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Norihiko Sukenaga,1 Yuka Matsuki,2 Lynn Maeda,3 Takako Nagai,1 Kazuma Hashimoto,1 Yumiko Takao,1 Munetaka Hirose1 1Department of Anesthesiology and Pain Medicine, Hyogo College of Medicine, Hyogo, Japan; 2Department of Anesthesiology and Reanimatology, Faculty of Medicine Sciences, University of Fukui, Fukui, Japan; 3Department of Anesthesiology and Pain Management, Nishinomiya Municipal Central Hospital, Hyogo, JapanCorrespondence: Munetaka HiroseDepartment of Anesthesiology and Pain Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, JapanTel +81-798-45-6392Email mhirose@hyo-med.ac.jpBackground: Persistent idiopathic facial pain (PIFP) is a subtype of painful cranial neuropathies and other facial pains. The involvement of neuropathic mechanisms in PIFP, however, remains controversial. Using the Douleur Neuropathique 4 (DN4) questionnaire, the present study examined neuropathic characteristics in patients with PIFP.Methods: The multi-institutional retrospective study collected the following clinical data from 205 consecutive patients with adult chronic pain: gender, age, BMI, diseases causing chronic pain, disease duration, visual analogue scale score of pain strength, and DN4 score. To compare neuropathic characteristics between PIFP and postherpetic neuralgia (PHN), we selected patients with PIFP (n=19) and patients with PHN (n=33), and performing a case–control study in which each patient with PHN or PIFP was matched by age and gender (n=16 in each group).Results: DN4 score was significantly lower in the PIFP group than in the PHN group before and after matching. The incidence when DN4 was ≥4 was 10.5% before matching and 12.5% after matching in the PIFP group, both of which were significantly lower than those in the PHN group before and after matching (66.7% and 75.0%).Conclusion: Ten percent of the PIFP patients likely show neuropathic pain characteristics.Keywords: DN4, neuropathic pain, orofacial pain

Abstract DNA hypomethylating agents (HMAs) are used for the treatment of myeloid malignancies, although their therapeutic effects have been unsatisfactory. Here we show that CRISPR-Cas9 screening reveals that knockout of topoisomerase 1-binding arginine/serine-rich protein (TOPORS), which encodes a ubiquitin/SUMO E3 ligase, augments the efficacy of HMAs on myeloid leukemic cells with little effect on normal hematopoiesis, suggesting that TOPORS is involved in resistance to HMAs. HMAs are incorporated into the DNA and trap DNA methyltransferase-1 (DNMT1) to form DNA-DNMT1 crosslinks, which undergo SUMOylation, followed by proteasomal degradation. Persistent crosslinking is cytotoxic. The TOPORS RING finger domain, which mediates ubiquitination, is responsible for HMA resistance. In TOPORS knockout cells, DNMT1 is stabilized by HMA treatment due to inefficient ubiquitination, resulting in the accumulation of unresolved SUMOylated DNMT1. This indicates that TOPORS ubiquitinates SUMOylated DNMT1, thereby promoting the resolution of DNA-DNMT1 crosslinks. Consistently, the ubiquitination inhibitor, TAK-243, and the SUMOylation inhibitor, TAK-981, show synergistic effects with HMAs through DNMT1 stabilization. Our study provides a novel HMA-based therapeutic strategy that interferes with the resolution of DNA-DNMT1 crosslinks.

Lymphoepithelial carcinoma of the submandibular gland is an extremely rare condition; therefore, no clear clinical features or established treatment is available for this. A 58-year-old Japanese man who came to our hospital with the complaint of swelling of the left submandibular region was diagnosed with stage IVa, T4aN2bM0 lymphoepithelial carcinoma of the submandibular gland. We also examined the relationship between the tumor and Epstein-Barr virus by Epstein-Barr virus encoded ribonucleoprotein in situ hybridization. The patient was treated by performing segmental mandibulectomy, neck dissection, mandibular reconstruction, and adjuvant chemoradiotherapy. After 2 years of treatment, good progress has been observed in the patient without any signs of recurrence. Here, we have reported the treatment of a patient with lymphoepithelial carcinoma of the submandibular gland using literature review.

