to remove cholesteatoma, prevent recurrence, and avoid complications. Previously, microscopy was used for tympanoplasty; however, endoscopy has become increasingly popular for this procedure. The effectiveness of endoscopy and the appropriate candidacy for endoscopic ear surgery remain controversial. In this retrospective chart review study, we enrolled 107 patients with cholesteatoma who underwent tympanoplasty and compared the microscopic approach (71 patients) and the endoscopic approach (36 patients) at different stages to clarify the benefits of using endoscopy and to determine candidacy for endoscopic ear surgery. Approach selection, complication rate, recurrence rate, and postoperative hearing threshold were compared between microscopic and endoscopic approaches in stages I, II, and III. Endoscopy was used more often than microscopy for early-stage (stage I) cholesteatoma ( p = 0.005) and less frequently for advanced-stage (stage II) cholesteatoma ( p = 0.02). Endoscopy surgery resulted in chorda tympani injury less often than microscopic surgery ( p = 0.049); however, there were no significant differences between these two groups in terms of recurrence rate or postoperative hearing outcome. Endoscopy is particularly useful for early-stage cholesteatoma, and both approaches show no difference in hearing outcome in stage I and II; nevertheless, further research is required to determine an appropriate approach for more advanced stages (stage III).

Aims: High uric acid (HUA), as a pro-oxidant, plays a significant role in the pathophysiology of cardiovascular disease. Studies have indicated that elevated uric acid levels can adversely affect cardiovascular health. Nevertheless, the impact of hyperuricemia on cardiomyopathy remains uncertain. Further research is needed to elucidate the relationship between HUA and cardiomyopathy, shedding light on its potential implications for heart health. Results: We demonstrated that uricase knockout (Uox-KO) mice accelerated the development of cardiomyopathy, causing significantly impaired cardiac function and myocardial fibrosis. Meanwhile, the mitochondrial morphology was destroyed, the lipid peroxidation products increased in number and the antioxidant function was weakened. In addition, we evaluated the effects of ferrostatin-1 (Fer-1), the ferroptosis inhibitor. Myocardial damage can be reversed by the Fer-1 treatment caused by HUA combined with doxorubicin (DOX) treatment. Benzbromarone, a uric acid-lowering drug, decreases myocardial fibrosis, and ferroptosis by alleviating hyperuricemia in Uox-KO mice by DOX administration. In vitro, we observed that the activity of cardiomyocytes treated with HUA combined with DOX decreased significantly, and lipid reactive oxygen species (ROS) increased significantly. Afterward, we demonstrated that HUA can promote oxidative stress in DOX, characterized by increased mitochondrial ROS, and downregulate protein levels of glutathione peroxidase 4 (GPX4). N -acetyl-l-cysteine, an antioxidant, inhibits the process by which HUA promotes DOX-induced ferroptosis by increasing the GPX4 expression. Innovation: We verified that HUA can exacerbate myocardial damage. This has clinical implications for the treatment of cardiac damage in patients with hyperuricemia. Conclusions: Our data suggested that HUA promotes the cardiomyopathy. HUA promotes DOX-induced ferroptosis by increasing oxidative stress and downregulating GPX4. Antioxid. Redox Signal. 00, 00-00.

This review presents a comprehensive history of Artificial Intelligence (AI) in the context of the revolutionary application of machine learning (ML) to medical research and clinical utilization, particularly for the benefit of researchers interested in the application of ML in otology. To this end, we discuss the key components of ML-input, output, and algorithms. In particular, some representation algorithms commonly used in medical research are discussed. Subsequently, we review ML applications in otology research, including diagnosis, influential identification, and surgical outcome prediction. In the context of surgical outcome prediction, specific surgical treatments, including cochlear implantation, active middle ear implantation, tympanoplasty, and vestibular schwannoma resection, are considered. Finally, we highlight the obstacles and challenges that need to be overcome in future research., Competing Interests: Declaration of competing interest The author has no conflict of interest to disclose regarding this article., (Copyright © 2024. Published by Elsevier B.V.)

Agriculture and changing environmental conditions are closely related, as weather changes could adversely affect living organisms or regions of crop cultivation. Changing environmental conditions trigger different abiotic stresses, which ultimately cause the accumulation of reactive oxygen species (ROS) in plants. Common ROS production sites are the chloroplast, endoplasmic reticulum, plasma membrane, mitochondria, peroxisomes, etc. The imbalance in ROS production and ROS detoxification in plant cells leads to oxidative damage to biomolecules such as lipids, nucleic acids, and proteins. At low concentrations, ROS initiates signaling events related to development and adaptations to abiotic stress in plants by inducing signal transduction pathways. In plants, a stress signal is perceived by various receptors that induce a signal transduction pathway that activates numerous signaling networks, which disrupt gene expression, impair the diversity of kinase/phosphatase signaling cascades that manage the stress response in the plant, and result in changes in physiological responses under various stresses. ROS production also regulates ABA-dependent and ABA-independent pathways to mitigate drought stress. This review focuses on the common subcellular location of manufacturing, complex signaling mechanisms, and networks of ROS, with an emphasis on cellular effects and enzymatic and non-enzymatic antioxidant scavenging mechanisms of ROS in Poaceae crops against drought stress and how the manipulation of ROS regulates stress tolerance in plants. Understanding ROS systems in plants could help to create innovative strategies to evolve paths of cell protection against the negative effects of excessive ROS in attempts to improve crop productivity in adverse environments.

Measuring mechanical forces of cell-cell interactions is important for studying morphogenesis in multicellular organisms. We previously reported an image-based statistical method for inferring effective mechanical potentials of pairwise cell-cell interactions by fitting cell tracking data with a theoretical model. However, whether this method is applicable to tissues with non-cellular components such as cavities remains elusive. Here we evaluated the applicability of the method to cavity-harboring tissues. Using synthetic data generated by simulations, we found that the effect of expanding cavities was added to the pregiven potentials used in the simulations, resulting in the inferred effective potentials having an additional repulsive component derived from the expanding cavities. Interestingly, simulations by using the effective potentials reproduced the cavity-harboring structures. Then, we applied our method to the mouse blastocysts, and found that the inferred effective potentials can reproduce the cavity-harboring structures. Pairwise potentials with additional repulsive components were also detected in two-dimensional cell sheets, by which curved sheets including tubes and cups were simulated. We conclude that our inference method is applicable to tissues harboring cavities and cell sheets, and the resultant effective potentials are useful to simulate the morphologies., 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 Koyama, Okumura, Otani, Ito, Nakamura, Kato and Fujimori.)

