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ABSTRACT Aims/Introduction PIONEER REAL Japan was a non‐interventional prospective study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice. Materials and Methods Adults naïve to injectable glucose‐lowering therapies initiated oral semaglutide in routine clinical practice and were followed for 34–44 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study; the co‐primary endpoint was number of adverse events (AEs). Secondary endpoints included change in bodyweight from baseline to end of study. Analyses were also carried out for subgroups aged

ABSTRACT Aims/Introduction PIONEER REAL Japan was a non‐interventional, multicenter, prospective study investigating oral semaglutide in adults with type 2 diabetes in routine clinical practice. We report baseline characteristics of participants enrolled in this study. Materials and Methods Adults aged ≥20 years with type 2 diabetes but no previous treatment with injectable glucose‐lowering medication were enrolled. Participants initiated oral semaglutide at their treating physician's discretion and were followed for 34–44 weeks. Participants were stratified into

Abstract Aims/Introduction Despite the emergence of new drugs with novel mechanisms of action, treatment options for older people and those with chronic kidney disease are still limited. Materials and Methods Using a medical database compiled from Diagnostic Procedure Combination hospitals, we retrospectively analyzed treatment status, glycemic control and kidney function over 3 years after the first oral antidiabetic drugs in Japanese adults with type 2 diabetes who were aged ≥65 years. Results Among 5,434 study participants, 3,246 (59.7%) were men, the median age was 72.0 years, the baseline median hemoglobin A1c was 7.1% and the baseline median estimated glomerular filtration rate was 66.6 mL/min/1.73 m2. Treatment was intensified in 40.0% of people during the 3‐year observation period, and the median time to the first treatment intensification was 198 days. Insulin was the most commonly used agent for treatment intensification (36.9%, 802/2,175). Hemoglobin A1c of

Abstract The prenatal diagnosis of fetal heart disease potentially influences parental decision-making regarding pregnancy termination. Existing literature indicates that the severity, whether in complexity or lethality, significantly influences parental decisions concerning abortion. However, questions remain as to how fetal heart disease severity impacts parental decisions, given recent advancements in postsurgical outcomes. Therefore, we investigated risk factors associated with parents’ decision-making regarding abortion following a prenatal diagnosis of fetal heart disease. Our analysis included 73 (terminated: n = 37; continued: n = 36) pregnancies with a fetal heart disease diagnosed before 22 weeks of gestation. Increased gestational age at diagnosis reduced the likelihood of parents’ decision on termination (Model 1: adjusted odds ratio, 0.94; 95% confidence interval 0.89–0.99; Model 2: 0.95 0.90–0.997). Critical disease (5.25; 1.09–25.19) and concurrent extracardiac or genetic abnormalities (Model 1: 4.19, 1.21–14.53; Model 2: 5.47, 1.50–19.96) increased the likelihood of choosing abortion. Notably, complex disease did not significantly influence parental decisions (0.56; 0.14–2.20). These results suggest that parental decision-making regarding abortion may be influenced by earlier gestational age at diagnosis, the lethality of heart disease, and extracardiac or genetic abnormalities, but not its complexity if prenatal diagnosis and parental counseling are provided at a cardiovascular-specialized facility.

Abstract In recent years, there has been an increasing number of studies on neurological symptoms induced as paraneoplastic neurological syndrome (PNS) or neurological immune‐related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). Herein, we report a 68‐year‐old male patient with small‐cell lung cancer who developed memory impairment and autonomic nervous system dysfunction after three courses of carboplatin, etoposide, and durvalumab therapy. Brain magnetic resonance imaging revealed hyperintense areas restricted to the bilateral temporal lobes. Moreover, based on the blood test results, the patient was strongly positive for anti‐neuronal nuclear antibodies. Hence, he was diagnosed with autoimmune limbic encephalitis (ALE). Corticosteroid pulse therapy was administered. After treatment, the patient exhibited gradual improvement in memory impairment. However, while tapering the prednisolone dose, the patient exhibited relapse of memory disturbance owing to ALE. It is challenging to distinguish PNS from neurological irAEs. However, ICI‐induced ALE with positivity for anti‐Hu antibodies has an extremely poor prognosis.

Abstract The aim of this study was to identify angiogenic microRNAs (miRNAs) that could be used in the treatment of hindlimb ischemic tissues. miRNAs contained in extracellular vesicles (EVs) deriving from the plasma were analyzed in C57BL/6 mice, which have ischemia tolerance, and in BALB/c mice without ischemia tolerance as part of a hindlimb ischemia model; as a result 43 angiogenic miRNA candidates were identified. An aortic ring assay was employed by using femoral arteries isolated from BALC/c mice and EVs containing miRNA; as a result, the angiogenic miRNA candidates were limited to 14. The blood flow recovery was assessed after injecting EVs containing miRNA into BALB/c mice with hindlimb ischemia, and miR-709 was identified as a promising angiogenic miRNA. miR-709-encapsulating EVs were found to increase the expression levels of the fibroblast growth factor 2 (FGF2) mRNA in the thigh tissues of hindlimb ischemia model BALB/c mice. miR-709 was also found to bind to the 3′UTR of glycogen synthase kinase 3 beta (GSK3B) in three places. GSK3B-knockdown human artery-derived endothelial cells were found to express high levels of FGF2, and were characterized by increased cell proliferation. These findings indicate that miR-709 induces an upregulation of FGF2 through the downregulation of GSK3B.

Objective: Leptospirosis is an important bacterial zoonosis which is widespread in tropical and subtropical islands and influences human and animal health which has secondary economic effects. Although leptospirosis is endemic in Palau, an Oceanian Pacific Island country, few systematic surveys of potential risk factors for Leptospira infection, such as weather and host animals, have been conducted in the natural environment. We used environmental DNA metabarcoding to assess the distribution, species diversity, and abundance of pathogenic Leptospira in this endemic region to investigate the potential environmental risks. Methods: Forty-two paired water samples, representing fine and rainy weather conditions, were collected from four representative waterfalls and lakes on Babeldaob Island, the largest island in Palau. High-throughput sequencing analysis was conducted for polymerase chain reaction products of leptospiral 16S rRNA and vertebrate animal mitochondrial 12S rRNA genes. Results: We revealed greater Leptospira diversity and abundance in samples collected after continuous rain, particularly in the presence of flooding, compared with samples collected under typhoon, monsoon, or fine weather conditions. From same samples, six mammalian species including cats (Felis catus), mice (Mus musculus), Yap flying fox (Pteropus yapensis), rats (Rattus spp.), and pigs (Sus scrofa) were repeatedly detected. These may be candidates of host animals of Leptospira in Palau; however, their detection was not clearly correlated with that of Leptospira. Conclusion: We repeatedly detected several species of pathogenic Leptospira from water samples of a wide region of Babeldaob Island. We confirmed that Leptospira contamination in freshwater environments increased under rainy conditions, particularly in the presence of flooding. This information could be used to improve public health control measures in this region.