Abstract Epidural spinal cord stimulation (SCS) is indicated for the treatment of intractable pain and is widely used in clinical practice. In previous basic research, the therapeutic effects of SCS have been demonstrated for epileptic seizure. However, the mechanism has not yet been elucidated. In this study, we investigated the therapeutic effect of SCS and the influence of epileptic seizure. First, SCS in the cervical spine was performed. The rats were divided into four groups: control group and treatment groups with SCS conducted at 2, 50, and 300 Hz frequency. Two days later, convulsions were induced by the intraperitoneal administration of kainic acid, followed by video monitoring to assess seizures. We also evaluated glial cells in the hippocampus by fluorescent immunostaining, electroencephalogram measurements, and inflammatory cytokines such as C–C motif chemokine ligand 2 (CCL2) by quantitative real-time polymerase chain reaction. Seizure frequency and the number of glial cells were significantly lower in the 300 Hz group than in the control group. SCS at 300 Hz decreased gene expression level of CCL2, which induces monocyte migration. SCS has anti-seizure effects by inhibiting CCL2-mediated cascades. The suppression of CCL2 and glial cells may be associated with the suppression of epileptic seizure.

Badminton is one of the most popular racket sports played by all age groups worldwide. Anyone can practice and play badminton as a leisure or competitive sport, regardless of age, experience, or skill level. It does not require physical contact among players or expensive equipment. Compared with closed-skill exercises (e.g., running and swimming), open-skill exercises (e.g., badminton and table tennis) have been reported to significantly improve cognitive function and prevent cognitive decline. This mini review aimed to investigate the findings related to badminton intervention for cognitive function, with attention to the modifiable risk factors of dementia in adults. Additionally, we outlined the characteristics of badminton’s physical demands. This narrative review encompassed studies reported from 2013 to 2023 from multiple databases, including PubMed and Google Scholar. Keywords such as “badminton”, “dementia”, “cognitive function”, “physical activity”, and “depression” were used to identify relevant articles. Various studies, including randomized controlled trials, cohort studies, and case–control studies, were selected to provide a comprehensive overview of badminton intervention. Quantitative data analysis suggests that at a cognitive level, high-intensity badminton can enhance cognitive function with at least 10 min of play once weekly or 20 min of play once weekly on average, whereas moderate-intensity badminton can be effective when played for at least 30 min once weekly or 35 min twice weekly on average. For modifiable risk factors, recreational badminton for about 3 h weekly could effectively manage blood pressure. For body fat percentage and fasting serum glucose levels, recreational badminton for about 10 h weekly exerted positive effects. For depressive states, a moderate-intensity badminton program for 100 min weekly was effective. For lipid profiles associated with dementia occurrence, prolonged badminton intervention for more than 3 months may be beneficial. The characteristics presented here indicate that intervention with regular badminton exercise could effectively improve cognitive function and prevent cognitive decline in older adults.

Abstract Antisense oligonucleotides (ASOs) are synthetic single-stranded oligonucleotides that bind to RNAs through Watson–Crick base pairings. They are actively being developed as therapeutics for various human diseases. ASOs containing unmethylated deoxycytidylyl-deoxyguanosine dinucleotide (CpG) motifs are known to trigger innate immune responses via interaction with toll-like receptor 9 (TLR9). However, the TLR9-stimulatory properties of ASOs, specifically those with lengths equal to or less than 20 nucleotides, phosphorothioate linkages, and the presence and arrangement of sugar-modified nucleotides—crucial elements for ASO therapeutics under development—have not been thoroughly investigated. In this study, we first established SY-ODN18, an 18-nucleotide phosphorothioate oligodeoxynucleotide with sufficient TLR9-stimulatory activity. We demonstrated that an unmethylated CpG motif near its 5′-end was indispensable for TLR9 activation. Moreover, by utilizing various sugar-modified nucleotides, we systematically generated model ASOs, including gapmer, mixmer, and fully modified designs, in accordance with the structures of ASO therapeutics. Our results illustrated that introducing sugar-modified nucleotides in such designs significantly reduces TLR9-stimulatory activity, even without methylation of CpG motifs. These findings would be useful for drug designs on several types of ASOs.