Optimal timing for intubating patients with coronavirus disease 2019 (COVID-19) has been debated throughout the pandemic. Early use of high-flow nasal cannula (HFNC) can help reduce the need for intubation, but delay can result in poorer outcomes. This study examines trends in laboratory parameters and serum severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA levels of patients with COVID-19 in relation to HFNC failure. Patients requiring HFNC within three days of hospitalization between July 1 and September 30, 2021 were enrolled. The primary outcome was HFNC failure (early failure ≤Day 3; late failure ≥Day 4), defined as transfer to intensive care just before/after intubation or in-hospital death. We examined changes in laboratory markers and SARS-CoV2-RNAemia on Days 1, 4, and 7, together with demographic data, oxygenation status, and therapeutic agents. We conducted a univariate logistic regression with the explanatory variables defined as 10% change rate in each laboratory marker from Day 1 to 4. We utilized the log-rank test to assess the differences in HFNC failure rates, stratified based on the presence of SARS-CoV2 RNAemia. Among 122 patients, 17 (13.9%) experienced HFNC failure (early: n = 6, late: n = 11). Seventy-five patients (61.5%) showed an initial SpO2/FiO2 ratio ≤243, equivalent to PaO2/FiO2 ratio ≤200, and the initial SpO2/FiO2 ratio was significantly lower in the failure group (184 vs. 218, p = 0.018). Among the laboratory markers, a 10% increase from Day 1 to 4 of lactate dehydrogenase (LDH) and interleukin (IL)-6 was associated with late failure (Odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.09-1.89 and OR: 1.04, 95%CI: 1.00-1.19, respectively). Furthermore, in patients with persistent RNAemia on Day 4 or 7, the risk of late HFNC failure was significantly higher (Log-rank test, p<0.01). In conclusion, upward trends in LDH and IL-6 levels and the persistent RNAemia even after treatment were associated with HFNC failure., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Koyama 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.)

Objective: This study aimed to evaluate the differences in electrically evoked compound action potential (ECAP) thresholds and postoperative mapping current (T) levels between electrode types after cochlear implantation, the correlation between ECAP thresholds and T levels, and the performance of machine learning techniques in predicting postoperative T levels., Study Design: Retrospective case review., Setting: Tertiary hospital., Patients: We reviewed the charts of 124 ears of children with severe-to-profound hearing loss who had undergone cochlear implantation., Interventions: We compared ECAP thresholds and T levels from different electrodes, calculated correlations between ECAP thresholds and T levels, and created five prediction models of T levels at switch-on and 6 months after surgery., Main Outcome Measures: The accuracy of prediction in postoperative mapping current (T) levels., Results: The ECAP thresholds of the slim modiolar electrodes were significantly lower than those of the straight electrodes on the apical side. However, there was no significant difference in the neural response telemetry thresholds between the two electrodes on the basal side. Lasso regression achieved the most accurate prediction of T levels at switch-on, and the random forest algorithm achieved the most accurate prediction of T levels 6 months after surgery in this dataset., Conclusion: Machine learning techniques could be useful for accurately predicting postoperative T levels after cochlear implantation in children., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

Objective: To investigate if cartilage conduction (CC) rerouting devices are noninferior to air-conduction (AC) rerouting devices for single-sided deafness (SSD) patients by measuring objective and subjective performance using speech-in-noise tests that resemble a realistic hearing environment, sound localization tests, and standardized questionnaires., Study Design: Prospective, single-subject randomized, crossover study., Setting: Anechoic room inside a university., Patients: Nine adults between 21 and 58 years of age with severe or profound unilateral sensorineural hearing loss., Interventions: Patients' baseline hearing was assessed; they then used both the cartilage conduction contralateral routing of signals device (CC-CROS) and an air-conduction CROS hearing aid (AC-CROS). Patients wore each device for 2 weeks in a randomly assigned order., Main Outcome Measures: Three main outcome measures were 1) speech-in-noise tests, measuring speech reception thresholds; 2) proportion of correct sound localization responses; and 3) scores on the questionnaires, "Abbreviated Profile of Hearing Aid Benefit" (APHAB) and "Speech, Spatial, and Qualities of Hearing Scale" with 12 questions (SSQ-12)., Results: Speech reception threshold improved significantly when noise was ambient, and speech was presented from the front or the poor-ear side with both CC-CROS and AC-CROS. When speech was delivered from the better-ear side, AC-CROS significantly improved performance, whereas CC-CROS had no significant effect. Both devices mainly worsened sound localization, whereas the APHAB and SSQ-12 scores showed benefits., Conclusion: CC-CROS has noninferior hearing-in-noise performance except when the speech was presented to the better ear under ambient noise. Subjective measures showed that the patients realized the effectiveness of both devices., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

Several crustaceans including shrimps change the amount of specific free amino acids to regulate the osmotic pressure in their bodies. Kuruma shrimp Penaeus japonicus also increases the concentration of alanine (Ala) in the abdominal muscle following the increase of environmental salinity. In the present study, to elucidate the mechanisms of changes in Ala accumulation of kuruma shrimp depending on salinity, we cloned the gene encoding alanine aminotransferase (ALT), an enzyme involved in Ala biosynthesis, and examined its expression profile. It was found that the full-length kuruma shrimp ALT1 cDNA consisted of 3,301 bp, encoding 514 amino acids, and that all amino acid residues important for ALT activity were conserved. Phylogenetic analysis also indicated that the ALT gene cloned in this study was classified as ALT1. Moreover, we examined the expression levels of the ALT1 gene in the abdominal muscle and the hepatopancreas of kuruma shrimp acclimated at 17‰, 34‰, and 40‰ salinities, resulting that the mRNA levels of the ALT1 genes in both tissues of the shrimp acclimated at 40‰ were significantly higher than those at 17‰ for 12 h (p < 0.05). The mRNA levels of the ALT1 gene in the abdominal muscle of the shrimp acclimated for more than 24 h tended to increase following the increase of environmental salinity. These results indicate that ALT1 is responsible for the increase of free Ala concentration in the abdominal muscle of kuruma shrimp to regulate osmotic pressure at high salinity., (© 2024 Wiley Periodicals LLC.)

Hearing is an essential sensation, and its deterioration leads to a significant decrease in the quality of life. Thus, great efforts have been made by otologists to preserve and recover hearing. Our knowledge regarding the field of otology has progressed with advances in technology, and otologists have sought to develop novel approaches in the field of otologic surgery to achieve higher hearing recovery or preservation rates. This requires knowledge regarding the anatomy of the temporal bone and the physiology of hearing. Basic research in the field of otology has progressed with advances in molecular biology and genetics. This review summarizes the current views and recent advances in the field of otology and otologic surgery, especially from the viewpoint of young Japanese clinician-scientists, and presents the perspectives and future directions for several topics in the field of otology. This review will aid next-generation researchers in understanding the recent advances and future challenges in the field of otology., Competing Interests: Declaration of Competing Interest MH was founding scientists of Otolink Inc. Other authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2024. Published by Elsevier B.V.)

Background: Anthropogenic gadolinium (Gd), originating from Gd-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI), is widely identified in the aquatic environment with concerns about toxicity and accumulation. We aimed to present new data on anthropogenic Gd in the Tone River, which has the largest drainage area in Japan, and then to compare the current data with those obtained in 1996., Methods: The water samples were collected on August 9-10, 2020, at 15 different locations of the Tone River in Japan. The concentrations of the rare earth elements (REEs) were measured by inductively coupled plasma-mass spectrometry and normalized to Post-Archean Australian Shale to construct shale-normalized REE patterns. The degree of Gd-anomaly was defined as the percentage of anthropogenic Gd to the geogenic background and used to compare the water samples from different locations. Pearson's correlation coefficients were calculated., Results: All the samples displayed positive Gd anomalies. The Gd-anomaly ranged from 121 to 6,545% and displayed a repeating decrease-and-increase trend. The Gd-anomaly showed strong positive correlations to the number of hospitals (r = 0.88; p < 0.001) and their MRI units (r = 0.89; p < 0.001)., Conclusions: Our study revealed notable anomalies of Gd concentrations in river water in Japan, with strong positive correlations to the number of major hospitals and their MRI units. Compared with the previous report in 2000, the Gd-anomaly in Tone River increased from 851% (sampled in 1996) to 6,545%, i.e., 7.7 times, reflecting the increased use of GBCAs in hospitals., Relevance Statement: Notable Gd concentration anomalies in river water in Japan were observed. This result underlines the importance of more extensive research on anthropogenic gadolinium, and investigations of risks to human health as well as the development of effective removal technologies may be necessary., Key Points: • All water samples from Tone River displayed positive Gd anomalies. • The Gd anomalies increased to 7.7 times higher over the past 24 years. • Correlations between Gd values and the number of hospitals and MRI units were observed., (© 2024. The Author(s).)

