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Abstract The fear or disgust of clustered patterns, such as honeycomb or lotus seed pods, is known as trypophobia. A previous developmental study reported that 4-year-old children prefer neutral images over clustered images. However, whether those results indicated higher rating scores for trypophobic images has been controversial. In this study, we examined discomfort with trypophobic images in adults and children aged 4–9 years using an identical experimental procedure. A modified rating scale applicable for children was used that was based on the established Trypophobia Scale for adults. The participants were required to rate five trypophobic and five neutral images on four rating items (disgusting, fear, feel itchiness, and like) on a 4-point scale ranging from 1 (not at all) to 4 (very much). The participants in all age groups indicated higher rate scores for trypophobic images than for neutral images in terms of ‘disgust’, ‘fear’, and ‘feeling itchiness’, whereas they indicated higher scores for neutral images than for trypophobic images in terms of ‘like’. These results suggest that children aged 4–5 years have responses comparable to the responses of adults with respect to trypophobic and neutral images; thus, trypophobia appears to emerge at least by the age of 4–5 years.

Measurement(s) COVID-19 Protocols, Restrictions • Health Behaviors • Personality and Behavioral Change, CTCAE • Emotion • Message Framing • Self-Determination Technology Type(s) Survey • Experiment Design Type Factor Type(s) COVID-19 Protocols, Restrictions • Health Behaviors • Loss-Gain Framing • Cognitive Reappraisal • Self-Determination Messaging Sample Characteristic - Organism Homo Sample Characteristic - Environment Daily Life Sample Characteristic - Location North America • South America • Africa • Australia • Europe • United Kingdom • Asia

Supramolecular drug carriers are a promising approach for delivering anticancer drugs with high blood retention after administration. We previously synthesized folic acid‐modified methyl‐β‐cyclodextrin (FA‐MβCD) as an anticancer drug. FA‐MβCD has a selective autophagy‐mediated antitumor effect on folic acid receptor (FR)‐expressing cancer cells. Here, we enhanced the antitumor effect and safety of FA‐MβCD by preparing a supramolecular nanoparticle formulation of FA‐MβCD via host–guest interactions using an adamantane conjugate with human serum albumin (Ad‐HSA). The Ad‐HSA/FA‐MβCD supramolecular complex prolonged the blood retention of FA‐MβCD and improved its antitumor effect and safety after intravenous administration in tumor‐bearing mice xenografted with FR‐expressing cancer cells. These results suggest that the supramolecular technique using Ad‐HSA is a promising approach for the delivery of CD‐based anticancer drugs.

This paper focuses on the estimation of a driver’s psychological characteristics using driving data for driving assistance systems. Driving assistance systems that support drivers by adapting individual psychological characteristics can provide appropriate feedback and prevent traffic accidents. As a first step toward implementing such adaptive assistance systems, this research aims to develop a model to estimate drivers’ psychological characteristics, such as cognitive function, psychological driving style, and workload sensitivity, from on-road driving behavioral data using machine learning and deep learning techniques. We also investigated the relationship between driving behavior and various cognitive functions, including the Trail Making Test (TMT) and Useful Field of View (UFOV) test, through regression modeling. The proposed method focuses on road type information and captures various durations of time-series data observed from driving behaviors. First, we segment the driving time-series data into two road types, namely, arterial roads and intersections, to consider driving situations. Second, we further segment data into many sequences of various durations. Third, statistics are calculated from each sequence. Finally, these statistics are used as input features of machine learning models to estimate psychological characteristics. The experimental results show that our model can estimate a driver’s cognitive function, namely, the TMT (B) and UFOV test scores, with Pearson correlation coefficients $r$ of 0.579 and 0.708, respectively. Some characteristics, such as psychological driving style and workload sensitivity, are estimated with high accuracy, but whether various duration segmentation improves accuracy depends on the characteristics, and it is not effective for all characteristics. Additionally, we reveal important sensor and road types for the estimation of cognitive function.

Adverse events after surgery not only affect the patient’s recovery but also increase the burden on doctors and patients due to prolonged hospitalization. Predicting adverse events from patient data before surgery with a machine learning method is highly expected. It is difficult to collect a large amount of patient data since the number of surgeries in a year is limited and predict the occurrence of adverse events accurately since patient data are imbalanced data. To improve the accuracy of adverse event prediction, this paper proposes data generation with Filtered $\beta $ -VAE for the preoperative prediction of adverse events. Filtered $\beta $ -VAE has filters by the reconstruction error and by a machine learning method. After $\beta $ -VAE generates minority class data, the two layers of filtering are used to remove low-quality minority class data that have little contribution to the adverse event prediction. In the evaluations, patient data obtained from Tokyo Dental University Ichikawa General Hospital were used. The proposed method can predict adverse events with a recall of 0.848, which is 5.6% more accurate than existing methods. The effects of filtering in Filtered $\beta $ -VAE are visualized, and the reasons for the improvement in prediction accuracy are clarified. Furthermore, this paper shows that $\beta $ -VAE can generate arbitrary patient data even in table data, corresponding to the distribution of the original patient data.

Abstract The diagnostic criteria of aspiration pneumonia have not been established, and it remains an underdiagnosed entity. Diagnosis and cause investigation is essential in improving the management of aspiration pneumonia. The Japanese Respiratory Society Guidelines for the Management of Pneumonia in Adults (JRS Guidelines) show a list of risk factors for aspiration pneumonia. We developed an algorithm to aid physicians in evaluating these possible underlying factors and guide their management with a focus on aspiration pneumonia. The algorithm was developed based on the JRS Guidelines. The algorithm suggested dysphagia screening, pneumococcal and influenza vaccination, and other preventative measures for pneumonia. The algorithm was implemented in the acute setting of a general hospital among older patients admitted with pneumonia. Their outcomes were compared with a historical control group constituting similar patients from the previous year. Forty patients with pneumonia were assessed with the algorithm group, and 44 patients were included in the control group. In the algorithm group, significantly more cases (95.0% vs. 15.9%, p

Background: Home hot-tub bathing substantially increases drowning mortality rates among older adults in Japan. Previous laboratory studies on hemodynamic responses during hot-tub bathing have been inconsistent depending on the thermal conditions. Furthermore, real-world hemodynamic changes that occur during bathing remain poorly understood. This study investigated the association between individual thermal states and hemodynamic parameters during hot-tub bathing among community-dwelling older adults. Methods: In this cross-sectional study conducted between January 2016 and April 2019, which involved 1,479 older adults (median [range] age, 68 [40–90] years), skin temperature on the abdominal surface was measured every minute. Ambulatory blood pressure and pulse rate were recorded at 15-min intervals for 24 h. Participants underwent simultaneous living room temperature measurements in their homes, and the time and methods of bathing were recorded. Associations between skin temperature and hemodynamic parameters during bathing and between the pre-bath living room temperature and in-bath maximum proximal skin temperature were evaluated using mixed-effects and linear regression models, respectively. Results: A 1 °C increase in skin temperature was significantly associated with a 2.41 mmHg (95% confidence interval [CI]: 2.03–2.79) increase in systolic blood pressure and a 2.99 bpm (95% CI: 2.66–3.32) increase in pulse rate, after adjusting for potential confounders, including age, sex, body mass index, antihypertensive medication use, dyslipidemia, diabetes, and living room and outdoor temperatures. Significant interactions were not observed between sex and skin temperature in relation to systolic blood pressure and pulse rate (P = 0.088 and 0.490, respectively). One standard deviation lower living room temperature before bathing was significantly associated with a 0.41 °C (95% CI: 0.35–0.47) higher maximum skin temperature during bathing. Conclusions: Our findings suggest that pre-bath cold exposure may increase the skin temperature during hot-tub bathing, possibly resulting in excessive hemodynamic changes. This provides a framework for future interventions that utilize pre-bath thermal conditions and bathing environments to prevent bath-related deaths.

