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Mutations in SARS-CoV-2 caused multiple waves of pandemics. To identify the function of such mutations, we investigated the binding affinity of the S protein with its receptor, ACE2. Omicron BA.1 showed significantly lower binding affinity with human ACE2 than prototype SARS-CoV-2 and Alpha strain, indicating that pre-Omicron to Omicron transition was not mediated by increasing the ACE2-binding affinity. Meanwhile, the later Omicron variants, BA.5 and XBB.1.5, showed significantly higher ACE2-binding affinity, suggesting that the increased ACE2-binding could be involved in the variant transition within Omicron strains. Furthermore, Alpha and Omicron variants, but not prototype SARS-CoV-2, bound mouse ACE2, which lead to a hypothesis that early Omicron strains evolved from Alpha strain by acquiring multiple mutations in mice., Competing Interests: Declaration of Competing interest All authors declare that there is no conflict of interest in this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: We aimed to identify factors that contribute to the discontinuation of perampanel., Methods: We retrospectively analyzed patients with epilepsy at the Department of Psychiatry, Hokkaido University Hospital. We evaluated the factors contributing to perampanel discontinuation as primary outcomes using Cox proportional hazards regression. Then, we explored the components contributing to the primary outcomes using logistic regression analysis., Results: A total of 118 patients were included, 44.9% of whom discontinued participation, 22.0% had intellectual disability, and 23.7% had a psychiatric disorder other than intellectual disability. Adverse effects occurred in 65% of the patients, 23.7% had psychiatric adverse effects (PAE), and 49.2% had common adverse effects (CAE). The effect of PER to suppress seizures was confirmed in 65.3% of them. Discontinuation was influenced by non-response (Hazard Ratio (HR) 6.70, 95% Confidence Interval (CI) 3.42-13.1), the occurrence of PAE (HR 3.68, 95% CI 1.89-7.16), CAE (HR 1.90, 95% CI 1.06-3.41), and comorbid psychiatric disorders (HR 2.35, 95% CI 1.21-4.59). Moreover, comorbid intellectual disability correlated with a low risk of PAE (OR 0.19, 95% CI 0.04-0.89)., Conclusion: The discontinuation of perampanel is influenced by poor efficacy and the occurrence of common/psychiatric adverse effects. The discontinuation of perampanel is influenced by poor efficacy and the occurrence of common/psychiatric adverse effects. Consideration of factors contributing to perampanel discontinuation may assist in determining the indication for perampanel treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Japan is often assumed to have a highly homogeneous ethnic population, because it is an island country. This is evident in human cell lines collected from cell banks; however, these genotypes have not been thoroughly characterized. To examine the population genotypes of human cell lines established in Japan, we conducted SNP genotyping on 57 noncancerous cell lines and 43 lung cancer cell lines. Analysis of biogeographic ancestry revealed that 58 cell lines had non-admixed Japanese genotypes, 21 cell lines had an admixture of Japanese and East Asian genotypes, and the remaining 21 cell lines had East Asian genotypes. The proportion of non-admixed Japanese genotypes was similar between lung cancer and noncancerous cell lines, suggesting that patients in Japan may not exclusively have Japanese genotypes. This could influence the incidence of inherited diseases and should be taken into account in personalized medicine tailored to genetic background. The genetic makeup of the present-day Japanese population cannot be fully explained by the ancestral Jomon and Yayoi lineages. Instead, it is necessary to consider a certain level of genetic admixture between Japanese and neighboring Asian populations. Our study revealed genetic variation among human cell lines derived from Japanese individuals, reflecting the diversity present within the Japanese population., (© 2024. The Author(s).)

Background: The mitochondrial unfolded protein response (UPR mt ) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPR mt may be a potential therapeutic target for ischemic stroke., Methods: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPR mt . We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro., Results: Inducing UPR mt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPR mt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPR mt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPR mt in vivo, which reduced infarction and improved neurological outcomes., Conclusions: These findings suggest that the UPR mt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPR mt mechanism may provide a new therapeutic avenue for ischemic stroke., Competing Interests: Disclosures None.