Micro/nanoplastics (MPs/NPs) in the environment exhibit various effects on ecosystems as well as living organisms, such as immune system toxicity. To understand the effects of MPs/NPs experimentally, preparing synthetic MPs/NPs with their geometrical morphology closely similar to the MPs/NPs present in natural environments and with specific material composition is necessary. A pin-on-disc method with plastic pins and micro-textured glass discs has been employed to generate MPs/NPs with defined composition for biological tests. However, these previous studies did not clarify the repeated elastic deformation and stress distribution inside the pin causing the fatigue of degraded areas. Accordingly, in this study, MPs/NPs were generated using a pin-on-disc method, and the interfacial pressure of the pin and disc and the micro-texture pattern were assessed as factors that could change the elastic deformation and the stress distribution inside the pin; additionally, how these factors affect the MP/NP geometrical morphology were investigated. Polyethylene, polypropylene, polyvinyl chloride, polystyrene, and polyethylene terephthalate were used as test materials. Almost all the MPs/NPs of these materials had a fragmented morphology. Further, these MPs/NPs were compared to those identified and they showed almost the same geometrical morphology as the fragmented MPs/NPs in the environment. The equivalent circle diameters of the generated MPs/NPs were suggested to be affected by micro-textures on the discs, which promoted fatigue failure. Additionally, by increasing the interfacial pressure, the stress was distributed deeper inside the pin depending on the plastic materials, which accelerated the crack propagation and generated a large amount of MPs/NPs. From these results, the fragmented morphology of MP/NP which is similar to those present in environments is expected to be generated with defined morphology and material composition for application to biological tests.

Abstract In a recent letter we presented the equations which describe tensionless limit of the excited-state spectrum for strings on AdS 3 × S 3 × T 4 supported by Ramond-Ramond flux, and their numerical solution. In this paper, we give a detailed account of the derivation of these equations from the mirror TBA equations proposed by Frolov and Sfondrini, discussing the contour-deformation trick which we used to obtain excited-state equations and the tensionless limit. We also comment at length on the algorithm for the numerical solution of the equations in the tensionless limit, and present a number of explicit numerical results, as well as comment on their interpretation.

Abstract Background Total arch replacement (TAR) using a frozen elephant trunk (FET) allows for simultaneous treatment of the aortic arch and descending aortic pathology via median sternotomy. In addition, an extra-anatomical bypass performed between the left common carotid artery (CCA) and subclavian artery (SCA) prior to TAR allowed further proximalisation of the FET prosthesis, facilitated distal anastomosis of the TAR and spared the demanding left subclavian artery (LSA) anastomosis in the deep thorax. We investigated the efficacy of this debranching-first technique, followed by TAR using a frozen elephant trunk, as a two-stage operation for extensive thoracic aortic aneurysms in high-risk patients. Methods Forty-nine consecutive patients with diffuse degenerative aneurysms from the aortic arch to the descending aorta or chronic aortic dissection who underwent left common carotid to subclavian artery bypass followed by TAR using a frozen elephant trunk and subsequent thoracic endovascular aortic repair between 2016 and 2021 were analysed. The baseline characteristics and clinical outcomes were assessed. The estimated overall survival, 5-year aortic event-free survival, and aortic reintervention rates were analysed. Results The average European System for Cardiac Operative Risk Evaluation (EuroSCORE II) was 4.7 ± 2.5. The operative mortality rate was 4.1%, with no paraplegia events. The estimated 5-year overall survival, cumulative aortic-related mortality rates were 76.8% and 2%, respectively. The estimated 5-year overall cumulative aortic reintervention rate, including the intended intervention, was 31.3%. The estimated 5-year cumulative rate of non-intended reintervention was 4.5%. Conclusions The assessed technique enables a less technically demanding surgery with reasonable outcomes. The estimated 5-year aortic event-free survival and reintervention rates were acceptable, suggesting that multiple stages of alternative open and endovascular interventions, such as this technique, may reduce the morbidity and mortality rates of high-risk patients with diffuse thoracic aortic aneurysm. UMIN-CTR (University hospital Medical Information Network-Clinical Trial Registry) https://center6.umin.ac.jp/cgi-open-bin/ctr_e/index.cgi Clinical registration number: UMIN000051531

Abstract The “eat me” signal, phosphatidylserine is exposed on the surface of dying cells by phospholipid scrambling. Previously, we showed that the Xkr family protein Xkr4 is activated by caspase-mediated cleavage and binding of the XRCC4 fragment. Here, we show that extracellular calcium is an additional factor needed to activate Xkr4. The constitutively active mutant of Xkr4 is found to induce phospholipid scrambling in an extracellular, but not intracellular, calcium-dependent manner. Importantly, other Xkr family members also require extracellular calcium for activation. Alanine scanning shows that D123 and D127 of TM1 and E310 of TM3 coordinate calcium binding. Moreover, lysine scanning demonstrates that the E310K mutation-mediated salt bridge between TM1 and TM3 bypasses the requirement of calcium. Cysteine scanning proves that disulfide bond formation between TM1 and TM3 also activates phospholipid scrambling without calcium. Collectively, this study shows that extracellular calcium functions as a molecular glue for TM1 and TM3 of Xkr proteins for activation, thus demonstrating a regulatory mechanism for multi-transmembrane region-containing proteins.

