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Background: Previous in vitro and in vivo studies on Alzheimer’s disease (AD) models have reported that rosmarinic acid (RA) can inhibit the formation of amyloid-β fibrils as well as the oligomerization and deposition of amyloid-β protein. Melissa officinalis (M. officinalis) extract containing 500 mg of RA is tolerable and safe in healthy individuals and patients with mild AD dementia. Objective: This randomized placebo-controlled double-blind trial aimed to assess the effects of M. officinalis extract on cognition in older adults without dementia. Methods: This study included individuals who were diagnosed with subjective or mild cognitive impairment (n = 323). The trial involved M. officinalis extract supplementation (500 mg of RA per day) period of 96 weeks followed by a washout period of 24 weeks. The primary endpoint was the Alzheimer’s Disease Assessment Scale-cognitive subscale score, and the secondary endpoints were other cognitive measure results as well as safety and tolerability. Results: There were no significant differences in cognitive measures between the placebo and M. officinalis groups from baseline to 96 weeks. However, based on the analysis of Clinical Dementia Rating Sum of Boxes scores in participants without hypertension, the score was found to be increased by 0.006 and decreased by 0.085 in the M. officinalis and placebo groups, respectively; this difference was statistically significant (p = 0.036). Furthermore, there were no differences in vital signs, physical and neurological measures, or hippocampal volume between the two groups. Conclusion: These results indicate that M. officinalis extract may help prevent cognitive decline in older adults without hypertension.

Transforming growth factor (TGF)-β/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-β/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-β/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-β and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl

Mimicking bioactive conformations of peptide segments involved in the formation of protein-protein interfaces with small molecules is thought to represent a promising strategy for the design of protein-protein interaction (PPI) inhibitors. For compound design, the use of three-dimensional (3D) scaffolds rich in sp3-centers makes it possible to precisely mimic bioactive peptide conformations. Herein, we introduce DeepCubist, a molecular generator for designing peptidomimetics based on 3D scaffolds. Firstly, enumerated 3D scaffolds are superposed on a target peptide conformation to identify a preferred template structure for designing peptidomimetics. Secondly, heteroatoms and unsaturated bonds are introduced into the template via a deep generative model to produce candidate compounds. DeepCubist was applied to design peptidomimetics of exemplary peptide turn, helix, and loop structures in pharmaceutical targets engaging in PPIs.

金沢大学理工研究域フロンティア工学系, ObjectivePendrin is a transmembrane protein encoded by the SLC26A4 gene that functions in maintaining ion concentrations in the endolymph of the inner ear, most likely by acting as a chloride/bicarbonate transporter. Variants in the SLC26A4 gene are responsible for sensorineural hearing loss. Although pendrin localizes to the plasma membrane, we previously identified that 8 missense allele products of SLC26A4 were retained in the intracellular region and lost their anion exchange function. We also found that 10 mM salicylate induced the translocation of 4 out of 8 allele products from the intracellular region to the plasma membrane and restored their anion exchanger activity. However, since 10 mM salicylate exhibits cytotoxicity, the use of chemical compounds with less cell toxicity is needed. In the present study, therefore, salicylate derivatives were used as the chemical compounds and their effects on the p.H723R allele products of SLC26A4 were investigated.MethodsHEK293 cells were transfected with the cDNA of p.H723R. Cell proliferation, viability and toxicity assays were performed to investigate the response and health of cells in culture after treatment with four types of salicylate derivatives, i.e., 2-hydroxybenzyl alcohol, 2,3-dihydroxybenzoic acid, 2’-hydroxyacetophenone and methyl salicylate. The effects of these salicylate derivatives on the localization of the p.H723R were investigated by immunofluorescence microscopy.ResultsThe application of 10 mM salicylate showed an increase in cell toxicity and decrease in cell viability, leading to a significant decrease in cell proliferation. In contrast, the application of 1 mM salicylate derivatives did not show any significant increase in cell toxicity and decrease in cell viability, corresponding to a logarithmic increase in cell concentration with an increase in culture time. Immunofluorescence experiments showed that the p.H723R retained in the endoplasmic reticulum (ER). Among the salicylate derivatives applied, 2-hydroxybenzyl alcohol induced the translocation of p.H723R from the ER to the plasma membrane 3 h after its application.ConclusionThe results obtained showed that 2-hydroxybenzyl alcohol restored the localization of the p.H723R allele products of SLC26A4 from the ER to the plasma membrane at a concentration of 1 mM by 3 h after its administration with less cytotoxicity than 10 mM salicylate., Embargo Period 12 months

OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium–glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. RESEARCH DESIGN AND METHODS We conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles. RESULTS Fibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin. CONCLUSIONS Tofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.

Increased food selectivity among children with autism spectrum disorder may lead to nutritional inadequacy. We designed this study to examine the prospective relationship between autistic traits in children and subsequent nutrient intake in later childhood and whether this relationship changes over time. We utilized longitudinal data obtained at two time points from the Shika study, an ongoing population-based study conducted in a rural area of Japan. Participants were 759 Japanese children aged between 7 and 12 years at baseline and between 10 and 15 years in the follow-up. The results obtained showed relatively lower intakes of sodium, calcium, magnesium, iron, vitamin D, vitamin B2, and vitamin B12 among children with than without autistic traits. Interactions were observed among autistic traits and time points for iron, vitamin B2, folic acid, and pantothenic acid. The results of this study suggest the importance of screening the nutrient intake of children with autistic traits across childhood in order to reduce the risk of restricted intake. Lay Abstract It is known about food selectivity among children with autism spectrum disorder. However, the nutritional inadequacy among children with ASD is not clear. Especially, long-term evaluation has not been studied. We examined the prospective relationship between autistic traits in children and subsequent nutrient intake in later childhood. We utilized data obtained at two time points from a study conducted in Japan. Participants were 759 Japanese children aged between 7 and 12 years at baseline and between 10 and 15 years in the follow-up. The results showed relatively lower intakes of sodium, calcium, magnesium, iron, vitamin D, vitamin B2, and vitamin B12 among children with than without autistic traits. Relatively lower intake of minerals and vitamins in children with autistic traits is more evident in later childhood. The results suggest the importance of screening the nutrient intake of children with autistic traits across childhood.

Keita Suzuki,1 Hiromasa Tsujiguchi,1– 3 Akinori Hara,1– 3 Oanh Kim Pham,1 Sakae Miyagi,3,4 Thao Thi Thu Nguyen,5 Haruki Nakamura,1 Fumihiko Suzuki,2,6 Tomoko Kasahara,2 Yukari Shimizu,7 Yohei Yamada,2 Yasuhiro Kambayashi,8 Hirohito Tsuboi,9 Takehiro Sato,3,10 Takayuki Kannon,3,10 Kazuyoshi Hosomichi,3,10 Atsushi Tajima,3,10 Toshinari Takamura,11 Hiroyuki Nakamura1– 3 1Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; 2Department of Public Health, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; 3Kanazawa University Advanced Preventive Medical Sciences Research Center, Kanazawa, Ishikawa, Japan; 4Innovative Clinical Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan; 5Department of Epidemiology, Faculty of Public Health, Haiphong University of Medicine and Pharmacy, Hai Phong, Vietnam; 6Community Medicine Support Dentistry, Ohu University Hospital, Koriyama, Fukushima, Japan; 7Department of Nursing, Faculty of Health Sciences, Komatsu University, Komatsu, Ishikawa, Japan; 8Department of Public Health, Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Ehime, Japan; 9Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; 10Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; 11Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, JapanCorrespondence: Keita Suzuki, Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan, Tel +81 76 265 2218, Fax +81 76 234 4233, Email ksuzuk@staff.kanazawa-u.ac.jpBackground: Previous studies examined the association between chronic pain (CP) and serum 25-hydroxyvitamin D (25(OH)D) concentrations; however, the findings obtained were inconsistent. Single nucleotide polymorphisms (SNP) associated with the transcriptional activity of the vitamin D receptor (VDR) gene may influence the association of 25(OH)D levels with CP. We aimed to clarify the association between CP, serum 25(OH)D concentration, and SNPs.Methods: In the Shika study, we performed a cross-sectional analysis of 551 participants older than 40 years who were asked whether they had been having persistent pain lasting for at least 3 months in any part of the body on a self-administered questionnaire. Serum 25(OH)D concentrations were assessed as a biomarker of the vitamin D status using a radioimmunoassay. rs731236, rs7975232, rs1544410, rs2228570, and rs11568820 were identified using peripheral blood samples, and participants were assigned to those with or without the minor allele for each SNP.Results: The prevalence of CP was 37.2%. We observed a tendency for lower 25(OH)D levels in participants with CP than in those without CP in the hetero/minor group of rs11568820, which is a polymorphism within the CDX2-binding site in the 1e promoter region of the VDR gene. Furthermore, a logistic regression analysis revealed that lower serum 25(OH)D concentrations were significantly associated with CP in the hetero/minor group, but not in the major group.Conclusion: These results suggest that sufficient serum 25(OH)D concentration reduces the risk of CP in individuals with the minor allele of the CDX2 polymorphism.Keywords: chronic pain, 25-hydroxyvitamin D, vitamin D receptor gene, promoter, polymorphism, epidemiology