An increasing number of antisense oligonucleotides (ASOs) have been approved for clinical use. However, improvements of both efficacy and safety in the central nervous system (CNS) are crucial for the treatment with CNS diseases. We aimed to overcome the crucial issues by our development of various gapmer ASOs with a novel nucleoside derivative including a 2′,4′-BNA/LNA with 9-(aminoethoxy)phenoxazine (BNAP-AEO). The various gapmer ASOs with BNAP-AEO were evaluated for thermal stability, in vitro and in vivo efficacy, and acute CNS toxicity. Thermal stability analysis of the duplexes with their complementary RNAs showed that ASOs with BNAP-AEO had a higher binding affinity than those without BNAP-AEO. In vitro assays, when transfected into neuroblastoma cell lines, demonstrated that ASOs with BNAP-AEO, had a more efficient gene silencing effect than those without BNAP-AEO. In vivo assays, involving intracerebroventricular injections into mice, revealed ASOs with BNAP-AEO potently suppressed gene expression in the brain. Surprisingly, the acute CNS toxicity in mice, as assessed through open field tests and scoring systems, was significantly lower for ASOs with BNAP-AEO than for those without BNAP-AEO. This study underscores the efficient gene-silencing effect and low acute CNS toxicity of ASOs incorporating BNAP-AEO, indicating the potential for future therapeutic applications.

Abstract Congenital diaphragmatic hernia (CDH) is a life‐threatening condition with high morbidity and mortality rates. The survival rate of neonates with severe CDH is reportedly only 10%–15%. However, prenatal prediction of severe cases is difficult, and the discovery of new predictive markers is an urgent issue. In this study, we focused on microRNAs (miRNAs) in amniotic fluid‐derived small EVs (AF‐sEVs). We identified four miRNAs (hsa‐miR‐127‐3p, hsa‐miR‐363‐3p, hsa‐miR‐493‐5p, and hsa‐miR‐615‐3p) with AUC > 0.8 to classify good prognosis group and poor prognosis group in human study. The AUC for hsa‐miR‐127‐3p and hsa‐miR‐615‐3p, for predicting the poor prognosis, were 0.93 and 0.91, respectively. In addition, in the in vivo study, the miRNA profiles of the lung tissues of CDH rats were different from those of control rats. Additionally, two elevated miRNAs (rno‐miR‐215‐5p and rno‐miR‐148a‐3p) in the lung tissues of CDH rats were increased in the AF‐sEVs of CDH rats. Our results suggest that severe CDH neonates can be predicted prenatally with high accuracy using miRNAs contained in AF‐sEVs. Furthermore, miRNA profile changes in AF‐sEVs reflected the lung status in CDH. Our findings may contribute to the development of advanced perinatal care for patients with CDH.

Due to the sporadic distribution and trace amount of environmental DNA (eDNA) in deep-sea water, in the context of biodiversity monitoring, large volumes of filtration and multiple filtration replicates are required for eDNA metabarcoding. To address issues tied to the use of multiple filtration devices and large filtration volumes (e.g., contamination, time consumption, etc.), we have developed two systems for simple, rapid, and contamination-less filtration simultaneously that allow for the processing of multiple sample replicates from large volumes of water. First, the water from a Niskin bottle was filtered directly using a solenoid pump. Second, the pumped deep-sea water, using the siphon effect, was directly filtered by a filtration device driven by water pressure. This system can process 24 replicates simultaneously without the need for expensive equipment and active driving force. Compared with conventional filtering methods, e.g., peristaltic pumps, the proposed systems reduce filtration time, minimizing contamination, and enabling the simultaneous acquisition of multiple replicates. Overall, the systems presented here provide an effective approach for eDNA metabarcoding analysis, particularly for the filtration of large volumes of water containing small amounts of eDNA, such as deep-sea water. • The present systems reduce filtration time and contamination without water having to be transferred. • Simultaneous multiple replicates improve the efficiency and reliability of biodiversity assessments.