Abstract Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development. To identify dysregulated lncRNAs in gastric cancer (GC), we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the non-tumorous gastric mucosa of patients with GC and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 was specifically upregulated in GC patients and that the expression of TM4SF1-AS1 was significantly elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell growth in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interactions with purine-rich element-binding protein α (Pur-α) and Y-box binding protein 1 (YB-1). TM4SF1-AS1 also activates interferon signaling in GC cells, which is dependent on Pur-α and RIG-I. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1-AS1 was associated with several stress granule (SG)-related proteins, including G3BP2, RACK1, and DDX3. Notably, TM4SF1-AS1 promoted SG formation and inhibited apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1-AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggested that TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

Objective: To examine the feasibility, acceptability, and effects of a self-stigma reduction program for patients with type 2 diabetes mellitus11 T2DM: type 2 diabetes mellitus. (T2DM). Methods: We adopted a within-subjects pre–post study design, measuring self-stigma among T2DM patients who received treatment at a tertiary-level hospital. Results: Of the 17 participants, 11 participants completed the program (mean age: 54.36 ± 8.58 years; women: 63.6%; mean T2DM duration: 12.09 ± 10.41 years). Participants experienced reduced levels of self-stigma between the pre- and post-study time points (mean pre-study score: 35.82 ± 16.26; mean post-study score: 25.55 ± 16.91). The difference in self-stigma was not significant (effect size: d = 0.8, χ2 = 3.6, p = 0.057). Overall, participants who completed the program were satisfied except for the duration of each session. Conclusion: The self-stigma reduction program was relatively feasible and acceptable. Although due to the small sample size our results were not statistically significant, a large reduction of self-stigma was found in those who completed the program, which is promising. Future studies with larger sample sizes are needed to measure the program’s long-term effects on the reduction of self-stigma. Innovation: This program is innovative as the researchers and healthcare professionals collaborated with patients who contributed their narratives.

ABSTRACT Needle phobia is a specific phobia classified as an anxiety disorder in the Diagnostic and Statistical Manual of Mental Disorders‐5, and can be a serious problem for patients requiring insulin injections. However, there have been few reports to date on the management of adults with diabetes and needle phobia. We here report a case of a woman with pancreatic diabetes who developed needle phobia and could no longer perform self‐injections. She started to use a sensor‐augmented pump (SAP), and was able to perform a puncture for the insulin pump and the continuous glucose monitoring sensor by herself. The SAP treatment achieved self‐management, better glycemic control, and high treatment satisfaction quantified using the Diabetes Treatment Satisfaction Questionnaire in this patient. Our case suggests the therapeutic potential of SAP in adults with needle phobia and diabetes requiring insulin therapy.

Abstract Background Redo mitral valve surgery using resternotomy after coronary artery bypass grafting (CABG) is challenging as previous CABG with patent internal thoracic artery (ITA) poses a risk of injury due to dense adhesion. It is paramount to have alternative method to minimize this risk. Case presentation : We report a case of redo mitral and tricuspid valve repair via right thoracotomy under hypothermia and systemic potassium administration with axillary artery cannulation in a patient after CABG with patent bilateral ITA grafts crossing over the sternum. Herein, critical dissection around the aorta and functioning ITA grafts was avoided by performing the procedure under systemic hypothermia via thoracotomy. Furthermore, considering the presence of atheroma in the aorta, the axillary artery was used as a perfusion route to prevent stroke events. Postoperative course was uneventful and echocardiography demonstrated preserved cardiac function. Conclusion Performing axillary artery cannulation and right thoracotomy under hypothermic cardiac arrest with systemic hyperkalemia without clamping the patent bilateral ITAs and aorta allowed us to perform redo mitral valve surgery after CABG without major postoperative cardiac or cerebral complications.

A degradative solvent extraction method for upgrading low-rank coal was performed at 200–350 °C for 90 min to obtain a substance dissolved in the solvent at room temperature (Soluble). Because the resulting mixture exhibited a high carbon content without ash, it could be readily used as a fuel. Furthermore, deep eutectic solvents (DESs) have attracted attention for improving the Soluble yield and decreasing the oxygen content in Soluble. DES is known to cleave oxygen-containing functional groups in biomass and is considered effective for deoxidizing low-rank coal. Herein, DES was prepared by mixing choline chloride, FeCl3·6H2O, and Adaro subbituminous coal (AD) and then added to 1-methylnaphthalene (1-MN) in a non-polar solvent, followed by degradative solvent extraction in the range of 200–350 °C. The effects of reaction temperature and added DES amount on the product yield and the composition were evaluated. As the reaction temperature and amount of DES added increased, the Soluble yield and carbon content increased. It was also found that the thermal decomposition temperature and oxygen content decreased with the increasing DES amounts. This decrease indicates that DES promotes the deoxygenation and decomposition of AD and increases the soluble yield of the fuel source.

In our previous study, we found that dry-preserved multilayered fibroblast cell sheets promoted angiogenesis and wound healing in a mouse ulcer model by releasing high levels of intracellular fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF), from dried cells. In the present study, to identify which cell types are suitable for human dry-preserved cell sheets (dry sheets), we compared the intracellular FGF2 levels in seven types of cells reported as cell sheets for clinical use or preclinical studies. FGF2 levels were high in mesenchymal cells, including human oral fibroblasts (HOFs) and human dermal fibroblasts (HDFs), human dental pulp stem cells (DPSCs), and human mesenchymal stem cells (MSCs); in contrast, FGF2 levels in human umbilical vascular endothelial cells (HUVECs), human skeletal muscle myoblasts (SkMMs), and human epidermal keratinocytes (HEKs) were remarkably low, approximately 25% those in fibroblasts. In addition, we prepared dry sheets from HOFs, DPSCs, and MSCs, and analyzed the growth factors released from each dry sheet upon rehydration. High levels of FGF2, HGF, and VEGF were detected in the eluate prepared by immersing each dry sheet. In particular, FGF2 and HGF were the most abundant in HOFs. An in vitro cell proliferation assay showed that these eluates significantly enhanced HUVEC proliferation compared to control cells. Furthermore, cells incubated with HOF eluate showed significantly higher cell proliferation than cells incubated with DPSC and MSC eluates. However, this proliferative response was significantly blocked by FGF2-neutralizing antibodies. These results demonstrate that growth factors released from human dry sheets have physiological activity and that this activity is mainly mediated by the effect of FGF2. Fibroblasts are ideal for the clinical application of dry-preserved cell sheets in humans owing to their high intracellular FGF2 content, fast cell proliferation, ease of handling, availability, and low culture costs, making them the most suitable cell source for regenerative medicine, with FGF2 release as the mechanism of action.