In nonequilibrium statistical physics, quantifying the nearest (and higher-order) neighbors and free volumes of particles in many-body systems is crucial to elucidating the origin of macroscopic collective phenomena, such as glass/granular jamming transitions and various aspects of the behavior of active matter. However, conventional techniques (based on a fixed-distance cutoff or the Voronoi construction) have mainly been applied to equilibrated, homogeneous, and monodisperse particle systems. In this paper, we implement simple and efficient methods for local structure analysis in nonequilibrium, inhomogeneous, and polydisperse hard disk systems. We show how these novel methods can overcome the difficulties encountered by conventional techniques as well as demonstrate some applications., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Dystonia is thought to arise from abnormalities in the motor loop of the basal ganglia; however, there is an ongoing debate regarding cerebellar involvement. We adopted an established cerebellar dystonia mouse model by injecting ouabain to examine the contribution of the cerebellum. Initially, we examined whether the entopeduncular nucleus (EPN), substantia nigra pars reticulata (SNr), globus pallidus externus (GPe) and striatal neurons were activated in the model. Next, we examined whether administration of a dopamine D1 receptor agonist and dopamine D2 receptor antagonist or selective ablation of striatal parvalbumin (PV, encoded by Pvalb)-expressing interneurons could modulate the involuntary movements of the mice. The cerebellar dystonia mice had a higher number of cells positive for c-fos (encoded by Fos) in the EPN, SNr and GPe, as well as a higher positive ratio of c-fos in striatal PV interneurons, than those in control mice. Furthermore, systemic administration of combined D1 receptor agonist and D2 receptor antagonist and selective ablation of striatal PV interneurons relieved the involuntary movements of the mice. Abnormalities in the motor loop of the basal ganglia could be crucially involved in cerebellar dystonia, and modulating PV interneurons might provide a novel treatment strategy., Competing Interests: Competing interests The Department of Advanced Brain Research is a joint research department with Beauty Life Corporation. There are no other competing interests to disclose., (© 2024. Published by The Company of Biologists Ltd.)

Aims: Glomerular damage and proximal tubular damage play an important role in the pathogenesis of diabetic kidney disease. This study aimed to investigate the relationship between the urinary markers of proximal tubular injury, including urinary liver-type fatty acid-binding protein-to-creatinine ratio (uL-FABP/Cr) and urinary N-acetyl-β-D-glucosaminidase-to-creatinine ratio (uNAG/Cr), and glycemic control status., Methods: This cross-sectional study included 245 and 39 patients with type 2 diabetes mellitus (T2DM) and non-T2DM (NDM), respectively. The participants of this study were fitted with retrospective CGM, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated., Results: The results were presented as medians (interquartile ranges). The uL-FABP/Cr was significantly higher in the microalbuminuria than in the normo-albuminuria group [4.2 (2.7-7.1) and 2.2 (1.4-3.4) μg/gCr, respectively, P < 0.001], while the uNAG/Cr in the normo-albuminuria group [6.3 (4.5-10.1) U/gCr] was significantly higher than that in the NDM group [5.3 (3.8-6.3) U/gCr, P = 0.048] but significantly lower than that in the microalbuminuria group [9.2 (6.4-11.1) U/gCr, P = 0.004]. The multivariate logistic regression analysis indicated that CGM-derived TIR was significantly associated with the urinary albumin-to-creatinine ratio [uAlb/Cr, odds ratio (OR) 0.985, 95% confidence interval (CI) 0.971-0.998, P = 0.029] and uNAG/Cr (OR 0.973, 95% CI 0.957-0.989, P = 0.001) independent of renal function. GRI was similarly associated with uAlb/Cr and uNAG/Cr., Conclusion: The findings of this study indicated that uNAG/Cr was elevated before albuminuria development and was associated with CGM-derived TIR and GRI., (© 2023. The Author(s).)

Background: Heat shock proteins (HSPs) are present throughout the brain. They function as molecular chaperones, meaning they help with the folding and unfolding of large protein complexes. These chaperones are vital in the development of neuropathological conditions such as Alzheimer's disease and Lewy body disease, with HSP90, a specific subtype of HSP, playing a key role. Many studies have shown that drugs that inhibit HSP90 activity have beneficial effects in the neurodegenerative diseases. Therefore, HSP90 PET imaging ligand can be used effectively to study HSP90 in neurodegenerative diseases. Among four HSP90 isoforms, two cytosolic isoforms (HSP90α and HSP90β) thought to be involved in the structural homeostasis of the proteins related to the neurodegenerative diseases. Currently, no useful PET imaging ligands selectively targeting the two cytosolic isoforms of HSP90 have been available yet., Results: In this study, we developed a novel positron emission tomography (PET) imaging ligand, [ 11 C]BIIB021, by 11 C-radiolabeling (a positron emitter with a half-life of 20.4 min) 6-Chloro-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-2-amine (BIIB021), an inhibitor with a high affinity for and selectivity to HSP90α and HSP90β. [ 11 C]BIIB021 was synthesized with a high yield, molar activity and radiochemical purity. [ 11 C]BIIB021 showed a high binding affinity for rat brain homogenate as well as human recombinant HSP90α and HSP90β proteins. Radioactivity was well detected in the rat brain (SUV 1.4). It showed clear specific binding in PET imaging of healthy rats and autoradiography of healthy rat and human brain sections. Radiometabolite was detected in the brain, however, total distribution volume was well quantified using dual-input graphical model. Inhibition of p-glycoprotein increased brain radioactivity concentrations. However, total distribution volume values with and without p-glycoprotein inhibition were nearly the same., Conclusions: We have developed a new PET imaging agent, [ 11 C]BIIB021, specifically targeting HSP90α/β. We have been successful in synthesizing [ 11 C]BIIB021 and in vitro and in vivo imaging HSP90α/β. However, the quantification of HSP90α/β is complicated by the presence of radiometabolites in the brain and the potential to be a substrate for p-glycoprotein. Further efforts are needed to develop radioligand suitable for imaging of HSP90α/β., (© 2024. The Author(s).)

Although adverse events related to extracorporeal membrane oxygenation have been reported, epidemiological data on life-threatening events are insufficient to study the causes of such adverse events. Data from the Japan Council for Quality Health Care database were retrospectively analyzed. The adverse events extracted from this national database included events associated with extracorporeal membrane oxygenation reported between January 2010 and December 2021. We identified 178 adverse events related to extracorporeal membrane oxygenation. At least 41 (23%) and 47 (26%) accidents resulted in death and residual disability, respectively. The most common adverse events were cannula malposition (28%), decannulation (19%), and bleeding (15%). Among patients with cannula malposition, 38% did not undergo fluoroscopy-guided or ultrasound-guided cannulation, 54% required surgical treatment, and 18% required trans-arterial embolization. In this epidemiological study in Japan, 23% of the adverse events related to extracorporeal membrane oxygenation had fatal outcomes. Our findings suggest that a training system for cannulation techniques may be needed, and hospitals offering extracorporeal membrane oxygenation should perform emergency surgeries., (© 2023. The Author(s).)