Background: Although positron emission tomography combined with computed tomography (PET-CT) plays an important role in detecting various types of childhood malignancy, it has low positive predictive value, owing to the nonspecific uptake of 18F-fluorodeoxyglucose (FDG) by normal tissue in various benign conditions. Case summary: A 5-year-old male patient with a malignant rhabdoid tumor originating in the left neck underwent primary tumor resection concurrently with ipsilateral lymph node dissection after receiving neoadjuvant chemotherapy consisting of cyclophosphamide, carboplatin, etoposide, vincristine, and doxorubicin. He later received the same adjuvant chemotherapy as well as proton therapy for the primary tumor. Sixteen months after completing the initial therapy, follow-up PET-CT revealed a novel area of glucose hypermetabolism in the right side of the tongue, which was suspected of being a recurrence. However, a physical examination and magnetic resonance imaging (MRI) demonstrated no evidence of tumor recurrence. The patient had a significant leftward deviation of the tongue, suggesting left hypoglossal nerve paralysis. Denervation of the ipsilateral intrinsic tongue muscles secondary to the treatment had caused atrophy in the ipsilateral muscles and compensatory hypertrophy in the contralateral muscles, which increased FDG uptake. Physicians should carefully confirm any diagnosis of a locally recurrent tumor because PET-CT often produces ambiguous findings.

Acute lymphoblastic leukemia (ALL) is the most common disease in pediatric oncology. The history of developmental therapeutics for ALL began in the 1960s with the repetition of “unreliable” medical interventions against this lethal disease. By the 1990s, the development of multi-agent chemotherapy and various types of supportive care rendered ALL treatable. Highly sophisticated, molecular, diagnostic techniques have enabled highly accurate prediction of the relapse risk, and the application of risk-adapted treatments has increased the survival rate in the standard-risk group to nearly 100% in most European nations and North America. Incorporation of state-of-the-art, molecularly targeted agents and novel treatments, including cell and immunotherapy, is further improving outcomes even in the high-risk group. On the other hand, the financial burden of treating children with ALL has increased, imperiling the availability of these diagnostic and treatment strategies to patients in low- and middle-income countries (LMICs). The fundamental treatment strategy, consisting of corticosteroid and classical cytotoxic therapy, has achieved fairly good outcomes and should be feasible in LMICs as well. The present review will discuss the history of developmental therapeutics for childhood ALL in various countries through an extensive literature review with the aim of proposing a model for a treatment backbone for pediatric ALL. The discussion will hopefully benefit LMICs and be useful as a base for future clinical trials of novel treatments.

Atacama Large Millimeter/submillimeter Array (ALMA) data toward QSO J1851+0035 ( l = 33.°498, b = +0.°194) were used to study absorption lines by Galactic molecular gas. We detected 17 species (CO, ^13 CO, C ^18 O, HCO ^+ , H ^13 CO ^+ , HCO, H _2 CO, C _2 H, c -C _3 H, c -C _3 H _2 , CN, HCN, HNC, CS, SO, SiO, and C) and set upper limits to 18 species as reference values for chemical models. About 20 independent velocity components at 4.7–10.9 kpc from the Galactic center were identified. Their column density and excitation temperature estimated from the absorption study, as well as the CO intensity distributions obtained from the FUGIN survey, indicate that the components with τ ≲1 correspond to diffuse clouds or cloud outer edges. Simultaneous multiple-Gaussian fitting of CO J = 1–0 and J = 2–1 absorption lines shows that these are composed of narrow- and broad-line components. The kinetic temperature empirically expected from the high HCN/HNC isomer ratio (≳4) reaches ≳40 K and the corresponding thermal width accounts for the line widths of the narrow-line components. CN-bearing molecules and hydrocarbons have tight and linear correlations within the groups. The CO/HCO ^+ abundance ratio showed a dispersion as large as 3 orders of magnitude with a smaller ratio in a smaller N (HCO ^+ ) (or lower A _V ) range. Some of the velocity components are detected in single-dish CO emission and ALMA HCO ^+ absorption but without corresponding ALMA CO absorption. This may be explained by the mixture of clumpy CO emitters not resolved with the ∼1 pc single-dish beam surrounded by extended components with a very low CO/HCO ^+ abundance ratio (i.e., CO-poor gas).

Molecular lines are powerful diagnostics of the physical and chemical properties of the interstellar medium (ISM). These ISM properties, which affect future star formation, are expected to differ in starburst galaxies from those of more quiescent galaxies. We investigate the ISM properties in the central molecular zone of the nearby starburst galaxy NGC 253 using the ultrawide millimeter spectral scan survey from the Atacama Large Millimeter/submillimeter Array Large Program ALCHEMI. We present an atlas of velocity-integrated images at a 1.″6 resolution of 148 unblended transitions from 44 species, including the first extragalactic detection of HCNH ^+ and the first interferometric images of C _3 H ^+ , NO, and HCS ^+ . We conduct a principal component analysis (PCA) on these images to extract correlated chemical species and to identify key groups of diagnostic transitions. To the best of our knowledge, our data set is currently the largest astronomical set of molecular lines to which PCA has been applied. The PCA can categorize transitions coming from different physical components in NGC 253 such as (i) young starburst tracers characterized by high-excitation transitions of HC _3 N and complex organic molecules versus tracers of on-going star formation (radio recombination lines) and high-excitation transitions of CCH and CN tracing photodissociation regions, (ii) tracers of cloud-collision-induced shocks (low-excitation transitions of CH _3 OH, HNCO, HOCO ^+ , and OCS) versus shocks from star formation-induced outflows (high-excitation transitions of SiO), as well as (iii) outflows showing emission from HOC ^+ , CCH, H _3 O ^+ , CO isotopologues, HCN, HCO ^+ , CS, and CN. Our findings show these intensities vary with galactic dynamics, star formation activities, and stellar feedback.