The immune system is involved in hypertension development with different immune cells reported to have either pro or anti-hypertensive effects. In hypertension, immune cells have been thought to infiltrate blood pressure-regulating organs, resulting in either elevation or reduction of blood pressure. There is controversy over whether macrophages play a detrimental or beneficial role in the development of hypertension, and the few existing studies have yielded conflicting results. This study aimed to determine the effects of angiotensin II (Ang II) salt-induced hypertension on renal immune cells and to determine whether renal macrophages are involved in the induction of hypertension. Hypertension was induced by administration of Ang II and saline for two weeks. The effects of hypertension on kidney immune cells were assessed using flow cytometry. Macrophage infiltration in the kidney was assessed by immunohistochemistry and kidney fibrosis was assessed using trichrome stain and kidney real time-qPCR. Liposome encapsulated clodronate was used to deplete macrophages in C57BL/6J mice and investigate the direct role of macrophages in hypertension induction. Ang II saline mice group developed hypertension, had increased renal macrophages, and had increased expression of Acta2 and Col1a1 and kidney fibrotic areas. Macrophage depletion blunted hypertension development and reduced the expression of Acta2 and Col1a1 in the kidney and kidney fibrotic areas in Ang II saline group. The results of this study demonstrate that macrophages infiltrate the kidneys and increase kidney fibrosis in Ang II salt-induced hypertension, and depletion of macrophages suppresses the development of hypertension and decreases kidney fibrosis. This indicates that macrophages play a direct role in hypertension development. Hence macrophages have a potential to be considered as therapeutic target in hypertension management., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest exists., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This retrospective study was conducted to investigate the diagnostic accuracy of ultrasound-derived fat fraction (UDFF) for grading hepatic steatosis using liver histology as the reference standard., Methods: Seventy-three patients with liver disease were assessed using UDFF and liver biopsy. Pearson's test and the Bland-Altman plot were used to assess the correlation between UDFF and histological fat content in liver sections. The UDFF cutoff values for histologically proven steatosis grades were determined using the area under the receiver operating characteristic curve (AUROC)., Results: The median age of the patients was 66 (interquartile range 54-74) years, and 33 (45%) were females. The UDFF values showed a stepwise increase with increasing steatosis grade (p < .001) and were strongly correlated with the histological fat content (r = .7736, p < .001). The Bland-Altman plot revealed a mean bias of 2.384% (95% limit of agreement, - 6.582 to 11.351%) between them. Univariate regression analysis revealed no significant predictors of divergence. The AUROCs for distinguishing steatosis grades of ≥ 1, ≥2, and 3 were 0.956 (95% confidence interval [CI], 0.910-1.00), 0.926 (95% CI, 0.860-0.993), and 0.971 (95% CI, 0.929-1.000), respectively. The UDFF cutoff value of > 6% had a sensitivity and specificity of 94.8% and 82.3%, respectively, for diagnosing steatosis grade ≥ 1. There was no association between UDFF and the fibrosis stage., Conclusion: UDFF shows strong agreement with the histological fat content and excellent diagnostic accuracy for grading steatosis. UDFF is a promising tool for detecting and quantifying hepatic steatosis in clinical practice., (© 2024. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Neurotoxins have been extensively investigated, particularly in the field of neuroscience. They induce toxic damage, oxidative stress, and inflammation on neurons, triggering neuronal dysfunction and neurodegenerative diseases. Here we demonstrate the neuroprotective effect of a silicon (Si)-based hydrogen-producing agent (Si-based agent) in a juvenile neurotoxic mouse model induced by 6-hydroxydopamine (6-OHDA). The Si-based agent produces hydrogen in bowels and functions as an antioxidant and anti-inflammatory agent. However, the effects of the Si-based agent on neural degeneration in areas other than the lesion and behavioral alterations caused by it are largely unknown. Moreover, the neuroprotective effects of Si-based agent in the context of lactation and use during infancy have not been explored in prior studies. In this study, we show the neuroprotective effect of the Si-based agent on 6-OHDA during lactation period and infancy using the mouse model. The Si-based agent safeguards against the degradation and neuronal cell death of dopaminergic neurons and loss of dopaminergic fibers in the striatum (STR) and ventral tegmental area (VTA) caused by 6-OHDA. Furthermore, the Si-based agent exhibits a neuroprotective effect on the length of axon initial segment (AIS) in the layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC). As a result, the Si-based agent mitigates hyperactive behavior in a juvenile neurotoxic mouse model induced by 6-OHDA. These results suggest that the Si-based agent serves as an effective neuroprotectant and antioxidant against neurotoxic effects in the brain, offering the possibility of the Si-based agent as a neuroprotectant for nervous system diseases., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cell biologists have long sought the ability to observe intracellular structures in living cells without labels. This study presents procedures to adjust a commercially available apodized phase-contrast (APC) microscopy system for better visualizing the dynamic behaviors of various subcellular organelles in living cells. By harnessing the versatility of this technique to capture sequential images, we could observe morphological changes in cellular geometry after virus infection in real time without probes or invasive staining. The tune-up APC microscopy system is a highly efficient platform for simultaneously observing the dynamic behaviors of diverse subcellular structures with exceptional resolution.