Purpose: Several reporting systems have been proposed for providing standardized language and diagnostic categories aiming for expressing the likelihood that lung abnormalities on CT images represent COVID-19. We developed a machine learning (ML)-based CT texture analysis software for simple triage based on the RSNA Expert Consensus Statement system. The purpose of this study was to conduct a multi-center and multi-reader study to determine the capability of ML-based computer-aided simple triage (CAST) software based on RSNA expert consensus statements for diagnosis of COVID-19 pneumonia., Methods: For this multi-center study, 174 cases who had undergone CT and polymerase chain reaction (PCR) tests for COVID-19 were retrospectively included. Their CT data were then assessed by CAST and consensus from three board-certified chest radiologists, after which all cases were classified as either positive or negative. Diagnostic performance was then compared by McNemar's test. To determine radiological finding evaluation capability of CAST, three other board-certified chest radiologists assessed CAST results for radiological findings into five criteria. Finally, accuracies of all radiological evaluations were compared by McNemar's test., Results: A comparison of diagnosis for COVID-19 pneumonia based on RT-PCR results for cases with COVID-19 pneumonia findings on CT showed no significant difference of diagnostic performance between ML-based CAST software and consensus evaluation (p > 0.05). Comparison of agreement on accuracy for all radiological finding evaluations showed that emphysema evaluation accuracy for investigator A (AC = 91.7%) was significantly lower than that for investigators B (100%, p = 0.0009) and C (100%, p = 0.0009)., Conclusion: This multi-center study shows COVID-19 pneumonia triage by CAST can be considered at least as valid as that by chest expert radiologists and may be capable for playing as useful a complementary role for management of suspected COVID-19 pneumonia patients as well as the RT-PCR test in routine clinical practice., (© 2023. The Author(s).)

Various complications can influence hematopoietic cell transplantation (HCT) outcomes. Renal complications can occur during the early to late phases of HCT along with various factors. However, studies focusing on fatal renal complications (FRCs) are scarce. Herein, we analyzed 36,596 first allogeneic HCT recipients retrospectively. Overall, 782 patients died of FRCs at a median of 108 (range, 0-3,440) days after HCT. The cumulative incidence of FRCs was 1.7% and 2.2% at one and five years, respectively. FRCs were associated with older age, male sex, non-complete remission (non-CR), lower performance status (PS), and HCT comorbidity index (HCT-CI) associated with renal comorbidity in multivariate analysis. The risk factors within 100 days included older age, multiple myeloma, PS, and HCT-CI comorbidities (psychiatric disturbance, hepatic disease, obesity, and renal disease). Older age and male sex were risk factors between 100 days and one year. After one year, HCT-CI was associated with the presence of diabetes and prior solid tumor; total body irradiation was identified as a risk factor. Non-CR was a common risk factor in all three phases. Furthermore, acute and chronic graft-versus-host disease, reactivation of cytomegalovirus, and relapse of underlying disease also affected FRCs. Systematic follow-up may be necessary based on the patients' risk factors and post-HCT events., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Aortic and valvular calcification are well-known risk factors for cardio-cerebrovascular events in patients undergoing hemodialysis. We investigated the clinical impact of an angulated aorto-septal angle as a result of aortic elongation due to aortic calcification on cardio-cerebrovascular outcomes in patients undergoing hemodialysis. We investigated 306 patients (mean age 65.4 years, 68% male) who underwent pre-scheduled routine echocardiography between April and September 2018. The angle between the anterior wall of the aorta and the ventricular septal surface (ASA) was quantified. We determined aortic and mitral valve calcification scores based on calcified cardiac changes; the aortic and mitral valve scores ranged between 0-9 and 0-6, respectively. The primary endpoint was a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The mean duration of dialysis among the patients in this analysis was 9.6 years. The primary endpoint was observed in 54 patients during the observational period (median 1095 days). Multivariable Cox proportional hazards analyses identified left ventricular ejection fraction (per 10% increase: hazard ratio [HR] 0.67; 95% confidential interval [CI] 0.53-0.84, P = 0.001), left ventricular mass index (per 10 g/m2 increase: HR 1.14; 95% CI 1.05-1.24, P = 0.001), ASA (per 10 degree increase: HR 0.69; 95% CI 0.54-0.88; P = 0.003), and aortic valve calcification score (HR 1.15; 95% CI 1.04-1.26, P = 0.005) as independent determinants of the primary endpoint. Kaplan-Meier analysis showed a higher incidence of the primary endpoint in patients with ASA <119.4 degrees than those with ASA ≥119.4 degrees (Log-rank P < 0.001). An angulated aorto-septal angle is an independent risk factor for cardio-cerebrovascular events and cardio-cerebrovascular death in patients undergoing hemodialysis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nakayama 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.)

Exosomes are small extracellular vesicles (EVs) found in culture supernatants, blood, and breast milk. The size of these nanocomplexes limits the methods of EV analyses. In this study, nitrobenzoxadiazole (NBD), a fluorophore, conjugated endosome-lysosome imager, GIF-2250 and its derivative, GIF-2276, were evaluated for exosome analyses. A correlation was established between GIF-2250 intensity and protein maker levels in bovine milk exosomes. We found that high-temperature sterilization milk may not contain intact exosomes. For precise analysis, we synthesized GIF-2276, which allows for the covalent attachment of NBD to the Lys residue of exosome proteins, and labeled milk exosomes were separated using a gel filtration system. GIF-2276 showed chromatographic peaks of milk exosomes containing >3 ng protein. The area (quantity) and retention time (size) of the exosome peaks were correlated to biological activity (NO synthesis suppression in RAW264.7 murine macrophages). Heat denaturation of purified milk-derived exosomes disrupted these indicators. Proteome analyses revealed GIF-2276-labeled immunomodulators, such as butyrophilin subfamily 1 member A1 and polymeric immunoglobulin receptor. The immunogenicity and quantity of these factors decreased by heat denaturation. When milk exosomes were purified from market-sourced milk we found that raw and low-temperature sterilization milk samples, contained exosomes (none in high-temperature sterilization milk). These results were also supported by transmission electron microscopy analyses. We also found that GIF-2276 could monitor exosome transportation into HEK293 cells. These results suggested that GIF-2250/2276 may be helpful to evaluate milk exosomes., Competing Interests: Declaration of competing interest H.T. and S.Y. owns 3600 USD of Gifu Exosome Co. LTD. shares. K.F. and Y.M. owns 1800 USD of Gifu Exosome shares. S.Y. is employed by Seki Milk Co. LTD. Others have nothing to declare. GIF-2250 and GIF-2276 have been submitted patents, WO2022163446 and PCT/JP2023/28846., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Latent chronic inflammation has been proposed as a key mediator of multiple derangements in metabolic syndrome (MetS), which are increasingly becoming recognized as risk factors for age-related cognitive decline. However, the question remains whether latent chronic inflammation indeed induces brain inflammation and cognitive decline., Methods: A mouse model of latent chronic inflammation was constructed by a chronic subcutaneous infusion of low dose lipopolysaccharide (LPS) for four weeks. A receptor for advanced glycation end products (RAGE) knockout mouse, a chimeric myeloid cell specific RAGE-deficient mouse established by bone marrow transplantation and a human endogenous secretory RAGE (esRAGE) overexpressing adenovirus system were utilized to examine the role of RAGE in vivo. The cognitive function was examined by a Y-maze test, and the expression level of genes was determined by quantitative RT-PCR, western blot, immunohistochemical staining, or ELISA assays., Results: Latent chronic inflammation induced MetS features in C57BL/6J mice, which were associated with cognitive decline and brain inflammation characterized by microgliosis, monocyte infiltration and endothelial inflammation, without significant changes in circulating cytokines including TNF-α and IL-1β. These changes as well as cognitive impairment were rescued in RAGE knockout mice or chimeric mice lacking RAGE in bone marrow cells. P-selectin glycoprotein ligand-1 (PSGL-1), a critical adhesion molecule, was induced in circulating mononuclear cells in latent chronic inflammation in wild-type but not RAGE knockout mice. These inflammatory changes and cognitive decline induced in the wild-type mice were ameliorated by an adenoviral increase in circulating esRAGE. Meanwhile, chimeric RAGE knockout mice possessing RAGE in myeloid cells were still resistant to cognitive decline and brain inflammation., Conclusions: These findings indicate that RAGE in inflammatory cells is necessary to mediate stimuli of latent chronic inflammation that cause brain inflammation and cognitive decline, potentially by orchestrating monocyte activation via regulation of PSGL-1 expression. Our results also suggest esRAGE-mediated inflammatory regulation as a potential therapeutic option for cognitive dysfunction in MetS with latent chronic inflammation., 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 © 2023 Elsevier Inc. All rights reserved.)