People perceive letters included in their name more favorably than those not included in their name. This tendency is called the name letter effect, and it can affect various types of decision-making, including brand choices. For instance, a consumer named Lundy is more likely than one named Thomas to purchase a Lexus car, as it shares the same initial. This study examines how the name letter affects consumers’ brand choices when brand names are written in Japanese Kanji script. Previous studies have shown that Kanji are processed as visual rather than auditory information. Based on this linguistic nature, the authors predicted that the name letter effect in Kanji would be elicited by congruence between a brand name and a consumer’s name in both spelling and pronunciation (vs. only in pronunciation). An analysis of actual purchase data concerned with the OTC stomach medicine Ohta-Isan (太田胃酸) revealed that consumers with names that matched the brand name (太田) in both pronunciation and Kanji spelling were more likely to purchase the medicine than consumers whose name was pronounced the same but written with different Kanji (e.g. 大田 and 多田, both pronounced Ohta) and consumers with names neither spelled nor pronounced the same way.

Abstract Aims/Introduction Clinical inertia, defined as a failure of healthcare providers to initiate or intensify treatment when indicated, is one of the challenges in achieving glycemic targets in type 2 diabetes patients. Materials and Methods Using a Japanese medical database compiled from Diagnostic Procedure Combination hospitals, this retrospective study investigated clinical inertia in type 2 diabetes patients treated with a single oral antidiabetic drug. We analyzed predictors of clinical inertia, measured the time to treatment intensification, and monitored patients' glycemic control and renal function for 2 years. The index date was defined as the first date of hemoglobin A1c ≥7.0% during the 180 (±60) days after the first oral antidiabetic drug was prescribed. Results Clinical inertia was identified in 35.3% of patients. The median time to treatment intensification from the index date was 75.5 days. The proportion of patients achieving hemoglobin A1c

Abstract Background Palpitations due to Graves’ disease are often caused by supraventricular arrhythmia. However, in rare cases, the background of coronary artery disease, genetic abnormalities, or channel abnormalities can cause ventricular fibrillation, which is a lethal arrhythmia. Here, we report a case of ventricular fibrillation after administration of beta-blockers early in the course of treatment for Graves’ disease coexisting with atypical angina and long QT syndrome. Case presentation A 48-year-old man consulted a local general physician for chest discomfort and palpitations for approximately 2 weeks. He was diagnosed with Graves’ disease and treated with thiamazole 15 mg, bisoprolol 1.25 mg, and nitroglycerin 0.3 mg. The patient continued to experience chest discomfort the next day and visited our hospital. The patient was treated with landiolol 0.125 mg/kg/min for heart rate control, and 20 min later, electrocardiography showed a change from the R-on-T phenomenon to ventricular fibrillation. After cardiopulmonary resumption and improvement of thyroid function, a stress test was performed, which revealed coronary angina and long QT syndrome. An implantable cardioverter defibrillator (ICD) was implanted in the patient for secondary prevention. Since then, no fatal arrhythmia has been observed to date. Conclusions When beta-blockers are administered to patients with Graves’ disease who have severe chest symptoms, fatal arrhythmias are possible. ICD implantation should be considered for the secondary prevention of fatal arrhythmias.

Alzheimer’s disease (AD) is a neurological disease, and its signs and symptoms appear slowly over time. Although current Alzheimer’s disease treatments can alleviate symptoms, they cannot prevent the disease from progressing. To accurately diagnose and treat Alzheimer’s disease, it is therefore necessary to establish effective methods for diagnosis. Apolipoprotein E4 (ApoE4), the most frequent genetic risk factor for AD, is expressed in more than half of patients with AD, making it an attractive target for AD therapy. We used molecular docking simulations, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations to investigate the specific interactions between ApoE4 and the naturally occurring compounds found in the plant Moringa Oleifera. According to the FMO calculations, quercetin had the highest binding affinity to ApoE4 among the sixteen compounds because its hydroxyl groups generated strong hydrogen bonds with the ApoE4 residues Trp11, Asp12, Arg15, and Asp130. As a result, we proposed various quercetin derivatives by introducing a hydroxyl group into quercetin and studied their ApoE4 binding properties. The FMO data clearly showed that adding a hydroxyl group to quercetin improved its binding capacity to ApoE4. Furthermore, ApoE4 Trp11, Asp12, Arg15, and Asp130 residues were discovered to be required for significant interactions between ApoE4 and quercetin derivatives. They had a higher ApoE4 binding affinity than our previously proposed epicatechin derivatives. Accordingly, the current results evaluated using the ab initio FMO method will be useful for designing potent ApoE4 inhibitors that can be used as a candidate agent for AD treatment.

Abstract This study investigated the therapeutic effects of dry-preserved multi-layered fibroblast cell sheets (dry sheets) on cutaneous ulcers. Dry sheets were prepared by air-drying multi-layered fibroblast cell sheets (living sheets) to cease their life activities. Before in vivo application, we tested the release of growth factors into the medium to examine the mechanisms of dry sheets in wound healing. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were released from both dry and living sheets, while high levels of fibroblast growth factor-2 (FGF-2) and high mobility group box 1 (HMGB1) protein were only from dry sheets. An in vitro fibroblast proliferation assay revealed that the dry sheet eluate significantly enhanced cell proliferation and VEGF and HGF production compared with living sheet eluate. FGF-2-neutralizing antibodies significantly blocked this proliferative response. In wounds created on diabetic mice, the dry sheet-treatment groups using autologous or allogeneic cells showed significantly accelerated wound closure compared with that in the no-treatment group. The storage stability of the dry sheet was better at refrigeration temperature than at room temperature and remained stable for at least 4 weeks. Our data indicated that allogeneic dry sheets represent a promising new tool for regenerative medicine that promotes wound healing.

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon in the air, triggers pulmonary inflammation. This study focused on BaP-induced inflammation in the alveolar epithelium. A549 cells were stimulated with BaP for four days. BaP treatment markedly increased NLRP1 expression but slightly decreased NLRP3. Furthermore, aryl hydrocarbon receptor (AhR) knockdown displayed no increase in BaP-induced NLRP1 expression. Similar results were also observed by blocking reactive oxygen species (ROS), which is mediated through AhR, suggesting that the AhR-ROS axis operates in BaP-induced NLRP1 expression. p53 involvement in ROS-mediated NLRP1 induction has also been implied. When we confirmed inflammasome activation in cells treated with BaP for four days, while BaP transiently activated NLRP3, it predominantly activated the NLRP1 inflammasome. These findings have led to the conclusion that BaP could be a potential ligand for the NLRP1 inflammasome persistently observed in the lung epithelium. Our study may provide additional evidence for the sustained pulmonary inflammation caused by environmental air pollution.