We present emission maps ( $1\buildrel{\,\prime}\over{.} 5\,\times \,1\buildrel{\,\prime}\over{.} 5$ scale, corresponding to 0.18 pc) of the DCN ( J = 2 − 1) and DCO ^+ ( J = 2 − 1) lines in the 2 mm band toward the Orion KL region obtained with the 2 mm receiver system named B4R installed on the Large Millimeter Telescope. The DCN emission shows a peak at the Orion KL hot core position, whereas no DCO ^+ emission has been detected there. The DCO ^+ emission shows enhancement at the west side of the hot core, which is well shielded from the UV radiation from OB massive stars in the Trapezium cluster. We have derived the abundance ratio of DCN/DCO ^+ at three representative positions where both species have been detected. The gas components with V _LSR ≈ 7.5–8.7 km s ^−1 are associated with low abundance ratios of ∼4–6, whereas much higher abundance ratios (∼22–30) are derived for the gas components with V _LSR ≈ 9.2–11.6 km s ^−1 . We have compared the observed abundance ratio to our chemical models and found that the observed differences in the DCN/DCO ^+ abundance ratios are explained by different densities.

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

This cross-sectional study aimed to explore the correlation between maxillofacial morphology and caries risk, assessed using salivary tests, in orthodontic patients. Despite enhancing the oral health-related quality of life, orthodontic treatment may adversely affect oral hygiene and increase caries risk. This study included 1071 patients all of whom underwent orthodontic examinations and salivary tests before starting orthodontic treatment at a hospital. Salivary tests were performed to assess the secretion rate, pH, buffering capacity, and counts of cariogenic bacteria. The maxillofacial morphology was evaluated using cephalometric X-rays and dental models. Statistical analyses revealed significant correlations among salivary characteristics, bacterial scores, and maxillofacial morphology. Notably, the facial angle and Y-axis values were associated with salivary secretion (p < 0.001), pH (p < 0.001), buffering capacity (p < 0.05), and cariogenic bacterial scores (p < 0.01), respectably. In conclusion, assessing the maxillofacial morphology before orthodontic treatment may aid in predicting the risk of bacterial oral diseases, offering valuable insights into personalized preventive measures. These findings underscore the potential for comprehensive evaluations to enhance caries risk assessment in orthodontic patients.

We present a spatially resolved excitation analysis for the central molecular zone (CMZ) of the starburst galaxy NGC 253 using the data from the Atacama Large Millimeter/submillimeter Array Comprehensive High-resolution Extragalactic Molecular Inventory, whereby we explore parameters distinguishing NGC 253 from the quiescent Milky Way’s Galactic center (GC). Non-LTE analyses employing a hierarchical Bayesian framework are applied to Band 3–7 transitions from nine molecular species to delineate the position–position–velocity distributions of column density ( ${N}_{{{\rm{H}}}_{2}}$ ), volume density ( ${n}_{{{\rm{H}}}_{2}}$ ), and temperature ( T _kin ) at 27 pc resolution. Two distinct components are detected: a low-density component with $({n}_{{{\rm{H}}}_{2}},{T}_{\mathrm{kin}})\sim ({10}^{3.3}\ {\mathrm{cm}}^{-3},85\ {\rm{K}})$ and a high-density component with $({n}_{{{\rm{H}}}_{2}},{T}_{\mathrm{kin}})\,\sim ({10}^{4.4}\ {\mathrm{cm}}^{-3},110\ {\rm{K}})$ , separated at ${n}_{{{\rm{H}}}_{2}}\sim {10}^{3.8}\ {\mathrm{cm}}^{-3}$ . NGC 253 has ∼10 times the high-density gas mass and ∼3 times the dense-gas mass fraction of the GC. These properties are consistent with their HCN/CO ratio but cannot alone explain the factor of ∼30 difference in their star formation efficiencies (SFEs), contradicting the dense-gas mass to star formation rate scaling law. The ${n}_{{{\rm{H}}}_{2}}$ histogram toward NGC 253 exhibits a shallow declining slope up to ${n}_{{{\rm{H}}}_{2}}\sim {10}^{6}\ {\mathrm{cm}}^{-3}$ , while that of the GC steeply drops in ${n}_{{{\rm{H}}}_{2}}\gtrsim {10}^{4.5}\ {\mathrm{cm}}^{-3}$ and vanishes at 10 ^5 cm ^−3 . Their dense-gas mass fraction ratio becomes consistent with their SFEs when the threshold ${n}_{{{\rm{H}}}_{2}}$ for the dense gas is taken at ∼10 ^4.2−4.6 cm ^−3 . The rich abundance of gas above this density range in the NGC 253 CMZ, or its scarcity in the GC, is likely to be the critical difference characterizing the contrasting star formation in the centers of the two galaxies.

The current coronavirus disease 2019 (COVID-19) pandemic that is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a significant threat to public health. Although vaccines based on the mRNA of the SARS-CoV-2 spike protein have been developed to induce both cellular and humoral immunity against SARS-CoV-2, there have been some concerns raised about their high cost, particularly in developing countries. In the present study, we aim to identify an immunogenic peptide in the SARS-CoV-2 spike protein to activate cellular immunity, particularly CD4+ helper T lymphocytes (Th cells), which are a commander of immune system. SARS-CoV-2 spike protein-derived peptides Spike448-477 and Spike489-513(N501Y)-specific CD4+ Th cell lines were generated by repetitive stimulation of healthy donor-derived CD4+T-cells with each peptide. Their HLA-restrictions were addressed by using blocking antibodies against HLA and HLA-transfected L-cells. The epitopes of Spike448-477-specific CD4+ Th cell lines were defined using a series of 7–14-mer overlapping truncated peptides and alanine-substituted epitope peptides. To address responsiveness of these CD4+ Th cell lines to several SARS-CoV-2 variants, we stimulated the CD4+ Th cell lines with mutated peptides. We addressed whether these identified peptides were useful for monitoring T-cell-based immune responses in vaccinated donors using the IFN-γ ELISpot assay. The Spike448-477 peptide was found to be a promiscuous peptide presented by HLA- DRB1*08:02, DR53, and DPB1*02:02. Although HLA-DPB1*02:02-restricted CD4+ Th cells did not response to some peptides with the L452R and L452Q mutations, the other CD4+ Th cells were not affected by any mutant peptides. We developed two tetramers to detect HLA-DRB1*08:02/Spike449-463- and Spike449-463(L452R/Y453F)-recognizing CD4+ Th cells. Spike489-513(N501Y) peptide was also a promiscuously presented to HLA-DRB1*09:01 and DRB1*15:02. The T-cell responses specific to both peptides Spike448-477 and Spike489-513 were detected in PBMCs after vaccinations. In addition, we observed that the Spike448-477 peptide activated both CD8+ T-cells and CD4+ Th cells in individuals receiving mRNA vaccines. SARS-CoV-2 spike protein-derived peptides, Spike448-477 and Spike489-513, include several epitopes that are presented by multiple HLA-class II alleles to activate CD4+ Th cells, which are considered useful for monitoring the establishment of acquired immunity after vaccination.