Recent studies have shown a role of inflammation in muscle atrophy and sarcopenia. However, no anti-inflammatory pharmacotherapy has been established for the treatment of sarcopenia. Here, we investigate the potential role of PPARα and its ligands on inflammatory response and PGC-1α gene expression in LPS-treated C2C12 myotubes. Knockdown of PPARα, whose expression was upregulated upon differentiation, augmented IL-6 or TNFα gene expression. Conversely, PPARα overexpression or its activation by ligands suppressed 2-h LPS-induced cytokine expression, with pemafibrate attenuating NF-κB or STAT3 phosphorylation. Of note, reduction of PGC-1α gene expression by LPS treatment for 24 hours was partially reversed by fenofibrate. Our data demonstrate a critical inhibitory role of PPARα in inflammatory response of C2C12 myotubes and suggest a future possibility of PPARα ligands as a candidate for anti-inflammatory therapy against sarcopenia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tomohiro Tanaka reports a relationship with Kowa Company Ltd that includes: speaking and lecture fees. All the other 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 © 2023 Elsevier Inc. All rights reserved.)

Introduction: In Japan, telemedicine has gradually expanded due to deregulation in response to the COVID-19 pandemic. However, its current status remains unclear, as it is primarily provided by general practitioners. Meanwhile, telemedicine has begun to be utilized for low-dose estrogen-progestin (LEP) prescriptions for dysmenorrhea., Methods: We conducted a retrospective analysis of medical record data from two gynecology clinics and performed an exploratory evaluation between a group that combined telemedicine and in-person visits during the initial 6 months of LEP treatment, and another group with only in-person visits., Results: After propensity score matching, 89 and 83 patients were eligible for the telemedicine and in-person groups, respectively, with 53 patients in both. The characteristics of both groups were similar after matching. There were no significant differences in the probability of abnormal uterine bleeding during the first 6 months of treatment (25% and 43% in each group; p  = 0.064), side effects, or treatment efficacy between the two groups. The withdrawal rate at 6 months was significantly higher in the telemedicine group than in the in-person group (13% and 0%, p  = 0.013). The average copayment for patients who covered 30% of the total cost was also significantly higher in the telemedicine group after 1 and 3 months of LEP prescription., Conclusion: The appropriate combination of telemedicine and in-person visits is currently employed in hospital visits, which does not differ significantly from in-person visits. Given the retrospective nature of this study and the limited number of cases, further investigation is necessary in the future., Competing Interests: Telemedicine at both facilities A and B used CLINICS® (provided Medley, Inc.), a telemedicine system in Japan. However, this study did not aim to validate the telemedicine system. In addition, the co-researcher, the first author of this article, was both a visiting researcher at Yokohama City University and an employee of Medley, Inc. However, this study did not receive any funding from the company. The Conflict of Interest Review Committee granted permission to conduct this study on the condition that the aforementioned information was stated in the protocol, disclosure documents, and published article, and that the researcher did not engage in statistical analysis work.Y.I. is employed at Medley, Inc., and receives a regular salary. The remaining authors have nothing to disclose., (© Yumi Inoo et al., 2024; Published by Mary Ann Liebert, Inc.)

Introduction: Although type 2 diabetes mellitus (T2DM) is associated with alterations in brain structure, the relationship between glycemic control indices and brain imaging markers remains unclear. This study aimed to investigate the association between continuous glucose monitoring (CGM)-derived glycemic control indices and brain imaging biomarkers assessed by MRI., Research Design and Methods: This cross-sectional study included 150 patients with T2DM. The severity of cerebral white matter lesions (WMLs) was assessed using MRI for deep and subcortical white matter and periventricular hyperintensities. The degree of medial temporal lobe atrophy (MTA) was assessed using voxel-based morphometry. Each participant wore a retrospective CGM for 14 consecutive days, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated., Results: The proportion of patients with severe WMLs showed a decreasing trend with increasing TIR ( P for trend=0.006). The proportion of patients with severe WMLs showed an increasing trend with worsening GRI ( P for trend=0.011). In contrast, no significant association was observed between the degree of MTA and CGM-derived glycemic control indices, including TIR ( P for trend=0.325) and GRI ( P for trend=0.447)., Conclusions: The findings of this study indicate that the severity of WMLs is associated with TIR and GRI, which are indices of the quality of glycemic control., Trial Registration Number: UMIN000032143., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Heavy metals are often found in soil and can contaminate drinking water, posing a serious threat to human health. Molecular pathways and curation therapies for mitigating heavy metal toxicity have been studied for a long time. Recent studies on oxidative stress and aging have shown that the molecular foundation of cellular damage caused by heavy metals, namely, apoptosis, endoplasmic reticulum stress, and mitochondrial stress, share the same pathways as those involved in cellular senescence and aging. In recent aging studies, many types of heavy metal exposures have been used in both cellular and animal aging models. Chelation therapy is a traditional treatment for heavy metal toxicity. However, recently, various antioxidants have been found to be effective in treating heavy metal-induced damage, shifting the research focus to investigating the interplay between antioxidants and heavy metals. In this review, we introduce the molecular basis of heavy metal-induced cellular damage and its relationship with aging, summarize its clinical implications, and discuss antioxidants and other agents with protective effects against heavy metal damage.