Summary: The extracellular matrix (ECM) plays crucial roles in animal development and diseases. Here, we report that Wnt/β-catenin signaling induces the ECM remodeling during Hydra axis formation. We determined the micro- and nanoscopic arrangement of fibrillar type I collagen along Hydra’s body axis using high-resolution microscopy and X-ray scattering. Elasticity mapping of the ECM ex vivo revealed distinctive elasticity patterns along the body axis. A proteomic analysis of the ECM showed that these elasticity patterns correlate with a gradient-like distribution of metalloproteases along the body axis. Activation of the Wnt/β-catenin pathway in wild-type and transgenic animals alters these patterns toward low ECM elasticity patterns. This suggests a mechanism whereby high protease activity under control of Wnt/β-catenin signaling causes remodeling and softening of the ECM. This Wnt-dependent spatiotemporal coordination of biochemical and biomechanical cues in ECM formation was likely a central evolutionary innovation for animal tissue morphogenesis.

The mechanical properties of C70 nanowhiskers (NWs) grown using the liquid–liquid interfacial precipitation method were investigated through bending and nanoindentation experiments. The results showed the solvated C70NWs exhibited a large elastic deformation with a maximum strain of 2.9% upon bending, similar to solvated C60NWs. However, it should be noted that the C70NWs with a face-centered cubic (FCC) retained a large elastic strain even in structure after desolvation, unlike C60NWs with an FCC-structure which showed a significant decrease in elastic strain after desolvation. This elastic strain preservation in C70NWs after desolvation was also observed in the elastic modulus and hardness measurements obtained during nanoindentation. These results suggest that the mechanical properties of C70NWs are independent of solvation and molecular arrangement. Additionally, the elastic modulus and hardness of the C70NWs before desolvation were 4.21 GPa and 216 MPa, respectively, which were lower than those of C60NWs even after desolvation. This indicates that C70NWs have weak C70–C70 and C70–solvent intermolecular interactions. According to recent reports on elastically flexible molecular crystals, corrugated/interlocked molecular packing that prevents slippage between molecular planes, which causes plastic deformation, is considered a key factor for large elastic deformation, with weak intermolecular interactions acting as structural buffers for the deformation. The ellipsoidal-shaped C70 molecules may have higher interlocked molecular packing and weaker intermolecular interactions in the crystal compared to spherical-shaped C60 molecules. These findings on the effect of molecular shape on the mechanical properties of molecular crystals, including fullerene crystals, provide valuable insight for a comprehensive understanding of these properties.

Producing plant secondary metabolites by microbes is limited by the known enzymatic reactions. Here, the authors apply machine learning to predict missing link enzymes of benzylisoquinoline alkaloid (BIA) biosynthesis in Papaver somniferum, and validate the specialized activities through heterologous production.

Glioblastoma is a highly invasive and fatal disease. Temozolomide, a blood–brain barrier (BBB)-penetrant therapeutic agent currently used for glioblastoma, does not exhibit sufficient therapeutic effect. Cisplatin (CDDP), a versatile anticancer drug, is not considered a therapeutic option for glioblastoma due to its low BBB permeability. We previously investigated the utility of microbubbles (MBs) in combination with ultrasound (US) in promoting BBB permeability and reported the efficacy of drug delivery to the brain using a minimally invasive approach. This study aimed to evaluate the feasibility of CDDP delivery to the brain using the combination of MBs and US for the treatment of glioblastoma. We used mice that were implanted with glioma-261 GFP-Luc cells expressing luciferase as the glioblastoma model. In this model, after tumor inoculation, the BBB opening was induced using MBs and US, and CDDP was simultaneously administered. We found that the CDDP concentrations were higher at the glioblastoma site where the US was applied, although CDDP normally cannot pass through the BBB. Furthermore, the survival was longer in mice treated with CDDP delivered via MBs and US than in those treated with CDDP alone or those that were left untreated. These results suggest that the combination of MBs and US is an effective antitumor drug delivery system based on BBB opening in glioblastoma therapy.

ABSTRACT Aims/Introduction The relationship between glycated hemoglobin (HbA1c) and cardiovascular events in older adults was investigated using a Japanese administrative medical database. Materials and Methods Anonymized medical data on patients with diabetes mellitus aged ≥65 years for the period from January 2010 to December 2019 were extracted from the EBM Provider database. The primary end‐point was a composite of cardiovascular events, whereas the other end‐points included severe hypoglycemia and fracture. The association between cardiovascular events and HbA1c at the index date (i.e., approximately 10 months after initial diabetes mellitus diagnosis) was evaluated using the Cox proportional hazards model. Results Among the 3,186,751 patients in the database, 3,946 older adults with diabetes mellitus were eligible for inclusion and were subsequently grouped according to HbA1c quartiles at the index date. Cardiovascular events occurred in 142 patients. Patients with HbA1c in the highest quartile had significantly higher risk of hospitalization for cardiovascular disease than those with HbA1c in the lowest quartile (hazard ratio 1.948; 95% confidence interval 1.252–3.031, P = 0.003). However, the events risk was similar across subgroups with HbA1c

Abstract Background A family member’s negative experiences with medical care have long-term effects on a patient’s attitudes and emotions. However, the impact of family members’ experiences on patients’ trust in their own physicians and in physicians generally is poorly understood. This study aims to quantify these associations. Methods A cross-sectional online survey involving adults with non-communicable diseases (cardiac disease, diabetes, cancer, depression, and rheumatic disease) was conducted in Japan during April 2020. The main exposure variable was dissatisfaction with the medical care that family members had received. The main outcomes were patients’ (N = 661) own trust in their personal physicians and in physicians generally. The study adopted the Japanese version of the Abbreviated Wake Forest Physician Trust Scales. Both 5-item scales (general and individual physician trust) were translated and validated for the study. The total scores were transformed into a scale of 0-100 points. A series of linear mixed-effects models with consideration for clustering effect by prefectures were fit. Results The results showed a lower rating for trust in physicians generally as compared to trust in the respondent’s personal physician (mean 57.0 vs. 66.4 points; p