Haptophytes synthesize unique β-glucans containing more β-1,6-linkages than β-1,3 linkages, as a storage polysaccharide. To understand the mechanism of the synthesis, we investigated the roles of Kre6 (yeast 1,6-β-transglycosylase) homologs, PhTGS, in the haptophyte Pleurochrysis haptonemofera. RNAi of PhTGS repressed β-glucan accumulation and simultaneously induced lipid production, suggesting that PhTGS is involved in β-glucan synthesis and that the knockdown leads to the alteration of the carbon metabolic flow. PhTGS was expressed more in light, where β-glucan was actively produced by photosynthesis, than in the dark. The crude extract of E. coli expressing PhKre6 demonstrated its activity to incorporate 14C-UDP-glucose into β-glucan of P. haptonemofera. These findings suggest that PhTGS functions in storage β-glucan synthesis specifically in light, probably by producing the β-1,6-branch.

The growth and yield of 13 red and green leaf lettuce (Lactuca sativa L.) cultivars were evaluated under two types of white LED irradiation. There was a difference in growth under the two types white LEDs, specifically in the fresh total weight, fresh leaf weight and dry weight in all cultivars. In addition, the main stem elongation was confirmed for red and green lettuce cultivars under all treatments, but some cultivars promoted the growth of the main stem and the others were inhibited by treatment with far-red light applied at the end of the day (EOD-FR). Furthermore, the EOD-FR treatment affected the characteristic reactions due to white LED light quality in each of the cultivars. These results showed that it is necessary to investigate the selection of white LEDs with and without EOD-FR treatment for each lettuce cultivar.

Summary: Prion-like protein propagation is considered a common pathogenic mechanism in neurodegenerative diseases. Here we investigate the in vivo propagation pattern and aggregation state of mutant α-synuclein by injecting adeno-associated viral (AAV)-α-synuclein-A53T-EGFP into the mouse olfactory cortex. Comparison of aggregation states in various brain regions at multiple time points after injection using western blot analyses shows that the monomeric state of the mutant/misfolded protein propagates to remote brain regions by 2 weeks and that the propagated proteins aggregate in situ after being incorporated into neurons. Moreover, injection of Alexa 488-labeled α-synuclein-A53T confirms the monomeric propagation at 2 weeks. Super-resolution microscopy shows that both α-synuclein-A53T proteins propagate via the lymphatic system, penetrate perineuronal nets, and reach the surface of neurons. Electron microscopy shows that the propagated mutant/misfolded monomer forms fibrils characteristic of Parkinson’s disease after its incorporation into neurons. These findings suggest a mode of propagation different from that of aggregate-dependent propagation.

The chemokine CCL21 regulates immune and cancer cell migration through its receptor CCR7. The Ccl21a gene encodes the isoform CCL21-Ser, predominantly expressed in the thymic medulla and the secondary lymphoid tissues. This study examined the roles of CCL21-Ser in the antitumor immune response in Ccl21a-knockout (KO) mice. The Ccl21a-KO mice showed significantly decreased growth of B16–F10 and YUMM1.7 melanomas and increased growth of MC38 colon cancer, despite no significant difference in LLC lung cancer and EO771 breast cancer. The B16–F10 tumor in Ccl21a-KO mice showed melanoma-specific activated CD8+ T cell and NK cell infiltration and higher Treg counts than wild-type mice. B16–F10 tumors in Ccl21a-KO mice showed a reduction in the positive correlation between the ratio of regulatory T cells (Tregs) to activated CD8+ T cells and tumor weight. In Ccl21a-KO tumor, the intratumoral Tregs showed lower co-inhibitory receptors TIM-3 and TIGIT. Taken together, these results suggest that endogenous CCL21-Ser supports melanoma growth in vivo by maintaining Treg function and suppressing antitumor immunity by CD8+ T cells.

Summary: The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

Summary: The BRCA1-interacting protein Obg-like ATPase 1 (OLA1) functions in centriole duplication. In this study, we show the role of the mitotic kinase Aurora A in the reduction of centrosomal OLA1. Aurora A binds to and polyubiquitinates OLA1, targeting it for proteasomal degradation. NIMA-related kinase 2 (NEK2) phosphorylates the T124 residue of OLA1, increases binding of OLA1 to Aurora A and OLA1 polyubiquitination by Aurora A, and reduces centrosomal OLA1 in G2 phase. The kinase activity of Aurora A suppresses OLA1 polyubiquitination. The decrease in centrosomal OLA1 caused by Aurora A-mediated polyubiquitination promotes the recruitment of pericentriolar material proteins in G2 phase. The E3 ligase activity of Aurora A is critical for centrosome amplification induced by its overexpression. The results suggest a dual function of Aurora A as an E3 ubiquitin ligase and a kinase in the regulation of centrosomal OLA1, which is essential for proper centrosome maturation in G2 phase.

Fibroblast growth factor (FGF) signaling plays essential roles in various biological events. FGF18 is one of the ligands to be associated with osteogenesis, chondrogenesis and bone healing. The mouse critical-sized calvarial defect healing induced by the bone morphogenetic protein 2 (BMP2)-hydrogel is stabilized when FGF18 is added. Here, we aimed to investigate the role of FGF18 in the calvarial bone healing model. We first found that FGF18 + BMP2 hydrogel application to the calvarial bone defect increased the expression of anti-inflammatory markers, including those related to tissue healing M2 macrophage (M2-Mø) prior to mineralized bone formation. The depletion of macrophages with clodronate liposome hindered the FGF18 effect. We then examined how FGF18 induces M2-Mø polarization by using mouse primary bone marrow (BM) cells composed of macrophage precursors and BM stromal cells (BMSCs). In vitro studies demonstrated that FGF18 indirectly induces M2-Mø polarization by affecting BMSCs. Whole transcriptome analysis and neutralizing antibody treatment of BMSC cultured with FGF18 revealed that chemoattractant chemokine (c-c motif) ligand 2 (CCL2) is the major mediator for M2-Mø polarization. Finally, FGF18-augmented activity toward favorable bone healing with BMP2 was diminished in the calvarial defect in Ccr2- deleted mice. Altogether, we suggest a novel role of FGF18 in M2-Mø modulation via stimulation of CCL2 production in calvarial bone healing.