Background: Diabetes is an important risk factor for heart failure (HF) and is associated with left ventricular (LV) diastolic dysfunction. However, diabetic comorbid conditions, such as nocturnal hypertension, as predictors of diastolic dysfunction are not known in the absence of an HF period. The present study was conducted as the longitudinal examination of the predictive value of nocturnal hypertension profiles on the progression of LV diastolic dysfunction in patients with and without diabetes without HF., Methods: The subjects (154 diabetes and 268 nondiabetes) in the absence of HF were followed for 36.8±18.2 months. The relationships among the patterns of nocturnal hypertension and the outcome of LV diastolic dysfunction, defined as an increase in E/e'>14, were investigated in the patients with and without diabetes., Results: The interaction effect of the diabetes status and the patterns of nocturnal hypertension on the hazard rate of the occurrence of E/e'>14 was statistically significant ( P =0.017). Kaplan-Meier analysis results revealed that patients with diabetes with nondipper ( P =0.021 versus dipper) and riser ( P =0.006 versus dipper) had a greater risk for a diastolic dysfunction event. Furthermore, multivariable Cox proportional hazards analysis revealed that nondipper (hazard ratio, 4.56 [95% CI, 1.49-13.96]; P =0.007) and riser (hazard ratio, 3.89 [95% CI, 1.31-11.57]; P =0.014) patterns were associated with elevated risk of the outcome of LV diastolic dysfunction. In contrast, no similar significant associations were found in patients without diabetes., Conclusions: During the absence of HF periods, nocturnal hypertension is an important predictor for the progression of LV diastolic dysfunction in patients with diabetes., Competing Interests: Disclosures None.

Abstract: Since lung magnetic resonance imaging (MRI) became clinically available, limited clinical utility has been suggested for applying MRI to lung diseases. Moreover, clinical applications of MRI for patients with lung diseases or thoracic oncology may vary from country to country due to clinical indications, type of health insurance, or number of MR units available. Because of this situation, members of the Fleischner Society and of the Japanese Society for Magnetic Resonance in Medicine have published new reports to provide appropriate clinical indications for lung MRI. This review article presents a brief history of lung MRI in terms of its technical aspects and major clinical indications, such as (1) what is currently available, (2) what is promising but requires further validation or evaluation, and (3) which developments warrant research-based evaluations in preclinical or patient studies. We hope this article will provide Investigative Radiology readers with further knowledge of the current status of lung MRI and will assist them with the application of appropriate protocols in routine clinical practice., Competing Interests: Conflicts of interest and sources of funding: Y. Ohno and H.N. received research grant from Canon Medical Systems Corporation. H.K. received research grant from GE Healthcare. The other authors have nothing to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Proton (H + ) release is linked to aluminum (Al)-enhanced organic acids (OAs) excretion from the roots under Al rhizotoxicity in plants. It is well-reported that the Al-enhanced organic acid excretion mechanism is regulated by SENSITIVE TO PROTON RHIZOTOXICITY1 (STOP1), a zinc-finger TF that regulates major Al tolerance genes. However, the mechanism of H + release linked to OAs excretion under Al stress has not been fully elucidated. Recent physiological and molecular-genetic studies have implicated the involvement of SMALL AUXIN UP RNAs (SAURs) in the activation of plasma membrane H + -ATPases for stress responses in plants. We hypothesized that STOP1 is involved in the regulation of Al-responsive SAURs , which may contribute to the co-secretion of protons and malate under Al stress conditions. In our transcriptome analysis of the roots of the stop1 (sensitive to proton rhizotoxicity1) mutant, we found that STOP1 regulates the transcription of one of the SAURs , namely SAUR55 . Furthermore, we observed that the expression of SAUR55 was induced by Al and repressed in the STOP1 T-DNA insertion knockout (KO) mutant ( STOP1 -KO). Through in silico analysis, we identified a functional STOP1-binding site in the promoter of SAUR55 . Subsequent in vitro and in vivo studies confirmed that STOP1 directly binds to the promoter of SAUR55 . This suggests that STOP1 directly regulates the expression of SAUR55 under Al stress. We next examined proton release in the rhizosphere and malate excretion in the T-DNA insertion KO mutant of SAUR55 ( saur55 ), in conjunction with STOP1 -KO. Both saur55 and STOP1 -KO suppressed rhizosphere acidification and malate release under Al stress. Additionally, the root growth of saur55 was sensitive to Al-containing media. In contrast, the overexpressed line of SAUR55 enhanced rhizosphere acidification and malate release, leading to increased Al tolerance. These associations with Al tolerance were also observed in natural variations of Arabidopsis. These findings demonstrate that transcriptional regulation of SAUR55 by STOP1 positively regulates H + excretion via PM H + -ATPase 2 which enhances Al tolerance by malate secretion from the roots of Arabidopsis. The activation of PM H + -ATPase 2 by SAUR55 was suggested to be due to PP2C.D2/D5 inhibition by interaction on the plasma membrane with its phosphatase. Furthermore, RNAi-suppression of NtSTOP1 in tobacco shows suppression of rhizosphere acidification under Al stress, which was associated with the suppression of SAUR55 orthologs, which are inducible by Al in tobacco. It suggests that transcriptional regulation of Al-inducible SAUR s by STOP1 plays a critical role in OAs excretion in several plant species as an Al tolerance mechanism., Competing Interests: The authors declare that there are no conflicts of interest., (© 2023 The Authors. Plant Direct published by American Society of Plant Biologists and the Society for Experimental Biology and John Wiley & Sons Ltd.)

IFN-alpha have been reported to suppress hepatitis B virus (HBV) cccDNA via APOBEC3 cytidine deaminase activity through interferon signaling. To develop a novel anti-HBV drug for a functional cure, we performed in silico screening of the binding compounds fitting the steric structure of the IFN-alpha-binding pocket in IFNAR2. We identified 37 compounds and named them in silico cccDNA modulator (iCDM)-1-37. We found that iCDM-34, a new small molecule with a pyrazole moiety, showed anti-HCV and anti-HBV activities. We measured the anti-HBV activity of iCDM-34 dependent on or independent of entecavir (ETV). iCDM-34 suppressed HBV DNA, pgRNA, HBsAg, and HBeAg, and also clearly exhibited additive inhibitory effects on the suppression of HBV DNA with ETV. We confirmed metabolic stability of iCDM-34 was stable in human liver microsomal fraction. Furthermore, anti-HBV activity in human hepatocyte-chimeric mice revealed that iCDM-34 was not effective as a single reagent, but when combined with ETV, it suppressed HBV DNA compared to ETV alone. Phosphoproteome and Western blotting analysis showed that iCDM-34 did not activate IFN-signaling. The transcriptome analysis of interferon-stimulated genes revealed no increase in expression, whereas downstream factors of aryl hydrocarbon receptor (AhR) showed increased levels of the expression. CDK1/2 and phospho-SAMHD1 levels decreased under iCDM-34 treatment. In addition, AhR knockdown inhibited anti-HCV activity of iCDM-34 in HCV replicon cells. These results suggest that iCDM-34 decreases the phosphorylation of SAMHD1 through CDK1/2, and suppresses HCV replicon RNA, HBV DNA, and pgRNA formation., (© 2023. The Author(s).)