Strategies for gene and nucleic acid delivery to skeletal muscles have been extensively explored to treat Duchenne muscular dystrophy (DMD) and other neuromuscular diseases. Of these, effective intravascular delivery of naked plasmid DNA (pDNA) and nucleic acids into muscles is an attractive approach, given the high capillary density in close contact with myofibers. We developed lipid-based nanobubbles (NBs) using polyethylene-glycol-modified liposomes and an echo-contrast gas and found that these NBs could improve tissue permeability by ultrasound (US)-induced cavitation. Herein, we delivered naked pDNA or antisense phosphorodiamidate morpholino oligomers (PMOs) into the regional hindlimb muscle via limb perfusion using NBs and US exposure. pDNA encoding the luciferase gene was injected with NBs via limb perfusion into normal mice with application of US. High luciferase activity was achieved in a wide area of the limb muscle. DMD model mice were administered PMOs, designed to skip the mutated exon 23 of the dystrophin gene, with NBs via intravenous limb perfusion, followed by US exposure. The number of dystrophin-positive fibers increased in the muscles of mdx mice. Combining NBs and US exposure, which can be widely delivered to the hind limb muscles via the limb vein, could be an effective therapeutic approach for DMD and other neuromuscular disorders.

Abstract Background Anti-streptavidin antibodies are causal determinants of analytical interference during Thyroid function tests, and numerous reports have detailed such interference, with anti-streptavidin antibodies attracting attention. Case presentation We conducted a straightforward investigation of interference due to anti-streptavidin antibodies, with a case of a 60-year-old Japanese man who consulted our department for inconsistencies between his clinical course and Thyroid function tests. Experiments were conducted using Cobas8000 e602, which employs assay procedures with pre-wash to evaluate FT4 and FT3 levels. Conclusions To our knowledge, this is the first published report to clearly investigate such interferences using a combination of polyethylene glycol precipitation, heterophilic blocking tube precipitation, streptavidin-coated magnetic particle precipitation, and different instruments with or without pre-wash. Clinicians should consider that interferences caused by anti-streptavidin antibodies could lead to a misdiagnosis of thyrotoxicosis. Moreover, discussions between laboratory specialists, clinicians, and manufacturers are required to identify interferences and avoid unnecessary examinations and inappropriate treatment.

Mast cells (MCs) are inflammatory cells involved in allergic reactions. Crosslinking of the high-affinity receptor for IgE (FcϵRI) with multivalent antigens (Ags) induces secretory responses to release various inflammatory mediators. These responses are largely mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Vesicle-associated membrane protein 3 (VAMP3) is a vesicular-SNARE that interacts with targeted SNARE counterparts, driving the fusion of MC secretory granules with the membrane and affecting subsequent assembly of the plasma membrane. However, the role of VAMP3 in FcϵRI-mediated MC function remains unclear. In this study, we comprehensively examined the role of VAMP3 and the molecular mechanisms underlying VAMP3-mediated MC function upon FcϵRI activation. VAMP3 shRNA transduction considerably decreased VAMP3 expression compared with non-target shRNA-transduced (NT) cells. VAMP3 knockdown (KD) cells were sensitized with an anti-DNP IgE antibody and subsequently stimulated with Ag. The VAMP3 KD cells showed decreased degranulation response upon Ag stimulation. Next, we observed intracellular granule formation using CD63-GFP fluorescence. The VAMP3 KD cells were considerably impaired in their capacity to increase the size of granules when compared to NT cells, suggesting that VAMP3 mediates granule fusion and therefore promotes granule exocytosis in MCs. Analysis of FcϵRI-mediated activation of signaling events (FcϵRI, Lyn, Syk, and intracellular Ca2+ response) revealed that signaling molecule activation was enhanced in VAMP3 KD cells. We also found that FcϵRI expression on the cell surface decreased considerably in VAMP3 KD cells, although the amount of total protein did not vary. VAMP3 KD cells also showed dysregulation of plasma membrane homeostasis, such as endocytosis and lipid raft formation. The difference in the plasma membrane environment in VAMP3 KD cells might affect FcϵRI membrane dynamics and the subsequent signalosome formation. Furthermore, IgE/Ag-mediated secretion of TNF-α and IL-6 is oppositely regulated in the absence of VAMP3, which appears to be attributed to both the activation of FcϵRI and defects in VAMP3-mediated membrane fusion. Taken together, these results suggest that enhanced FcϵRI-mediated signal transduction in VAMP3 KD cells occurs due to the disruption of plasma membrane homeostasis. Hence, a multifunctional regulation of VAMP3 is involved in complex secretory responses in MCs.

In the lymphatic vascular system, lymph nodes (LNs) play a pivotal role in filtering and removing lymph-borne substances. The filtering function of LNs involves resident macrophages tightly associated with unique lymphatic sinus structures. Moreover, an intermittently arranged LN in the lymphatic pathway is considered to cooperatively prevent lymph-borne substances from entering blood circulation. However, the functional significance of tissue microarchitecture, cellular composition, and individual LNs in the “LN chain” system is not fully understood. To explore the mechanistic and histo-anatomical significance of LNs as lymph fluid filters, we subcutaneously injected fluorescent tracers into mice and examined the details of lymphatic transport to the LNs qualitatively and quantitatively. Lymph-borne tracers were selectively accumulated in the MARCO+ subcapsular-medullary sinus border (SMB) region of the LN, in which reticular lymphatic endothelial cells and CD169+F4/80+ medullary sinus macrophages construct a dense meshwork of the physical barrier, forming the main body to capture the tracers. We also demonstrated stepwise filtration via the LN chain in the lymphatic basin, which prevented tracer leakage into the blood. Furthermore, inflammatory responses that induce the remodeling of LN tissue as well as the lymphatic pathway reinforce the overall filtering capacity of the lymphatic basin. Taken together, specialized tissue infrastructure in the LNs and their systematic orchestration constitute an integrated filtering system for lymphatic recirculation.

Abstract We propose a new example of the AdS/CFT correspondence between the system of multiple giant gravitons in AdS 5 × S 5 and the operators with O(N c ) dimensions in N $$ \mathcal{N} $$ = 4 super Yang-Mills. We first extend the mixing of huge operators on the Gauss graph basis in the su 2 $$ \mathfrak{su}(2) $$ sector to all loops of the ’t Hooft coupling, by demanding the commutation of perturbative Hamiltonians in an effective U(p) theory, where p corresponds to the number of giant gravitons. The all-loop dispersion relation remains gapless at any λ, which suggests that harmonic oscillators of the effective U(p) theory should correspond to the classical motion of the D3-brane that is continuously connected to non-maximal giant gravitons.