Tensioning technique at graft fixation is one of key factors for successful outcomes in ACL reconstruction. The tensioning boot, which had two tensioners and was fixed to the tibia with a bandage, was developed for precise graft tensioning. The purpose was to compare the anterior knee laxity between the manual tensioning and the tensioning boot techniques immediately after ACL reconstruction under anesthesia in order to elucidate the effectiveness of using the tensioning boot.33 patients had anatomic double-bundle ACL reconstruction with semitendinosus tendon graft. After grafts were fixed with EndoButton-CL on lateral femoral cortex, grafts were tied to Double Spike Plate (DSP). Each graft was pre-tensioning with 20 N (totally 40 N) at 20 degree of flexion for 3 minutes using manually-held tensioner in 11 patients and using tensioner installed to tensioning boot in the remaining 22 patients before graft fixation, and were then fixed in the same manner. Tibial displacement under 67 and 89 N of tibial anterior load was measured by KT-2000 Knee Arthrometer under anesthesia before and immediately after operation.The anterior knee laxity in the operated knee was 4.5 ± 1.0 mm in the manual tensioning group and 2.9 ± 0.9 mm in the tensioning boot group at 89 N of anterior load, showing a significant difference. (P .0001) The side-to-side difference in the manual tensioning group was significantly less than that in the tensioning boot group. (P = .002).Anterior laxity of the operated knees as well as KT side-to-side difference immediately after ACL reconstruction was larger in the tensioning boot technique than the manual tensioning technique, when the graft was fixed in the same manner. Thus, the initial tension at graft fixation with the tensioning boot can be smaller than 40 N.

Background: Glucose dysmetabolism is an important risk factor for dementia. Objective: We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study. Methods: In this study, 10,214 community-dwelling participants were enrolled. Hemoglobin A1c (HbA1c), the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), the HOMA of percent β-cell function (HOMA-β), and the glycated albumin (GA) was evaluated. The associations of each measure with Alzheimer’s disease (AD) and vascular dementia (VaD) were investigated. Results: The multivariable-adjusted odds ratios (ORs) of AD were significantly higher in participants with diabetes mellitus than in those without diabetes (1.46 [95% CI: 1.08–1.97]). Higher HbA1c levels were significantly associated with AD at diabetes (≥6.5%) and even at prediabetes (5.7 %–6.4 %) levels; multivariable-adjusted ORs for AD in participants at the diabetes level were 1.72 (95% CI: 1.19–2.49), and those in participants at the prediabetes level were 1.30 (95% CI: 1.00–1.68), compared with those in normal participants. Moreover, higher GA levels were associated with AD. No associations were observed between the diabetic status or the levels of glycemic measures and VaD. In addition, no significant relationships were observed between insulin resistance and secretion measurements and AD and VaD. Conclusion: Our findings indicate that diabetes mellitus and hyperglycemia are significantly associated with AD, even in individuals at the prediabetes level.