Abstract In recent years, the pretreatment inflammatory responses have proven to predict the prognosis, but no report exists analyzing the combined inflammatory response of the pre- and postsurgical treatment. The current study aims to extract the factors predicting the recurrence and create novel predictive scoring. This retrospective study was conducted at our institution between November 2006 and December 2020, with follow-up until September 2022. Demographic and clinicopathological data were collected from women who underwent primary debulking surgery. We created the scoring system named the prognosis predictive score around primary debulking surgery(PPSP) for progression-free survival(PFS). Univariate and multivariate analyses were performed to assess its efficacy in predicting PFS and overall survival(OS). Cox regression analyses were used to assess its time-dependent efficacy. Kaplan–Meier and the log-rank test were used to compare the survival rate. A total of 235 patients were included in the current study. The cut-off value of the scoring system was six. Multivariate analyses revealed that an advanced International Federation of Gynecology and Obstetrics(FIGO) stage (p

Abstract Background Kaposiform hemangioendothelioma (KHE) is a rare locally aggressive vascular neoplasm that occurs mainly in the pediatric population. KHE usually originates just underneath the skin and affects deeper tissues through infiltrative growth; however, visceral tissue involvement is quite rare. Case presentation An 8-month-old girl with jaundice and acholic stool was referred to our hospital for further evaluation of a hepatoduodenal ligament tumor. A blood examination revealed high bilirubin and liver enzyme levels, but no signs of coagulopathy. The first attempt at a diagnostic surgical procedure did not provide sufficient diagnostic information. However, the histopathological diagnosis of the cystic duct excised in the second surgery indicated KHE. Therefore, in our case, KHE was considered a cause of obstructive jaundice. Sirolimus (rapamycin) was initiated, and the patient was discharged 7 months after admission. Conclusions In cases of atypical hypervascular lesions in the abdominal cavity, especially in the pediatric population, it is important to consider the possibility of KHE, and surgical intervention with proper strategies is required for diagnosis, followed sequentially by promising treatments.

Background: People with poor health or mental conditions are generally unwilling to participate in the health examinations, and no studies have directly examined the relationship of psychological distress among disaster survivors with participation status to date. The present study thus examined psychosocial differences according to the respondent status in a 5-year follow-up survey among participants in the prospective health surveys on survivors of the Great East Japan Earthquake and Tsunami Disaster study in Iwate Prefecture, Japan. Methods: We analyzed data from 10,203 Japanese survivors aged ≥18 years (mean age, 65.6 years; 38.0% men) and who underwent health examinations at baseline in 2011. Participants were classified into responders and nonresponders according to their 2015 health examination participation status. Psychological distress was evaluated using the Kessler 6 scale and categorized as none, mild, and severe. Multinominal logistic regression was used to examine the risk of psychological distress in relation to participation status. Results: In the 2015 survey, 6,334 of 6,492 responders and 1,686 of 3,356 nonresponders were analyzed. The most common reasons for nonparticipation in the survey were participated in other health examinations, examined at a hospital, and did not have time to participate. Nonresponse in males was associated only with mild psychological stress, whereas nonresponse in females was associated with mild and severe psychological distress. Conclusion: Nonresponders in the follow-up survey had a higher risk of psychological distress than responders. Continuous monitoring of the health of nonresponders and responders may help to prevent future health deterioration.

Loss of the histone demethylase KDM5D (lysine‐specific demethylase 5D) leads to in vitro resistance of prostate cancer cells to androgen deprivation therapy (ADT) with and without docetaxel. We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP‐seq) of the LNCaP cell line (androgen‐sensitive human prostate adenocarcinoma) with and without silenced KDM5D, MYBL2‐binding sites were analyzed. Associations between MYBL2 mRNA expression and clinical outcomes were assessed in cohorts of men with localized and metastatic hormone‐sensitive prostate cancer. In vitro assays with silencing and overexpression of MYBL2 and KDM5D in androgen receptor (AR)‐positive hormone‐sensitive prostate cancer cell lines, LNCaP and LAPC4, were used to assess their influence on cellular proliferation, apoptosis, and cell cycle distribution, as well as sensitivity to androgen deprivation, docetaxel, and cabazitaxel. We found that silencing KDM5D increased histone H3 lysine K4 (H3K4) trimethylation and increased MYBL2 expression. KDM5D and MYBL2 were negatively correlated with some but not all clinical samples. Higher MYBL2 expression was associated with a higher rate of relapse in localized disease and poorer overall survival in men with metastatic disease in the CHAARTED trial. Lower MYBL2 levels enhanced LNCaP and LAPC4 sensitivity to androgen deprivation and taxanes. In vitro, modifications of KDM5D and MYBL2 altered cell cycle distribution and apoptosis in a cell line‐specific manner. These results show that the transcription factor MYBL2 impacts in vitro hormone‐sensitive prostate cancer sensitivity to androgen deprivation and taxanes, and lower levels are associated with better clinical outcomes in men with hormone‐sensitive prostate cancer.

The oviductal epithelium consists of ciliated and non-ciliated cells, and their numbers vary depending on the segment of the oviduct and stage of the estrous cycle. Compared with the ampulla, fewer cyclic changes in the number of the two types of cells occur in the isthmus. Recently, we have reported that the epithelium in the ampullary oviduct is composed of many types of cells during different translational/transcriptional states, and their numbers change during the estrous cycle. However, detailed information regarding the epithelial cell subtypes lining the isthmic oviductal epithelium has not yet been reported. In this study, we aimed to identify the epithelial subtypes in the isthmus of the oviduct using immunohistochemistry. Some similarities and differences were observed between the ampulla and isthmus. As observed in the ampulla, epithelial cells of the isthmus expressed either FOXJ1 (ciliogenesis marker) or PAX8 (non-ciliated cell marker). The estrous cycle affected the number of Ki67+ cells but not that of ciliated cells. A relatively high rate of Ki67+ cells (60%) was observed at 1–4 days after the ovulation. Interestingly, unlike the ampulla, Ki67+/FOXJ1+ cells (12.6 ± 1.1%) were discovered in the isthmus. Double staining for Ki67 with FOXJ1, PAX8, or Centrin-1 (a centriole marker) revealed that Centrin-1 was localized on the apical surface of some Ki67+/FOXJ1+ cells. In conclusion, some epithelial cell subtypes exist in the isthmus of the oviduct and isthmus-specific cell subtypes have been identified. These region-specific cells may provide functional and morphological differences between the ampulla and isthmus of the oviduct.

Abstract Background While immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs, the prevalence of irAEs and potential risk factors have not been clarified. We identified irAE predictive factors and examined the relationship between the effect of ICIs and irAEs for patients with malignancies. Methods A total of 533 cases treated with ICIs, including programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), for various malignancies were included retrospectively. We recorded irAEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 5. Prevalence and predictive factors associated with immune-related liver injury and the relationship between irAE and treatment response were analyzed. Results During a median of 10 (1–103) cycles with a median follow-up after several ICI initiations of 384 (21–1715) days, irAEs with all grades and with grade ≥ 3 developed in 144 (27.0%) and 57 (10.7%) cases. Cumulative irAE development rates were 21.9, 33.5, and 43.0% in all grades and 8.8, 14.9, and 20.7% in grade ≥ 3 at 5, 10, and 20 cycles, respectively. Patients who received anti-CTLA4 therapy were more likely to develop irAEs compared to those who received anti-PD-1 or anti-PD-L1 monotherapy. Liver injury was the most common irAE. Multivariate analysis identified the combination of PD-1 and anti-CTL-4 antibodies (hazard ratio [HR], 17.04; P