Abstract Aims/Introduction To prevent diabetic complications, strict glucose control and frequent monitoring of blood glucose levels with invasive methods are necessary. We considered the monitoring of tear glucose levels might be a possible method for non‐invasive glucose monitoring. To develop tear glucose monitoring for clinical application, we investigated the precise correlation between the blood and tear glucose concentrations. Materials and Methods A total of 10 participants and 20 participants with diabetes were admitted, and blood and tear samples were collected. Before statistical analysis, we eliminated tear samples contaminated with blood. We observed the daily blood and tear glucose dynamics, and carried out a random intercept model analysis to examine the association between the blood and tear glucose concentrations. Results Tear occult blood tests showed that the tear glucose concentrations and their variation increased in both participants with and without diabetes as contamination of blood increased. In both participants with and without diabetes, fluctuations of the plasma glucose concentrations were observed depending on the timing of collection of the samples, and the dynamics of the tear glucose concentrations paralleled those of the plasma glucose concentrations. The random intercept model analysis showed a significant association between the plasma and tear glucose concentrations in participants with diabetes (P

Chisato Kinoshita et al. use a microbubble and ultrasound delivery system to inhibit miR-96-5p in the mouse brain. They demonstrate that miR96-5p regulates glutathione levels through the NOVA1 RNA binding protein, suggesting that this microRNA could be a target for altering glutathione levels in neurodegenerative disease.

Abstract Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.

Pegylated liposomal doxorubicin (PLD) is a representative nanomedicine that has improved tumor selectivity and safety profile. However, the therapeutic superiority of PLD over conventional doxorubicin has been reported to be insignificant in clinical medicine. Combination treatment with microbubbles and ultrasound (US) is a promising strategy for enhancing the antitumor effects of chemotherapeutics by improving drug delivery. Recently, several preclinical studies have shown the drug delivery potential of lipid bubbles (LBs), newly developed monolayer microbubbles, in combination with low-intensity US (LIUS). This study aimed to elucidate whether the combined use of LBs and LIUS enhanced the intratumoral accumulation and antitumor effect of PLD in syngeneic mouse tumor models. Contrast-enhanced US imaging using LBs showed a significant decrease in contrast enhancement after LIUS, indicating that LIUS exposure induced the destruction of LBs in the tumor tissue. A quantitative evaluation revealed that the combined use of LBs and LIUS improved the intratumoral accumulation of PLD. Furthermore, tumor growth was inhibited by combined treatment with PLD, LBs, and LIUS. Therefore, the combined use of LBs and LIUS enhanced the antitumor effect of PLD by increasing its accumulation in the tumor tissue. In conclusion, the present study provides important evidence that the combination of LBs and LIUS is an effective method for enhancing the intratumoral delivery and antitumor effect of PLD in vivo.

Abstract This study investigated the combined effects of exercise training and D‐allulose intake on endurance capacity in mice. Male C57BL/6J mice were fed either a control diet (Con) or a 3% D‐allulose diet (Allu) and further divided into the sedentary (Sed) or exercise training (Ex) groups (Con‐Sed, Con‐Ex, Allu‐Sed, Allu‐Ex, respectively; n = 6–7/group). The mice in the Ex groups were trained on a motor‐driven treadmill 5 days/week for 4 weeks (15–18 m/min, 60 min). After the exercise training period, all mice underwent an exhaustive running test to assess their endurance capacity. At 48 h after the running test, the mice in the Ex groups were subjected to run at 18 m/min for 60 min again. Then the gastrocnemius muscle and liver were sampled immediately after the exercise bout. The running time until exhaustion tended to be higher in the Allu‐Ex than in the Con‐Ex group (p = 0.08). The muscle glycogen content was significantly lower in the Con‐Ex than in the Con‐Sed group and was significantly higher in the Allu‐Ex than in the Con‐Ex group (p

In this paper, we survey the emerging design space of expandable structures in robotics, with a focus on how such structures may improve human-robot interactions. We detail various implementation considerations for researchers seeking to integrate such structures in their own work and describe how expandable structures may lead to novel forms of interaction for a variety of different robots and applications, including structures that enable robots to alter their form to augment or gain entirely new capabilities, such as enhancing manipulation or navigation, structures that improve robot safety, structures that enable new forms of communication, and structures for robot swarms that enable the swarm to change shape both individually and collectively. To illustrate how these considerations may be operationalized, we also present three case studies from our own research in expandable structure robots, sharing our design process and our findings regarding how such structures enable robots to produce novel behaviors that may capture human attention, convey information, mimic emotion, and provide new types of dynamic affordances.

Abstract Background Despite the inferior patency compared to arterial grafts, a saphenous vein graft (SVG) is widely used for coronary artery bypass grafting (CABG). A lower atherosclerosis rate and higher patency have been reported for SVG obtained via the no-touch technique (NT) than via conventional preparation (CV). Although CV-mediated endothelial dysfunction is implied, the precise mechanism underlying the higher patency with NT is poorly understood. Methods Human residual SVGs during CABG and SVG sections after autopsy were analyzed. The endothelial surface was observed using scanning electron microscopy (SEM) and blindly compared between CV and NT. The endothelial integrity was also analyzed with immunohistochemistry. Results Unexpectedly, the hyperfine structure on SEM was comparable between CV and NT before grafting, and microvillus, a characteristic of endothelium, was indistinguishable between them. Von Willebrand Factor, an endothelial marker, was equally detected throughout the vascular wall in both groups from residual and postmortem sections. Conclusions The morphological integrity of the endothelium was successfully preserved in SVG with CV, even at an ultrastructural level. Although its functionality remains to be addressed, other factors than the endothelium may be involved in the high patency obtained by NT. The present findings suggest that the characteristics of NT and surgical methodology should be reconsidered.

The rational design of spatiotemporal patterns in artificial molecular systems remains at an early stage of development. Here, the authors design a reaction network to control the formation and degradation of nanofibers by orthogonal chemical stimuli and describe force generation by a propagating wave of supramolecular nanofibers.