Isoxazoloazaborines have been synthesized from 4-N-propargylaminoisoxazole via gold(i)-catalyzed propargyl aza-Claisen rearrangement followed by electrophilic borylative cyclization in 27–86% yields.

Curcumin derivatives B and N developed as disaggregation agents of amyloid β (Aβ) fibrils significantly rescued locomotion dysfunction in an Aβ-expressing Drosophila model of Alzheimer's disease.

A total of 42 trisubstituted carboranes categorised into five scaffolds were systematically designed and synthesized by exploiting the different reactivities of the twelve vertices of o-, m-, and p-carboranes to cover all directions in chemical space. Significant inhibitors of hypoxia inducible factor transcriptional activitay were mainly observed among scaffold V compounds (e.g., Vi–m, and Vo), whereas anti-rabies virus activity was observed among scaffold V (Va–h), scaffold II (IIb–g), and scaffold IV (IVb) compounds. The pharmacophore model predicted from compounds with scaffold V, which exhibited significant anti-rabies virus activity, agreed well with compounds IIb–g with scaffold II and compound IVb with scaffold IV. Normalized principal moment of inertia analysis indicated that carboranes with scaffolds I–V cover all regions in the chemical space. Furthermore, the first compounds shown to stimulate the proliferation of the rabies virus were found among scaffold V carboranes.

Although nutrient intake and alcohol consumption are both closely associated with the incidence of diabetes, their interrelationships remain unclear. Therefore, we herein have investigated the interrelationships among nutrient intake, alcohol consumption, and the incidence of diabetes using longitudinal data. This study included 969 residents ≥40 years living in Japan. In 2011 and 2012, a baseline study was conducted using questionnaires on basic demographics, diabetes, nutrient intake, and lifestyle habits. In 2018 and 2019, a follow-up study was performed using questionnaires and medical records on diabetes. Two-way analysis of covariance (two-way ANCOVA) was used to test the interactions of drinking habits and diabetes incidence on nutrients intake. The prospective relationship between nutrient intake at baseline and the incidence of diabetes in the follow-up stratified by drinkers and non-drinkers was evaluated using multiple logistic regression analysis. Interactions were observed for vegetable protein intake (p = 0.023) and animal fat intake (p = 0.016) in males. Vegetable protein intake negatively correlated with the incidence of diabetes in non-drinkers (odds ratio (OR): 0.208; 95% confidence interval (95% CI): 0.046–0.935; p = 0.041). Furthermore, animal fat intake positively correlated with the incidence of diabetes in non-drinkers (OR: 1.625; 95% CI: 1.020–2.589; p = 0.041). Therefore, vegetable protein and animal fat intakes in combination with drinking habits need to be considered for the prevention of diabetes.

Sjögren’s disease (SjD) is an autoimmune disease that affects exocrine tissues and is characterized by increased apoptosis in salivary and lacrimal glands. Although the pathogenic mechanism triggering SjD is not well understood, overexpression of lysosome-associated membrane protein 3 (LAMP3) is associated with the disease in a subset of SjD patients and the development of SjD-like phenotype in mice. In this study, histological analysis of minor salivary glands of SjD patients suggested that LAMP3-containing material is being ejected from cells. Follow-on in vitro experiments with cells exposed to extracellular particles (EPs) derived from LAMP3-overexpressing cells showed increased apoptosis. Proteomics identified LAMP3 as a major component of EPs derived from LAMP3-overexpressing cells. Live-cell imaging visualized release and uptake of LAMP3-containing EPs from LAMP3-overexpressing cells to naïve cells. Furthermore, experiments with recombinant LAMP3 protein alone or complexed with Xfect protein transfection reagent demonstrated that internalization of LAMP3 was required for apoptosis in a caspase-dependent pathway. Taken together, we identified a new role for extracellular LAMP3 in cell-to-cell communication via EPs, which provides further support for targeting LAMP3 as a therapeutic approach in SjD.