Abstract Background Maintenance therapy using poly(adenosine diphosphate-ribose)polymerase inhibitors may have adverse events, including hematological toxicity, and may limit therapeutic potential in patients with cancer. Niraparib-induced anemia negatively impacts one’s quality of life. Its amelioration by ferrous iron (for example, sodium ferrous citrate), folic acid, or vitamin B12 has not been supported. Oral ferric citrate hydrate increases circulating levels of iron and hepatic iron accumulation, improving renal anemia in patients with kidney failure receiving hemodialysis. The uptake of ferric iron is considered to be much higher than that of ferrous iron. Case presentation The admitted patient was a 57-year-old Japanese woman with stage IIIB ovarian cancer who underwent primary debulking surgery and standard carboplatin–paclitaxel chemotherapy combined with bevacizumab, followed by niraparib (200 mg/day) maintenance therapy. The patient started oral SFC (100 mg/day) to treat niraparib-related anemia. However, she required two units of packed red blood cell transfusions three times within 3 months after starting niraparib treatment. The patient was diagnosed with niraparib-related anemia. The blood test results after 1 month from the start of niraparib treatment were as follows: red blood cells, 211 × 104/μL; hemoglobin, 7.0 g/dL; hematocrit, 20.8%; reticulocyte, 0.2%; platelet count, 18.0 × 104/μL. She was switched to oral ferric citrate hydrate with a dose of 500 mg per day and resumed niraparib treatment. She did not experience grade 3 niraparib-related hematological toxicity and achieved blood transfusion independence. Conclusions Ferric citrate hydrate may be a safe, effective, and well-tolerated oral drug for treating patients with niraparib-related anemia.

Abstract Among several secreted glycoproteins belonging to the thrombospondin family, thrombospondin 2 (TSP2) is involved in various functions, including collagen/fibrin formation. Liver/serum TSP2 levels have been correlated to liver fibrosis stage and disease activity in nonalcoholic fatty liver disease. This study investigated whether serum TSP2 was associated with clinicopathological features in hepatitis C virus (HCV)-infected patients as well. A total of 350 patients with HCV who had undergone liver biopsy were retrospectively enrolled and divided into a discovery cohort (n = 270) and a validation cohort (n = 80). In the discovery cohort, serum TSP2 levels were moderately correlated with both liver fibrosis stage (r = 0.426, P

Abstract Background The incidence of nontuberculous mycobacterial lung disease (NTM-LD) peaks in middle- and old age groups, coinciding with senescence; thus, chronic infectious diseases can accelerate frailty and worsen mental health in the elderly. In this study, we aimed to compare the prevalence of physical and psychiatric frailty between patients with NTM-LD and bronchiectasis (BE). Methods The Kihon Checklist Questionnaire (KCQ) was used to assess physical and psychiatric frailties and identify those at risk of requiring care among patients with newly diagnosed NTM-LD and BE. Additionally, the Hospital Anxiety and Depression Scale (HADS) scores and chronic inflammatory biomarkers of the alveolar region (surfactant protein [SP]-A, SP-D, and human cationic antibacterial protein [hCAP]/LL-37) were assessed and compared between NTM-LD and BE patients. Results There were no significant differences in the background characteristics between the 33 NTM and 36 BE patients recruited. The KCQ revealed that the proportion of frail NTM patients at diagnosis was higher than that of frail BE patients (48.5% vs. 22.2%, p = 0.026). HADS scores were significantly higher in the NTM group than in the BE group (p

Abstract Background Pleuroparenchymal fibroelastosis (PPFE) is a rare fibrosing lung disease with a predilection for the upper lobe and its progression causes hypoventilation, resulting in hypercapnia. Even though the association between sleep-related hypoventilation (SRH) and chronic obstructive pulmonary disease was well documented, its impact in patients with PPFE was not evaluated. The aim of this study is to clarify the impact of SRH on prognosis in PPFE. Methods A retrospective review of the medical records of 52 patients with PPFE who underwent transcutaneous carbon dioxide monitoring during sleep was done. Patients were stratified into SRH (n = 28) and non-SRH (n = 24) groups based on American Academy of Sleep Medicine criteria. The impact of SRH on the prognosis of PPFE, as well as the clinical factors and comorbidities of PPFE associated with SRH, were evaluated. Results Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), and carbon monoxide diffusing capacity (DLco) in the SRH group were significantly lower than the non-SRH group (P

Background/purpose: The number of patients with oral hypofunction is increasing with the aging of the population, and such hypofunction increases their risk for dysphagia and malnutrition. The purpose of this study was to measure the hardness of commercially available confectioneries, select a confectionery with a hardness suitable for masticatory training for elderly patients, and evaluate the effects of 1-week masticatory training on oral function (occlusal force, masticatory ability, and tongue pressure). Materials and methods: The average hardness values of 25 confectioneries were determined. Among them, one of the softest confectioneries that the patients felt as “chewable but difficult to chew” was selected as the training confectionery for each patient. The patients in the training group continued training, which involved eating of approximately 5 g of one selected confectionery daily for 7 days. The patients in the control group did not undergo any training. Oral function (occlusal force, masticatory ability, and tongue pressure) on the first day and after 7 days was evaluated and compared between the groups. Results: The occlusal force of the patients in the training group increased significantly. However, their masticatory ability and tongue pressure did not change significantly. Conclusion: Patients aged 65 years and older underwent masticatory training, which involved eating of a confectionery with its hardness adjusted individually for a week. A significant increase in the occlusal force was observed, suggesting that masticatory training using confectioneries with a hardness suitable for each patient is effective.

The development of three-dimensional printers has facilitated the creation of patient-specific hollow vessel models. Preoperative simulations using these types of models have improved our ability to select appropriate devices and embolic materials before performing complex endovascular procedures. This report describes 2 cases of high-flow renal arteriovenous fistulas (r-AVFs) that were successfully treated via short-segment embolization using the preloading coil-in-plug (p-CIP) technique. To our knowledge, this is the first report of r-AVF being treated using the p-CIP technique. Our findings demonstrate that preoperative simulation has the potential to improve the safety and reliability of complex vascular embolization procedures.

Background: Maslinic acid (MA) is an olive-derived extract with the structure of pentacyclic triterpenes, which potents anti-inflammatory effects. It has been reported that the combination of MA and resistance exercise increases skeletal muscle mass, but there are many unknowns regarding its detailed molecular mechanism. The present study aimed to clarify the effect of MA supplementation on muscle hypertrophic response to acute muscle contraction-induced resistance exercise using animal model.Methods: Seven-week-old ICR (Institute of Cancer Research) male mice fed a diet containing 0.27% MA during an acclimatization of 1 week. After an overnight fast, the right gastrocnemius muscle was subjected to acute resistance exercise using percutaneous electrical stimulationinduced muscle contractions, while the left gastrocnemius muscle was saved as control. The muscle was excised at 1, 3, and 6 hours after exercise and protein synthesis-related signaling expressions were examined.Results: MA was demonstrated to significantly activate the downstream targets of mammalian/mechanistic target of rapamycin (mTOR), phosphorylated ribosomal protein S6 (rpS6) at Ser240/244 site particularly, while Akt/glycogen synthase kinase-3β (GSK-3β) pathway and mitogenactivated protein kinase (MAPK) signaling were unaffected.Conclusion: Our results suggested that acute resistance exercise-induced muscle protein synthesis-promoting effect of MA is supported by the activation of downstream signaling of mTOR.