Purpose: Knee joint line orientation (KJLO), an essential component of knee kinematics, has recently been of interest as a clinical parameter, but the factors that determine this are unknown. This study aims to clarify the effect of mechanical axis inclination of the lower limb on KJLO after total knee arthroplasty. Methods: The study included 95 knees of 95 patients who underwent kinematically aligned total knee arthroplasty in which two postoperative whole-leg standing radiographs (open and closed stance) were evaluated. We measured hip-knee-ankle angle, mechanical lateral distal femoral angle, medial proximal tibial angle, KJLO, joint line convergence angle, ankle joint line orientation and the inclination angle of lower limb mechanical axis (θ); the amount of change in each measurement was defined as delta (Δ). The correlation between ΔKJLO and each measured value was analysed, and a multiple linear regression analysis was performed to identify significant factors related to ΔKJLO. Results: The open and closed stance radiographs had differences in KJLO (3.4 ​± ​2.2° vs. −0.2 ​± ​2.3°,p ​

Abstract Extracellular vesicles (EVs), including exosomes, are recognized as promising functional targets involved in disease mechanisms. However, the intravital heterogeneity of EVs remains unclear, and the general limitation for analyzing EVs is the need for a certain volume of biofluids. Here, we present cellulose nanofiber (CNF) sheets to resolve these issues. We show that CNF sheets capture and preserve EVs from ~10 μL of biofluid and enable the analysis of bioactive molecules inside EVs. By attaching CNF sheets to moistened organs, we collect EVs in trace amounts of ascites, which is sufficient to perform small RNA sequence analyses. In an ovarian cancer mouse model, we demonstrate that CNF sheets enable the detection of cancer-associated miRNAs from the very early phase when mice did not have apparent ascites, and that EVs from different locations have unique miRNA profiles. By performing CNF sheet analyses in patients, we identify further location-based differences in EV miRNA profiles, with profiles reflecting disease conditions. We conduct spatial exosome analyses using CNF sheets to reveal that ascites EVs from cancer patients exhibit location-dependent heterogeneity. This technique could provide insights into EV biology and suggests a clinical strategy contributing to cancer diagnosis, staging evaluation, and therapy planning.

Judo is a well-known Japanese martial art that also features in Olympic games. Recently, an increasing interest has been observed in the application of judo as a multicomponent exercise, with a growing body of evidence showing that this feature improves physical and cognitive performance in older adults. Therefore, this review highlights the benefits of judo training in preventing physical and cognitive decline in older adults. Specifically, first, this review outlines the basic characteristics of judo (philosophy, match, and training). Subsequently, prior research examining the impacts of judo training on the physical and cognitive aspects of elderly individuals is reviewed. Thereafter, the brain mechanisms underlying the effects of judo training in improving physical and cognitive performance are discussed. Throughout this review, judo training demonstrated some positive effects on physical (gait and balance, among others) and cognitive (memory and executive function) function in older adults. These positive effects are attributed to a variety of changes in the brain (e.g., increased neurotrophic factor expression and increased cerebral blood flow, among others) that affect different brain regions and networks both functionally and structurally. From these findings, this review concludes that judo training can be an effective way to maintain and prevent physical and cognitive decline in older adults.

Abstract Ensemble simulations of climate models are used to assess the impact of climate change on precipitation, and require downscaling at the local scale. Statistical downscaling methods have been used to estimate daily and monthly precipitation from observed and simulated data. Downscaling of short-term precipitation data is necessary for more accurate prediction of extreme precipitation events and related disasters at the regional level. In this study, we developed and investigated the performance of a downscaling method for climate model simulations of hourly precipitation. Our method was designed to recognize time-varying precipitation systems that can be represented at the same resolution as the numerical model. Downscaling improved the estimation of the spatial distribution of hourly precipitation frequency, monthly average, and 99th percentile values. The climate change in precipitation amount and frequency were shown in almost all areas by using the 50 ensemble averages of estimated precipitation, although the natural variability was too large to compare with observations. The changes in precipitation were consistent with simulations. Therefore, our downscaling method improved the evaluation of the climatic characteristics of extreme precipitation events and more comprehensively represented the influence of local factors, such as topography, which have been difficult to evaluate using previous methods.