Knowledge of X-ray diffraction in macromolecular crystals is important for not only structural analysis of proteins but also diffraction physics. Dynamical diffraction provides evidence of perfect crystals. Until now, clear dynamical diffraction in protein crystals has only been observed in glucose isomerase crystals. We wondered whether there were other protein crystals with high quality that exhibit dynamical diffraction. Here we report the observation of dynamical diffraction in thin ferritin crystals by rocking-curve measurement and imaging techniques such as X-ray topography. It is generally known that in the case of thin crystals it is difficult to distinguish whether dynamical diffraction occurs from only rocking-curve profiles. Therefore, our results clarified that dynamical diffraction occurs in thin protein crystals because fringe contrasts similar to Pendellösung fringes were clearly observed in the X-ray topographic images. For macromolecular crystallography, it is hard to obtain large crystals because they are difficult to crystallize. For thin crystals, dynamical diffraction can be demonstrated by analysis of the equal-thickness fringes observed by X-ray topography.

Abstract We compute non-extremal three-point functions of scalar operators in N $$ \mathcal{N} $$ = 4 super Yang-Mills at tree-level in g YM and at finite N c , using the operator basis of the restricted Schur characters. We make use of the diagrammatic methods called quiver calculus to simplify the three-point functions. The results involve an invariant product of the generalized Racah-Wigner tensors (6j symbols). Assuming that the invariant product is written by the Littlewood-Richardson coefficients, we show that the non-extremal three- point functions satisfy the large N c background independence; correspondence between the string excitations on AdS5 × S5 and those in the LLM geometry.

Background Saphenous vein grafts (SVGs) are broadly used in coronary artery bypass grafting despite their inferior patency compared with arterial grafts. Recently, the no‐touch technique (NT), in which an SVG is harvested with a pedicle of perivascular adipose tissue (PVAT) without conduit distension, was shown to improve long‐term patency compared with conventional preparation (CV), wherein outer tissue is removed with distension. The NT was also reportedly associated with reduced atherosclerosis. Although endothelial damage provoked by conventional distension may underlie poor patency when CV is performed, the precise mechanisms underlying the salutary effects of the NT have been unclear. Methods and Results Residual SVGs prepared with CV (CV‐SVGs) or NT (NT‐SVGs) were obtained during coronary artery bypass grafting. Nitric oxide (NO2−/NO3− (NOx)) levels after 24 hours of tissue culture were quantified. The protein expression and localization were analyzed. The isometric force of SVG strips was measured. NT‐SVGs showed superior NOx production to CV‐SVGs. PVAT generated the majority of NOx in NT‐SVGs. PVAT highly expressed arginosuccinate synthase 1, a rate‐limiting enzyme in the molecular circuit for NO synthesis, thereby continuously providing the substrate for NO. A substantial level of endothelial NO synthase was also expressed in PVAT. Pharmacological inhibition of arginosuccinate synthase 1 or endothelial NO synthase significantly suppressed the NOx production in NT‐SVGs. PVAT induced vasorelaxation through NO production, even in the endothelium‐denuded SVG strips. Conclusions Preserving PVAT was predominantly involved in the superior NOx production in NT‐SVGs. Since NO plays crucial roles in suppressing atherosclerosis, this mechanism may greatly contribute to the excellent patency in NT‐SVGs.

To comparatively investigate the morphological adaptation of the human foot for achieving robust and efficient bipedal locomotion, we develop three-dimensional finite element models of the human and chimpanzee feet. Foot bones and the outer surface of the foot are extracted from computer tomography images and meshed with tetrahedral elements. The ligaments and plantar fascia are represented by tension-only spring elements. The contacts between the bones and between the foot and ground are solved using frictionless and Coulomb friction contact algorithms, respectively. Physiologically realistic loading conditions of the feet during quiet bipedal standing are simulated. Our results indicate that the center of pressure (COP) is located more anteriorly in the human foot than in the chimpanzee foot, indicating a larger stability margin in bipedal posture in humans. Furthermore, the vertical free moment generated by the coupling motion of the calcaneus and tibia during axial loading is larger in the human foot, which can facilitate the compensation of the net yaw moment of the body around the COP during bipedal locomotion. Furthermore, the human foot can store elastic energy more effectively during axial loading for the effective generation of propulsive force in the late stance phase. This computational framework for a comparative investigation of the causal relationship among the morphology, kinematics, and kinetics of the foot may provide a better understanding regarding the functional significance of the morphological features of the human foot.

We report on the case of a patient with dysgerminoma, a rare germ cell tumor, which showed hypercalcemia with an elevation of 1α,25-dihydroxycholecalciferol (calcitriol). A 27-year-old nulliparous woman presented with hypercalcemia during the examination of a right ovarian tumor with an elevation of calcitriol, lactate dehydrogenase, and alkaline phosphatase. Fractional excretion of calcium was elevated, and intact parathyroid hormone was suppressed. After undergoing right salpingo-oophorectomy, the patient’s serum calcium and calcitriol returned to the normal range within a week. A literature search was conducted on the topic by reviewing databases for dysgerminoma showing hypercalcemia. We identified 14 patients from the literature and performed a pooled analysis, including the results of our case. However, most cases lack data that can help investigate the potential association between parathyroid hormone, parathyroid hormone-related protein, calcitriol, and phosphorus in hypercalcemia. Thus, more case reports that include additional information are required to fully elucidate the mechanism of hypercalcemia associated with dysgerminoma.

In cell therapy, transplanting an appropriate number of cells to the target site is crucial. One way to achieve this is to transplant cell sheets. Transplantation of cell sheets has already been utilized for various diseases in clinical practice. However, reducing the cost of cell sheet utilization is essential so as to facilitate the spread of regenerative medicine. Several ways to reduce costs are available, one of which is the use of allogenic cells. Another alternative is the use of cell sheets, which necessitates the development of methods for freezing cell sheets. This is the first study to report the use of a 3D Freezer for freezing cells. 3D Freezers have been used in the field of food processing and technology for a long time. The 3D Freezer freezes objects using cold air at a uniform temperature from all directions. In this study, we analyzed the cooling speed of human fibroblast sheets in 11 cell preservation solutions using a 3D Freezer and a Program Freezer. The cooling speed was −2 °C per min in the 3D Freezer. Supercooling in 10 cell preservation solutions was lower in the 3D Freezer than in the Program Freezer. Cell viability after freeze–thaw of the cell sheets using 3D Freezer was more than 70% in five cell preservation solutions. The levels of hepatocyte growth factor and transforming growth factor-β1 were the same not only in the fibroblast sheets frozen using the five cell preservation solutions but also in the non-frozen fibroblast sheets. These results suggest that the 3D Freezer can freeze implantable cell sheets immediately after thawing.