Two colorimetric methods are used to determine the total polyphenol contents of tea, namely, "the Folin-Ciocalteu method," defined by the International Organization for Standardization, and the "iron tartrate method," specified in the Standard Tables of Food Composition in Japan. In this study, we compared the Folin-Ciocalteu and iron tartrate methods using green tea extracts. When comparing the 2 methods, the sum of the 4 major catechins measured using high-performance liquid chromatography (HPLC) was regarded as the standard value. The total polyphenol contents obtained using the Folin-Ciocalteu method were closer to the HPLC value than those obtained using the iron tartrate method. However, the iron tartrate method is adequate if the current official method is improved, that is, our results suggest that the coefficients appropriate for common green tea varieties, as well as the degree and duration of cover cultivation, in the official iron tartrate method must be considered., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

The recent progress with ruxolitinib treatment might improve quality-of-life as well as overall survival in patients with primary myelofibrosis (PMF). Therefore, the optimal timing of allogeneic hematopoietic cell transplantation (HCT) remains to be elucidated in the ruxolitinib era. We constructed a Markov model to simulate the 5-year clinical course of transplant candidates with PMF, and compared outcomes between immediate HCT and delayed HCT after ruxolitinib failure. Since older age was associated with an increased risk of mortality, we analyzed patients aged < 60 and ≥ 60 separately in subgroup analyses. The expected life years was consistently longer in delayed HCT after ruxolitinib failure regardless of patient age. Regarding quality-adjusted life years (QALYs), a baseline analysis showed that immediate HCT was inferior to delayed HCT after ruxolitinib failure (2.19 versus 2.26). In patients aged < 60, immediate HCT was equivalent to delayed HCT after ruxolitinib failure (2.31 versus 2.31). On the other hand, in patients aged ≥ 60, immediate HCT was inferior to delayed HCT after ruxolitinib failure (1.98 versus 2.21). A one-way sensitivity analysis showed that the utility of being alive without chronic graft-versus-host disease after immediate HCT was the most influential parameter for QALYs, and that a value higher than 0.836 could reverse the superiority of delayed HCT after ruxolitinib failure. As a result, delayed HCT after ruxolitinib failure is expected to be superior to immediate HCT, especially in patients aged ≥ 60, and is also a promising strategy even in those aged < 60.

Here, we use transcriptomic data from seeds of Musella lasiocarpa to identify five enzymes involved in the formation of dihydrocurcuminoids. Characterization of the substrate specificities of the enzymes reveals two distinct dihydrocurcuminoid pathways leading to phenylphenalenones and linear diarylheptanoid derivatives, the major seed metabolites. Furthermore, we demonstrate the stepwise conversion of dihydrobisdemethoxycurcumin to the phenylphenalenone 4'-hydroxylachnanthocarpone by feeding intermediates to M. lasiocarpa root protein extract.

Atopic dermatitis (AD), a prevalent Th2-dominant skin disease, involves complex genetic and environmental factors, including mutations in the Filaggrin gene and dysbiosis of skin microbiota characterized by an increased abundance of Staphylococcus aureus. Our recent findings emphasize the pivotal role of the skin barrier's integrity and microbial composition in infantile AD and allergic diseases. Early skin dysbiosis predisposes infants to AD, suggesting targeted skincare practices as a preventive strategy. The effects of skincare interventions, particularly the application of moisturizers with the appropriate molar concentration of ceramides, cholesterol, and fatty acids, play a crucial role in restoring the skin barrier. Notably, our study revealed that appropriate skincare can reduce Streptococcus abundance while supporting Cutibacterium acnes presence, thus directly linking skincare practices to microbial modulation in neonatal skin. Despite the mixed outcomes of previous Randomized Controlled Trials on the efficacy of moisturizers in AD prevention, our research points to the potential of skincare intervention as a primary preventive method against AD by minimizing the impact of genetic and environmental factors. Furthermore, our research supports the notion that early aggressive management of eczema may reduce the incidence of food allergies, highlighting the necessity for multifaceted prevention strategies that address both the skin barrier and immune sensitization. By focusing on repairing the skin barrier and adjusting the skin's microbiome from birth, we propose a novel perspective on preventing infantile AD and allergic diseases, opening new avenues for future studies and practices in allergy prevention., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This study proposed a two-stage pressurized microwave hydrothermal treatment with a catalyst, followed by enzymatic saccharification, as a pretreatment method for efficiently converting cellulose and hemicellulose from rice straw into glucose and xylose. The use of various inorganic salts and dilute sulfuric acid as catalysts enhances sugar production. Using 1 wt% sulfuric acid as a catalyst at 150 °C for 5 min for the first-stage