The lacunar-spinel chalcogenides exhibit magnetic centers in the form of transition-metal tetrahedra. On the basis of density-functional computations, the electronic ground state of an Mo413+ tetrahedron has been postulated as single-configuration a12 e4 t25, where a1, e, and t2 are symmetry-adapted linear combinations of single-site Mo t2g atomic orbitals. Here we unveil the many-body tetramer wave-function: we show that sizable correlations yield a weight of only 62% for the a12 e4 t25 configuration. While spin–orbit coupling within the peculiar valence orbital manifold is still effective, the expectation value of the spin–orbit operator and the g factors deviate from figures describing nominal t5jeff = 1/2 moments. As such, our data documents the dressing of a spin–orbit jeff = 1/2 object with intra-tetramer excitations. Our results on the internal degrees of freedom of these magnetic moments provide a solid theoretical starting point in addressing the intriguing phase transitions observed at low temperatures in these materials.

Background The coexistence of calcium pyrophosphate dihydrate crystal deposition (CPP) and synovial chondromatosis (SC) in the temporomandibular joint (TMJ) is rarely reported. CPP disease (CPPD) is complex arthritis synonymous with excessive pyrophosphate production and variable aberrations in mineral and organic phase metabolism of the joint cartilage, leading to local inundated CPP and crystal deposition of partially deciphered predispositions. Meanwhile, SC is a rare benign synovial joint proliferative disease of unclear etiology and has a low risk of malignant transformation. However, SC manifests severe joint disability and dysfunction because of connective tissue metaplasia of the synovial membrane, which forms cartilaginous nodules with or without calcifications or ossifications. These nodules often detach and form intra-articular loose bodies and very rarely within extraarticular spaces. Case presentation We report the case of a 61-year-old man to expand the body of literature on these unusual coexisting arthropathies of the TMJ. The patient presented to our hospital in 2020 with complaints of pain in the right TMJ and trismus for over 6 months. Radiographic assessments of the TMJ provided a preoperative provisional diagnosis of SC. However, the histopathology of the open biopsy revealed tumor-like lesions comprising several deposits of rhomboid and rod-shaped crystals that displayed positive birefringence in polarized light, confirming a coexistence of CPPD. A second-stage operation was performed for the complete removal of the loose bodies and chalk-like lesions including synovectomy. No evidence of recurrence was recorded after a follow-up of nearly 1.5 years. Conclusions Isolated CPPD and SC of the TMJ are prevalent in the literature however, monoarticular coexistence of these diseases is rare, due to the lack of consistency in the diagnostic criteria in clinical practice. Moreover, optimal treatment depends on several considerations. This report delineated the molecular etiopathology and underscored the need for continued deciphering of the causal mechanisms of coexisting CPPD and SC of the TMJ. In addition, the importance of confirmatory testing for accurate diagnosis, and appropriate management of these diseases were discussed.