Amino acids exist in two chiral forms, namely L and D. Although l-amino acids are predominant in vivo, certain limited circumstances have reported the usage of d-amino acids. d-aspartate (Asp), among them, plays crucial physiological roles in living organisms and is biosynthesized from L-Asp by the enzyme named aspartate racemase (AspRase). D-Asp is known to accumulate in large amounts in the nervous system of cephalopods. To understand the function of D-Asp in nervous system in more detail, it is necessary to elucidate its metabolic pathway; however, AspRase gene has not been identified in cephalopods as in the case of mammals. In this study, we successfully identified a novel gene encoding AspRase from the optic ganglion of Japanese common squid Todarodes pacificus. Our discovery of the squid AspRase challenges the prevailing assumption that AspRases across different animals share similar structures. Surprisingly, the squid AspRase is a unique enzyme that differs significantly from known AspRases, being structurally and phylogenetically related to aspartate aminotransferase (AST) and possessing both AspRase and AST activities. The optimum pH and temperature for AspRase activity using L-Asp as a substrate are approximately 7.0 and 20 °C, respectively. Moreover, we have found that AspRase activity is enhanced in the presence of 2-oxoacids. These findings have far-reaching implications for the understanding of enzymology and suggest that yet-to-be-identified mammalian AspRases may also be phylogenetically related to AST, rather than conventional AspRases. Furthermore, our results provide valuable insights into the evolution of the D-Asp biosynthetic pathway., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We aimed to investigate whether the degree of hearing loss with GJB2 mutations could be predicted by distinguishing between truncating and non-truncating mutations and whether the genotype could predict the hearing loss level. Additionally, we examined the progression of hearing loss in individuals monitored for over 2 years for an average of 6.9 years. The proportion of truncating mutations was higher in patients with profound and severe hearing loss, but it was not accurate enough to predict the degree of hearing loss. Via genotype analysis, mutations of the p.Arg143Trp variants were associated with profound hearing loss, while mutations of the p.Leu79Cysfs*3 allele exhibited a wide range of hearing loss, suggesting that specific genotypes can predict the hearing loss level. Notably, there were only three cases of progression in four ears, all of which involved the p.Leu79Cysfs*3 mutation. Over the long-term follow-up, 4000 Hz was significant, and there was a trend of progression at 250 Hz, suggesting that close monitoring at these frequencies during follow-up may be crucial to confirm progression. The progression of hearing loss was observed in moderate or severe hearing loss cases at the time of the initial diagnosis, emphasizing that children with this level of hearing loss need regular follow-ups.

Background: Although excessive daytime napping has been shown to be involved in diabetes occurrence, its impact on insulin secretion and sensitivity has not been elucidated. It is speculated that excessive napping disrupts the sleep-wake rhythm and increases sympathetic nerve activity during the day, resulting in decreased insulin sensitivity, which may be a mechanism leading to development of diabetes. We previously conducted a cross-sectional study that showed an association of autonomic dysfunction with decreased insulin sensitivity, though involvement of autonomic function in the association between napping and insulin sensitivity remained unclear. Furthermore, the effects of napping used to supplement to short nighttime sleep on insulin secretion and sensitivity are also unknown. In the present cross-sectional study, we examined the relationships of daytime nap duration and autonomic function with insulin secretion and sensitivity in 436 subjects enrolled in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Cohort Study who underwent a 75-g oral glucose tolerance test (75-g OGTT), after excluding those already diagnosed with diabetes., Methods: Daytime nap duration was objectively measured using actigraphy, with the subjects divided into the short (≤1 hour) and long (>1 hour) nap groups. Insulin secretion and sensitivity were determined using 75-g OGTT findings. Standard deviation of normal to normal R-R interval (SDNN), a measure of autonomic function, was also determined based on heart rate variability. Subgroup analysis was performed for the associations of napping with insulin secretion and sensitivity, with the results stratified by nighttime sleep duration of less or greater than six hours., Results: Subjects in the long nap group exhibited lower insulin sensitivity parameters (QUICKI: β=-0.135, p<0.01; Matsuda index: β=-0.119, p<0.05) independent of other clinical factors. In contrast, no associations with insulin secretion were found in either group. Furthermore, the association of long nap duration with insulin sensitivity was not confounded by SDNN. Specific subgroup analyses revealed more prominent associations of long nap habit with lower insulin sensitivity in subjects with a short nighttime sleep time (β=-0.137, p<0.05)., Conclusion: Long daytime nap duration may be a potential risk factor for decreased insulin sensitivity., 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 Kakutani-Hatayama, Kadoya, Morimoto, Miyoshi, Kosaka-Hamamoto, Kanzaki, Konishi, Kusunoki, Syoji and Koyama.)

Background: Receptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer's disease (AD) has been reported; RIPK1 is involved in microglia's phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD. Therefore, regulation of RIPK1 could be a potential therapeutic target for the treatment of AD, and in vivo imaging of RIPK1 may become a useful modality in studies of drug discovery and pathophysiology of AD. The purpose of this study was to develop a suitable radioligand for positron emission tomography (PET) imaging of RIPK1., Results: (S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one (GSK'963) has a high affinity, selectivity for RIPK1, and favorable physiochemical properties based on its chemical structure. In this study, since 11 C-labeling (half-life: 20.4 min) GSK'963 retaining its structure requiring the Grignard reaction of tert-butylmagnesium halides and [ 11 C]carbon dioxide was anticipated to give a low yield, we decided instead to 11 C-label a GSK'963 analog ((S)-2,2-dimethyl-1-(5-(m-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one, GG502), which has a high RIPK1 inhibitory activity equivalent to that of the original compound GSK'963. Thus, we successfully 11 C-labeled GG502 using a Pd-mediated cross-coupling reaction in favorable yields (3.6 ± 1.9%) and radiochemical purities (> 96%), and molar activity (47-115 GBq/μmol). On autoradiography, radioactivity accumulation was observed for [ 11 C]GG502 and decreased by non-radioactive GG502 in the mouse spleen and human brain, indicating the possibility of specific binding of this ligand to RIPK1. On brain PET imaging in a rhesus monkey, [ 11 C]GG502 showed a good brain permeability (peak standardized uptake value (SUV) ~3.0), although there was no clear evidence of specific binding of [ 11 C]GG502. On brain PET imaging in acute inflammation model rats, [ 11 C]GG502 also showed a good brain permeability, and no significant increased uptake was observed in the lipopolysaccharide-treated side of striatum. On metabolite analysis in rats at 30 min after administration of [ 11 C]GG502, ~55% and ~10% of radioactivity was from unmetabolized [ 11 C]GG502 in the brain and the plasma, respectively., Conclusions: We synthesized and evaluated a 11 C-labeled PET ligand based on the methylated analog of GSK'963 for imaging of RIPK1 in the brain. Although in autoradiography of the resulting [ 11 C]GG502 indicated the possibility of specific binding, the actual PET imaging failed to detect any evidence of specific binding to RIPK1 despite its good brain permeability. Further development of radioligands with a higher binding affinity for RIPK1 in vivo and more stable metabolite profiles compared with the current compound may be required., (© 2023. Springer Nature Switzerland AG.)

This study aimed to evaluate the relationship between the femoral and tibial component positions and postoperative knee range of motion after posterior-stabilized total knee arthroplasty (TKA). Forty-four patients (48 knees in total: 9 men, 9 knees; 35 women, 39 knees) who underwent posterior-stabilized TKA using a navigation system were included. The femoral and tibial component positions were measured from the preoperative and postoperative computed tomography data with three-dimensional evaluation software. We investigated the relationship between the knee range of motion, including extension restriction and maximum flexion angles at 2 years postoperatively, and the femoral and tibial component positions. Patients with knee extension restriction of 10° or more at 2 years postoperatively showed greater posterior flexion position of the tibial component than those with knee extension restriction less than 10° (6.2° and 3.9°, respectively, p =0.018). The postoperative knee flexion angle was positively associated with the internal rotational position of the femoral component ( p =0.032, 95% confidence interval: 0.105-2.178). Patients with a knee flexion angle more than 120° at 2 years postoperatively had greater internal rotational position of the femoral component than those with 120° or less (5.2° and 1.5°, respectively, p =0.002). In conclusions, after posterior-stabilized TKA, the postoperative knee extension restriction angle was associated with the posterior flexion position of the tibial component, and the knee flexion angle was positively related to the internal rotational position of the femoral component., Competing Interests: None declared., (Thieme. All rights reserved.)