and then 180 °C for 5 min for the second-stage yielded the highest sugar production from rice straw compared with other inorganic salts tested. The filtrate and enzymatic saccharification solution contained a total sugar of 0.434 g/g-untreated rice straw (i.e. 0.302 g-glucose/g-untreated rice straw and 0.132 g-xylose/g-untreated rice straw). When inorganic salts such as NaCl, MgCl 2 , CaCl 2 , and FeCl 3 were used as catalysts, the highest sugar yield of 0.414 g/g-untreated rice straw (i.e. 0.310 g-glucose/g-untreated rice straw and 0.104 g-xylose/g-untreated rice straw) was obtained when using 1 wt% FeCl 3 at 170 °C for 5 min in the first-stage and 190 °C for 5 min in the second-stage, with a value close to that of 1 wt% sulfuric acid. These findings suggest that two-stage treatment with a catalyst is a suitable pretreatment method for the production of glucose and xylose from rice straw owing to the different hydrolysis temperatures of cellulose and hemicellulose., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Pelvic exenteration (PE) is the last resort for achieving a complete cure for pelvic cancer; however, it is burdensome for patients. Minimally invasive surgeries, including robot-assisted surgery, have been widely used to treat malignant tumors and have also recently been used in PE. This study aimed to evaluate the safety and efficacy of robot-assisted PE (RPE) by comparing the outcomes of open PE (OPE) with those of conventional laparoscopic PE (LPE) for treating pelvic tumors., Methods: Following the ethics committee approval, a multicenter retrospective analysis of patients who underwent pelvic exenteration between January 2012 and October 2022 was conducted. Data on patient demographics, tumor characteristics, and perioperative outcomes were collected. A 1:1 propensity score-matched analysis was performed to minimize group selection bias., Results: In total, 261 patients met the study criteria, of whom 61 underwent RPE, 90 underwent OPE, and 110 underwent LPE. After propensity score matching, 50 pairs were created for RPE and OPE and 59 for RPE and LPE. RPE was associated with significantly less blood loss (RPE vs. OPE: 408 mL vs. 2385 ml, p < 0.001), lower transfusion rate (RPE vs. OPE: 32% vs. 82%, p < 0.001), and lower rate of complications over Clavien-Dindo grade II (RPE vs. OPE: 48% vs. 74%, p = 0.013; RPE vs. LPE: 48% vs. 76%, p = 0.002)., Conclusion: This multicenter study suggests that RPE reduces blood loss and transfusion compared with OPE and has a lower rate of complications compared with OPE and LPE in patients with locally advanced and recurrent pelvic tumors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cell-to-cell transmission of α-synuclein (α-syn) pathology underlies the spread of neurodegeneration in Parkinson's disease. α-Syn secretion is an important factor in the transmission of α-syn pathology. However, it is unclear how α-syn secretion is therapeutically modulated. Here, we investigated effects of monoamine oxidase (MAO)-B inhibitor selegiline on α-syn secretion. Treatment with selegiline promoted α-syn secretion in mouse primary cortical neuron cultures, and this increase was kept under glial cell-eliminated condition by Ara-C. Selegiline-induced α-syn secretion was blocked by cytosolic Ca 2+ chelator BAPTA-AM in primary neurons. Selegiline-induced α-syn secretion was retained in MAOA siRNA knockdown, whereas it was abrogated by ATG5 knockdown in SH-SY5Y cells. Selegiline increased LC3-II generation with a reduction in intracellular p62/SQSTM1 levels in primary neurons. The increase in LC3-II generation was blocked by co-treatment with BAPTA-AM in primary neurons. Additionally, fractionation experiments showed that selegiline-induced α-syn secretion occurred in non-extracellular vesicle fractions of primary neurons and SH-SY5Y cells. Collectively, these findings show that selegiline promotes neuronal autophagy involving secretion of non-exosomal α-syn via a change of cytosolic Ca 2+ levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although gastric neuroendocrine tumors (NETs) are uncommon compared with gastric carcinomas, the incidence of NETs has been recently increasing. Gastric NETs are classified into three subgroups, and among these, gastrin-independent sporadic type 3 gastric NETs have a poor prognosis because of frequent lymph node or distant metastasis. We experienced a case of an early-stage type 3 gastric NET associated with lymphovascular and submucosal invasion. In a 54 year-old woman, esophagogastroduodenoscopy performed during a health screening identified an elevated lesion of the upper body of the stomach. The results of immunohistochemical analyses of endoscopic biopsy specimens obtained from the lesion were positive for chromogranin A and synaptophysin, indicating an NET. Because the patient's serum gastrin level was normal and she had no predisposing conditions for NET development, the tumor was diagnosed as a type 3 gastric NET. The patient underwent local resection of the tumor and regional lymph node dissection. The resected specimen indicated a diagnosis of type 3 gastric NET with invasion into the submucosa and lymphatic duct. This is an extremely rare case of an early-stage type 3 gastric NET. Our discussion provides insight into the pathogenesis and development of these tumors and the appropriate therapeutic strategy., (© 2024. Japanese Society of Gastroenterology.)