ObjectivesTo examine the positive rate of sarcopenia using the ‘Yubi-wakka’ (finger-ring) test and associated risk factors among adults aged 65 years and older.DesignCross-sectional study.SettingWe used the Yubi-wakka test, which has been developed and validated as a predictor of sarcopenia, frailty, disability and mortality. A positive test result is indicated by a smaller calf circumference than the finger-ring. The test was administered during annual health check-ups among residents of Tama City, Japan.ParticipantsDuring the 2019 fiscal year, 12 894 individuals aged 65 years and older underwent the Yubi-wakka test at primary care clinics.InterventionsExaminees conducted the test themselves in a seated position. They formed a ring around their calf using both thumbs and index fingers and judged whether their calf was larger, the same or smaller than their finger-ring.Primary and secondary outcome measuresWe compared anthropometric and serological data between the positive (smaller calf) and negative (larger calf) test result groups.ResultsThe positive rate was 15.4% among men and 18.5% among women. The prevalence of a positive result was higher in those aged ≥80 years than in younger age groups in both sexes (men: 22.8%; women: 28.8%). Multivariate logistic regression analysis showed that a diagnosis of metabolic syndrome was a risk factor for detecting a positive test result in women aged 65–74 years (OR 3.445; 95% CI 1.44 to 8.29) and ≥75 years (OR 3.37; 95% CI 1.97 to 5.78).ConclusionsBecause the Japanese population is healthy and lives long, interventions against sarcopenia are important, especially for older adults aged >75 years. The presence of metabolic syndrome may be a risk factor for sarcopenia (as detected by the Yubi-wakka test) and future frailty, and requires closer attention, especially among women.

Advanced materials interfaces 9(36), 2201675 (2022). doi:10.1002/admi.202201675 special issue: "Special Issue: Interfaces in Spintronics", Published by Wiley-VCH, Weinheim

Spider’s minor ampullate silk, or MI-silk, exhibits distinct mechanical properties and water resistance compared to its major ampullate counterpart (MA-silk). The principal protein constituent of MI-silk is known as minor ampullate spidroin, or MiSp, and while its sequence has been deciphered and is thought to underlie the differences in properties with MA-silk, the composition of MI-silk and the relationship between its composition and properties remain elusive. In this study, we set out to investigate the mechanical properties, water resistance, and proteome of MA-silk and MI-silk fromAraneus ventricosusandTrichonephila clavata. We also synthesized artificial fibers from major ampullate spidroin, MaSp1 and 2, and MiSp to compare their properties. Our proteomic analysis reveals that the MI-silk of both araneids is composed of MiSp, MaSp1, and spidroin constituting elements (SpiCEs). The absence of MaSp2 in the MI-silk proteome and the comparison of the water resistance of artificial fibers suggest that the presence of MaSp2 is the reason for the disparity in water resistance between MI-silk and MA-silk.

Ambient polycyclic aromatic hydrocarbons’ (PAHs) specific components are likely involved in respiratory disease development and exacerbation in children and adults. Airborne PAH exposure’s effects on cough symptoms in children and adults with chronic coughs in Kanazawa and Fukuoka, Japan, were investigated in this longitudinal study. A total of 98 patients with chronic coughs were enrolled and followed up between 1 April and 31 May 2020. The enrolled patients were non-smoking adults and children aged 3–83 years. Cough diaries were used to record and collect daily cough symptoms. High-performance liquid chromatography coupled with a fluorescence detector was used to determine the particulate PAH content in daily total suspended particles collected on quartz fiber filters. Ambient concentrations of fine particulate matter, nitrogen dioxide, and sulfur dioxide were obtained from local monitoring sites. Generalized estimated equations were used to estimate the association between daily PAHs and cough symptoms. Among nine PAHs measured, benz[a]anthracene (BaA) was significantly associated with cough symptoms for both lag4 and lag5 PAH exposure. These findings suggest that airborne specific PAHs, especially BaA, affect cough symptoms in children and adults with chronic cough. Further studies are needed to develop effective measures to prevent respiratory diseases against specific PAHs.