A macro pituitary tumour or giant pituitary tumour is regarded as a rare causal factor in syndrome of inappropriate antidiuretic hormone (SIADH) cases. Previous reports have presented findings showing that blood flow insufficiency related to stress caused by an obstructive mass may lead to inappropriate secretion of arginine vasopressin. On the other hand, prolactin is known to influence water metabolism, and several cases of a macroprolactinoma or giant prolactinoma (PRLoma) in patients with SIADH have been reported. Nevertheless, few studies have examined such a relationship with SIADH and discussion of pathophysiological factors has been limited. The present report provides details of an elderly patient with SIADH in a chronic giant PRLoma. Of note, exacerbation of prolactin level accompanied the occurrence of SIADH. Findings obtained in this case suggest the possibility of development of SIADH in PRLoma cases due to more than only the effect of the mass., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective Although the coronavirus disease 2019 (COVID-19) Omicron variant causes less severe symptoms than previous variants, early indicators for respiratory failure are needed in hemodialysis patients, who have a higher mortality rate than the general population. Liver chemistries are known to reflect the severity of COVID-19 in the general population. This study explored the early indicators for worsened respiratory failure based on patient characteristics, including liver chemistries. Methods This retrospective study included 117 patients admitted for COVID-19 during the Omicron wave. Respiratory failure was defined as oxygen requirement during treatment. Information on the symptoms and clinical characteristics, including liver chemistries [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], at admission was collected. Results Thirty-five patients (29.9%) required oxygen supply during treatment. In the multivariate logistic regression analyses, AST [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.00-1.13, p=0.029], ALT (OR 1.09, 95% CI 1.02-1.18, p=0.009), and moderate COVID-19 illness (Model including AST, OR 6.95, 95% CI 2.23-23.17, p<0.001; Model including ALT, OR 7.19, 95% CI 2.21-25.22, p=0.001) were independent predictors for respiratory failure. Based on the cutoff values determined by the receiver operating characteristic curve, higher AST (≥23 IU/L) and ALT levels (≥14 IU/L) were also independently associated with respiratory failure (higher AST: 64.3% vs. 18.8%, OR 3.44, 95% CI 1.08-11.10, p=0.035; higher ALT: 48.8% vs. 19.7%, OR 4.23, 95% CI 1.34-14.52, p=0.013, respectively). Conclusion The measurement of AST and ALT levels at baseline may help predict oxygen requirement in hemodialysis patients with COVID-19.

Peretinoin is an acyclic retinoid that stimulates retinoic acid receptors (NR1Bs) and produces therapeutic effects on hepatocellular cancer. We have previously shown that NR1B agonists such as Am80 and all trans-retinoic acid suppress pathogenic events in intracerebral hemorrhage. The present study addressed the actions of peretinoin and Am80 against cytotoxicity of a blood protease thrombin on cortico-striatal slice cultures obtained from neonatal rat brains. Application of 100 U/ml thrombin to the slice cultures for 72 h caused cell death in the cortical region and tissue shrinkage in the striatal region. Peretinoin (50 μM) and Am80 (1 μM) counteracted these cytotoxic effects of thrombin, and the effect of peretinoin and Am80 was blocked by LE540, an NR1B antagonist. A broad-spectrum kinase inhibitor K252a (3 μM) attenuated the cytoprotective effect of peretinoin in the cortical region, whereas a specific protein kinase A inhibitor KT5720 (1 μM) attenuated the protective effect of peretinoin in the cortical and the striatal regions. On the other hand, nuclear factor-κB (NF-κB) inhibitors such as pyrrolidine dithiocarbamate (50 μM) and Bay11-7082 (10 μM) prevented thrombin-induced shrinkage of the striatal region. Peretinoin and Am80 as well as Bay11-7082 blocked thrombin-induced nuclear translocation of NF-κB in striatal microglia and loss of striatal neurons. We also found that daily administration of peretinoin reduced histopathological injury and alleviated motor deficits in a mouse model of intracerebral hemorrhage. These results indicate that NR1B agonists including peretinoin may serve as a therapeutic option for hemorrhagic brain injury., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this work and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Acute rupture or erosion of unstable atherosclerotic plaques is a major cause of adverse consequences of atherosclerotic cardiovascular disease, often leading to myocardial infarction or stroke. High uric acid (HUA) is associated with the increasing risk of cardiovascular events and death. However, the mechanism by which HUA promotes atherosclerosis and whether HUA affects plaque stability are still unclear., Methods: We constructed an atherosclerotic Apoe-/- mouse model with HUA. The progression of atherosclerosis and plaques was determined by Oil Red O staining, hematoxylin and eosin (H&E) staining, and Masson staining. TdT-mediated dUTP nick-end labeling assay and immunohistochemistry were used to observe the changes of apoptosis and autophagy in plaques, respectively. Then, we validated the in vivo results with RAW 264.7 cell line., Results: HUA promoted atherosclerosis and exacerbated plaque vulnerability, including significantly increased macrophage infiltration, lipid accumulation, enlarged necrotic cores, and decreased collagen fibers. HUA increased cell apoptosis and inhibited autophagy in plaques. In vitro results showed that HUA decreased cell viability and increased cell apoptosis in foam cells macrophages treated with oxidized low-density lipoprotein. An activator of autophagy, rapamycin, can partially reverse the increasing apoptosis., Conclusion: HUA promoted atherosclerosis and exacerbated plaque vulnerability, and HUA facilitates foam cell apoptosis by inhibiting autophagy.

Objective: This retrospective study aimed to evaluate the performance of machine learning techniques in predicting air-bone gap after tympanoplasty compared with conventional scoring models and to identify the influential factors., Methods: We reviewed the charts of 105 patients (114 ears) with chronic otitis media who underwent tympanoplasty. Two numerical scoring systems (middle ear risk index [MERI] and ossiculoplasty outcome parameter staging [OOPS]) and three algorithms (random forest [RF], support vector machine [SVM], and k nearest neighbor [kNN]) were created. Experimental variables included age, preoperative air-bone gap, soft-tissue density lesion in the tympanic cavity in CT, otorrhea, surgical history, ossicular bone problems in CT, tympanic perforation location, perforation type (central or marginal), grafting material, smoking history, endoscopy use, and the operator whose experience was 20 years or longer, or shorter. Binary classification, postoperative air-bone gap ≤15 or >15 dB, and multiclass classification, classification into seven categories by 10 dB, were performed, and the percentages of correct prediction were calculated. The importance of features in the RF model was calculated to identify influential factors., Results: The percentages of correct prediction in binary classification were 62.3%, 72.8%, 81.5%, 81.5%, and 81.5% in MERI, OOPS, RF, SVM, and kNN, respectively, and those in multiclass classification were 29.8%, 21.9%, 63.1%, 44.7%, and 50% in the same order. The RF model suggested larger preoperative air-bone gap, and older age could make the postoperative air-bone gap larger., Conclusion: The machine learning techniques, especially the RF model, are promising methods for precise postoperative air-bone gap prediction., Level of Evidence: 4 Laryngoscope, 133:2371-2378, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)