Abstract Background Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease. We report here the safe use of remimazolam in a pediatric MELAS patient. Case presentation A 10-year-old girl (118 cm, 16 kg) was scheduled for an open gastrostomy to improve nutrition and epileptic seizure control. We induced and maintained general anesthesia with remimazolam, remifentanil, fentanyl, and rocuronium. We also performed a bilateral subcostal transversus abdominis plane block before the surgery. The surgery finished uneventfully. After we discontinued remimazolam administration, the patient woke up immediately but calmly without flumazenil. Epileptic seizures did not occur during intra- and early post-operative periods. Conclusion Remimazolam enabled us to provide a pediatric MELAS patient with general anesthesia without causing delayed emergence or epileptic seizures.

Abstract The applicability of quantum annealing to various problems can be improved by expressing the Hamiltonian using a circuit satisfiability problem. We investigate the detailed characteristics of the NOR/NAND functions of a superconducting quantum circuit, which are the basic building blocks to implementing various types of problem Hamiltonians. The circuit is composed of superconducting flux qubits with all-to-all connectivity, where direct magnetic couplers are utilized instead of the variable couplers in the conventional superconducting quantum circuit. This configuration provides efficient scalability because the problem Hamiltonian is implemented using fewer qubits. We present an experiment with a complete logic operation of NOR/NAND, in which the circuit produces results with a high probability of success for arbitrary combinations of inputs. The features of the quantum circuit agree qualitatively with the theory, especially the mechanism for an operation under external flux modulation. Moreover, by calibrating the bias conditions to compensate for the offset flux from the surrounding circuit, the quantum circuit quantitatively agrees with the theory. To achieve true quantum annealing, we discuss the effects of the reduction in electric noise in quantum annealing.

Abstract Aims/Introduction The importance of low‐density lipoprotein cholesterol (LDL‐C) in the primary prevention of cardiovascular disease has recently been reported in the population aged ≥75 years with hypercholesterolemia. Therefore, the current status of LDL‐C management for primary prevention of coronary artery disease in patients aged ≥75 years with type 2 diabetes mellitus was investigated. Materials and Methods A total of 124 patients aged ≥75 years who had type 2 diabetes mellitus, but no coronary artery disease, were investigated. The patients' background characteristics, LDL‐C, glycemic status, ankle‐brachial index and cardio‐ankle vascular index were compared between patients taking and not taking LDL‐C‐lowering agents, such as hydroxymethylglutaryl‐CoA reductase inhibitors (statins) and ezetimibe. The details of the antihyperlipidemic and antidiabetic agents used in the present study were also examined. Results LDL‐C was significantly lower in patients taking LDL‐C‐lowering agents (LDLCLT[+]) than in patients not taking them (LDLCLT[−]), although LDL‐C was maintained

Abstract Background Generalized pustular psoriasis (GPP) usually presents with fever, generalized flushing, and multiple sterile pustules on the skin, which histopathologically form subcorneal pustules characterized by Kogoj spongiform pustules. Granulocyte/monocyte adsorption apheresis (GMA) was approved in Japan in 2012. The use of biologics for psoriasis treatment is increasing. Several case reports have evaluated the combination of GMA and cyclosporine (CyA) for GPP. However, very few English reports on combining biologics and GMA in treating GPP exist. Case presentation A 79-year-old man with a history of hypertension, diabetes mellitus, chronic kidney disease, and atrial fibrillation was admitted. He had been consulting a dermatologist for psoriasis vulgaris (PV) since the age of 44. The patient was diagnosed with severe GPP and treated with 300 mg secukinumab (SEC) on day 3. SEC is a fully human monoclonal IgG1 antibody that targets IL-17A. Five doses were administered. In addition, GMA was administered once a week, three times from day 4. After the first administration of GMA, the inflammatory response and skin condition improved markedly. The patient was discharged from the hospital on day 34. Conclusions The present study is the first English-written report on the combined administration of SEC and GMA both instituted since admission for severe GPP, with immediate patient response to treatment. Notably, IL-17A plays a vital role in the pathogenesis of GPP. GMA can eliminate activated leukocytes, and the early introduction of combined IL-17 monoclonal antibody and GMA may allow disease suppression in patients with severe GPP, thus avoiding progression to multiorgan failure. Further studies may verify the effects of IL-17 monoclonal antibodies and GMA on severe GPP.

Abstract Background Health literacy among Japanese is often low, making it difficult for them to evaluate health information and make informed decisions. However, the health literacy scales applied measure the perceived difficulty of health-related tasks; they do not directly assess the specific skills needed to perform the tasks: the skills to judge the reliability of diverse information using evaluation criteria and implement rational decision-making. Therefore, the study objectives were to investigate the following issues using a nationwide survey in Japan. (1) When obtaining information, to what extent do people apply criteria for evaluating information to confirm its reliability; when making decisions, to what extent do they seek out available options and compare pros and cons based on their own values? (2) How strongly are such skills associated with health literacy and demographic characteristics? (3) What opportunities are available to learn these skills? Methods We conducted an online questionnaire survey using a Japanese Internet research company; 3,914 valid responses were received. The measures comprised health literacy (European Health Literacy Survey Questionnaire), five items on information evaluation, four items on decision-making, and items on the availability and location of learning opportunities. We calculated Pearson correlations to explore the association of health literacy with information-evaluation and decision-making skills. Multivariate analyses were also conducted using these factors as dependent variables. Results Fewer than half (30%–50%) of respondents reported always or often evaluating information and engaging in decision-making. Health literacy was significantly and positively correlated with the specific skills of information evaluation and decision-making (r = .26 and .30, respectively) as were multivariate analyses (beta = .15 and .22, respectively). Over 40% of respondents had never learned those skills. The most common resources for learning the skills were the Internet and television; less-used resources were schools and workplaces. Conclusions Both information-evaluation and decision-making skills were associated with health literacy. However, these skills are not sufficiently widespread in Japan because there are few opportunities to acquire them. More research is needed to raise awareness of the importance of such skills for improving health literacy and providing learning opportunities.