Introduction Boron neutron capture therapy (BNCT) is a biologically targeted, cell-selective particle irradiation therapy that utilizes the nuclear capture reaction of boron and neutron. Recently, accelerator neutron generators have been used in clinical settings, and expectations for developing new boron compounds are growing. Methods and Results In this study, we focused on serum albumin, a well-known drug delivery system, and developed maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) as a boron carrying system for BNCT. Our biodistribution experiment involved F98 glioma-bearing rat brain tumor models systemically administered with MID-AC and demonstrated accumulation and long retention of boron. Our BNCT study with MID-AC observed statistically significant prolongation of the survival rate compared to the control groups, with results comparable to BNCT study with boronophenylalanine (BPA) which is the standard use of in clinical settings. Each median survival time was as follows: untreated control group; 24.5 days, neutron-irradiated control group; 24.5 days, neutron irradiation following 2.5 h after termination of intravenous administration (i.v.) of BPA; 31.5 days, and neutron irradiation following 2.5 or 24 h after termination of i.v. of MID-AC; 33.5 or 33.0 days, respectively. The biological effectiveness factor of MID-AC for F98 rat glioma was estimated based on these survival times and found to be higher to 12. This tendency was confirmed in BNCT 24 h after MID-AC administration. Conclusion MID-AC induces an efficient boron neutron capture reaction because the albumin contained in MID-AC is retained in the tumor and has a considerable potential to become an effective delivery system for BNCT in treating high-grade gliomas.

Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-β1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. The current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.

Sphingolipids (SLs), such as ceramide, glucosylceramide (GlcCer), and sphingomyelin, play important roles in the normal development/functions of the brain and peripheral tissues. Disruption of SL homeostasis in cells/organelles, specifically up-regulation of ceramide, is involved in multiple diseases including Alzheimer's disease (AD). One of the pathological features of AD is aggregates of amyloid beta (Aβ) peptides, and SLs regulate both the formation/aggregation of Aβ and Aβ-induced cellular responses. Up-regulation of ceramide levels via de novo and salvage synthesis pathways is reported in Aβ-treated cells and brains with AD; however, the effects of Aβ on ceramide decomposition pathways have not been elucidated. Thus, we investigated the effects of the 25-35-amino acid Aβ peptide (Aβ25-35), the fundamental cytotoxic domain of Aβ, on SL metabolism in cells treated with the fluorescent nitrobenzo-2-oxa-1,3-diazole-labeled C6-ceramide (NBD-ceramide). Aβ25-35 treatment reduced the formation of NBD-GlcCer mediated by GlcCer synthase (GCS) without affecting the formation of NBD-sphingomyelin or NBD-ceramide-1-phosphate, and reduced cell viability. Aβ25-35-induced responses decreased in cells treated with D609, a putative inhibitor of sphingomyelin synthases. Aβ25-35-induced cytotoxicity significantly increased in GCS-knockout cells and pharmacological inhibition of GCS alone demonstrated cytotoxicity. Our study revealed that Aβ25-35-induced cytotoxicity is at least partially mediated by the inhibition of GCS activity.

The β3-adrenergic receptor (A total of 600 Japanese adults aged ≥40 years in a population-based cohort study were analyzed. TheThe frequency of Arg64 allele carriers was 36%. There was no significant difference in BMI, WC, or BF between the groups with or without the Trp64Arg polymorphism. Multivariable logistic regression analysis showed that the Trp64Arg polymorphism was not associated with these three indicators, but lifestyle factors including physical inactivity, higher energy and sodium consumption, and less animal protein intake were significantly related to increased WC and BF percentages.The Trp64Arg polymorphism of

Asymmetric construction of densely functionalized three-dimensional aza-tetracyclic scaffolds were achieved by intramolecular Diels-Alder reaction of bicyclic precursors derived from L-tyrosine. Three substituents were systematically introduced into the developed scaffolds in various combinations, demonstrating their high utility in drug discovery.

Focusing on the components of fine particulate matter, i.e., PM2.5, we have analyzed the factors that led to the high concentrations of each chemical component in PM2.5 during our observations in Fukuoka, Japan in spring 2020. The backward trajectory showed that air masses reached Fukuoka via the Yellow Sea and the southern part of South Korea when PM2.5 and each chemical component were high in concentrations. On the other hand, diurnal variations in ozone were also observed, suggesting that both transboundary and local air pollution are involved. Air masses reached the southern part of the Kyushu region when only sulfate concentrations were high. A volcano eruption led the high sulfate concentration. When only polycyclic aromatic hydrocarbons (PAHs) concentrations were high, air masses often reached the northern part of Kyushu, indicating that there may be a specific local source for PAHs.