Abstract Imeglimin is a new anti-diabetic drug commercialized in Japan (Twymeeg®) and has been drawing much attention in diabetes research area as well as in clinical practice. In this study, we evaluated the effect of imeglimin on pancreatic β-cells. First, single-dose administration of imeglimin enhanced insulin secretion from β-cells and decreased blood glucose levels in type 2 diabetic db/db mice. In addition, single-dose administration of imeglimin significantly augmented insulin secretion in response to glucose from islets isolated from non-diabetic db/m mice. Second, during an oral glucose tolerance test 4-week chronic treatment with imeglimin enhanced insulin secretion and ameliorated glycemic control in diabetic db/db mice. Furthermore, the examination with electron microscope image showed that imeglimin exerted favorable effects on morphology in β-cell mitochondria and substantially increased the number of insulin granules in type 2 diabetic db/db and KK-Ay mice. Finally, imeglimin reduced the percentage of apoptotic β-cell death which was accompanied by reduced expression levels of various genes related to apoptosis and inflammation in β-cells. Taken together, imeglimin directly enhances insulin secretion in response to glucose from β-cells, increases the number of insulin granules, exerts favorable effects on morphology in β-cell mitochondria, and reduces apoptotic β-cell death in type 2 diabetic mice, which finally leads to amelioration of glycemic control.

Abstract The stiffness of a plant cell in response to an applied force is determined not only by the elasticity of the cell wall but also by turgor pressure and cell geometry, which affect the tension of the cell wall. Although stiffness has been investigated using atomic force microscopy (AFM) and Young’s modulus of the cell wall has occasionally been estimated using the contact-stress theory (Hertz theory), the existence of tension has made the study of stiffness more complex. Elastic shell theory has been proposed as an alternative method; however, the estimation of elasticity remains ambiguous. Here, we used finite element method simulations to verify the formula of the elastic shell theory for onion (Allium cepa) cells. We applied the formula and simulations to successfully quantify the turgor pressure and elasticity of a cell in the plane direction using the cell curvature and apparent stiffness measured by AFM. We conclude that tension resulting from turgor pressure regulates cell stiffness, which can be modified by a slight adjustment of turgor pressure in the order of 0.1 MPa. This theoretical analysis reveals a path for understanding forces inherent in plant cells.

Abstract Background We experienced the critical aspiration pneumonia during induction of anesthesia in elective abdominal surgery which standard fasting period was complied with. Case presentation A 64-year-old male was scheduled for gastrojejunostomy because of gastrointestinal obstruction. He fasted from the night before surgery. General anesthesia was induced, and cricoid pressure was applied during intubation. However, he vomited huge amount of gastric contents. The scheduled surgery was performed without surgical complications, and postoperatively respiratory management, including mechanical ventilation with prone positioning, was performed in high care unit. He was extubated on postoperative day 2. He was discharged from the hospital on POD 25. Conclusion The standard fasting period can prevent aspiration pneumonia in most cases. However, even in elective cases without abdominal symptoms, we consider that massive-volume gastric residual contents, especially in susceptible cases. We suggest that point-of-care gastric ultrasonography be performed in suspicious cases before induction of anesthesia.

Abstract Prime factorization (P = M × N) is a promising application for quantum computing. Shor’s algorithm is a key concept for breaking the limit for analyzing P, which cannot be effectively solved by classical computation; however, the algorithm requires error-correctable logical qubits. Here, we describe a quantum annealing method for solving prime factorization. A superconducting quantum circuit with native implementation of the multiplier Hamiltonian provides combinations of M and N as a solution for number P after annealing. This circuit is robust and can be expanded easily to scale up the analysis. We present an experimental and theoretical exploration of the multiplier unit. We demonstrate the 2-bit factorization in a circuit simulation and experimentally at 10 mK. We also explain how the current conditions can be used to obtain high success probability and all candidate factorized elements.

Metallothionein (MT), which is a small metal-binding protein with cysteine-rich motifs, functions in the detoxification of heavy metals in a variety of organisms. Even though previous studies suggest that MT is in-volved in the tolerance mechanisms against nitrosative stress induced by toxic levels of nitric oxide (NO) in mammalian cells, the physiological functions of MT in relation to NO have not been fully understood. In this study, we analyzed the functions of MT in nitrosative stress tolerance in the yeast Saccharomyces cerevisiae. Our phenotypic analyses showed that deletion or overexpression of the MT-encoding gene, CUP1, led to higher sensitivity or tolerance to nitrosative stress in S. cerevisiae cells, respectively. We further examined whether the yeast MT Cup1 in the cell-free lysate scavenges NO. These results showed that the cell-free lysate containing a higher level of Cup1 degraded NO more efficiently. On the other hand, the transcription level of CUP1 was not affected by nitrosative stress treatment. Our findings suggest that the yeast MT Cup1 contributes to nitrosative stress tolerance, possibly as a constitutive rather than an inducible defense mechanism.

Abstract Background Despite the potential benefits of effective communication, telling a child that they have a life-threatening condition is one of the most daunting challenges. This study aimed to explore the information needs of children with leukemia from the perspectives of children and their parents at the time of diagnosis. Methods We conducted an exploratory qualitative study using semi-structured individual interviews with children diagnosed with leukemia between seven and 13 years old (n = 7) and their parents (n = 9). Children and parents’ interview data were analyzed using thematic analysis. Results We identified three themes for the information needs of children with leukemia, 1) beginning to cope, 2) avoiding disclosure – protecting child, and 3) informational support. The children and their parents needed to receive understandable information at the best time to cope with cancer. However, the children and parents expressed different views about children’s information needs. The children needed clear information about the disease, treatment, hospitalization, and the benefits of hospitalization from the time of diagnosis. In contrast, the parents felt they should not tell their children about the disease if they were in shock by their child’s cancer diagnosis. Moreover, the parents believed that information that would be incomprehensible to the child and distress should be avoided to protect their children. Conclusions While the information needs of children with leukemia are varied, children and their parents need the information to cope with cancer. However, if the parents believe that the information would be distressful, they might manage communication with their children. Healthcare professionals should explore the motivations behind parents’ attitudes against communication with children and confront conflict. Healthcare professionals also should communicate with the children and their parents to understand their information needs and respect children’s views.

This paper investigates the super-resolution of velocity fields in two-dimensional flows from the viewpoint of rotational equivariance. Super-resolution refers to techniques that enhance the resolution of an image from low to high resolution, and it has recently been applied in fluid mechanics. Rotational equivariance of super-resolution models is defined as the property by which the super-resolved velocity field is rotated according to a rotation of the input, leading to inferences that are covariant with the orientation of fluid systems. In physics, covariance is often related to symmetries. To better understand the connection with symmetries, the notion of rotational consistency of datasets is introduced within the framework of supervised learning, which is defined as the invariance of pairs of low- and high-resolution velocity fields with respect to rotation. This consistency is sufficient and necessary for super-resolution models to learn rotational equivariance from large datasets. Such a large dataset is not required when rotational equivariance is imposed on super-resolution models through the use of prior knowledge in the form of equivariant kernel patterns. Nonetheless, even if a fluid system has rotational symmetry, this symmetry may not carry over to a velocity dataset, which is not rotationally consistent. This inconsistency can arise when the rotation does not commute with the generation of low-resolution velocity fields. These theoretical assertions are supported by the results of numerical experiments, where two existing convolutional neural networks (CNNs) are converted into rotationally equivariant CNNs and the inferences of these CNNs are compared after the supervised training.