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Abstract The therapeutic potential of suppressing polypyrimidine tract-binding protein 1 (Ptbp1) messenger RNA by viral transduction in a post-stroke dementia mouse model has not yet been examined. In this study, 3 days after cerebral ischemia, we injected a viral vector cocktail containing adeno-associated virus (AAV)-pGFAP-mCherry and AAV-pGFAP-CasRx (control vector) or a cocktail of AAV-pGFAP-mCherry and AAV-pGFAP-CasRx-SgRNA-(Ptbp1) (1:5, 1.0 × 1011 viral genomes) into post-stroke mice via the tail vein. We observed new mCherry/NeuN double-positive neuron-like cells in the hippocampus 56 days after cerebral ischemia. A portion of mCherry/GFAP double-positive astrocyte-like glia could have been converted into new mCherry/NeuN double-positive neuron-like cells with morphological changes. The new neuronal cells integrated into the dentate gyrus and recognition memory was significantly ameliorated. These results demonstrated that the in vivo conversion of hippocampal astrocyte-like glia into functional new neurons by the suppression of Ptbp1 might be a therapeutic strategy for post-stroke dementia.

The Okinawa Rail, Hypotaenidia okinawae (Yamashina and Mano, 1981), is a flightless bird restricted to the northern part of Okinawa Island, Ryukyu Islands, Japan. A new feather mite species, Metanalges (M.) agachi sp. n. (Analgidae: Megniniinae), is described from the Okinawa Rail. The new species is distinguished from the closest species, M. (M.) curtus Gaud and Mouchet, 1959, in having, in males, legs III extending slightly beyond the bases of setae h2, and setae ps1 approximately equidistant from setae h2 and h3, and in females, ventral setae 4a almost extending to the posterior margin of opisthosoma. This is the first report of feather mites associated with this avian host and the first record of the genus Metanalges Trouessart, 1919 in Japan. As the Okinawa Rail is considered to be at high risk of population decline, the new feather mite is thought to be under the risk of extinction.

Abstract As the effective use of carbon resources has become a pressing societal issue, the importance of chemical recycling of plastics has increased. The catalytic chemical decomposition for plastics is a promising approach for creating valuable products under efficient and mild conditions. Although several commodity and engineering plastics have been applied, the decompositions of stable resins composed of strong main chains such as polyamides, thermoset resins, and super engineering plastics are underdeveloped. Especially, super engineering plastics that have high heat resistance, chemical resistance, and low solubility are nearly unexplored. In addition, many super engineering plastics are composed of robust aromatic ethers, which are difficult to cleave. Herein, we report the catalytic depolymerization-like chemical decomposition of oxyphenylene-based super engineering plastics such as polyetheretherketone and polysulfone using thiols via selective carbon–oxygen main chain cleavage to form electron-deficient arenes with sulfur functional groups and bisphenols. The catalyst combination of a bulky phosphazene base P4-tBu with inorganic bases such as tripotassium phosphate enabled smooth decomposition. This method could be utilized with carbon- or glass fiber-enforced polyetheretherketone materials and a consumer resin. The sulfur functional groups in one product could be transformed to amino and sulfonium groups and fluorine by using suitable catalysts.

Abstract Background Inflammatory bowel disease involves chronic inflammation and ulceration, primarily Crohn’s disease and ulcerative colitis. The prevalence of inflammatory bowel disease is rising in industrialized countries. We describe the case of a patient with inflammatory bowel disease and multiple electrolyte disturbances that emphasize the link between a vitamin D deficiency and electrolyte imbalances. Case An 86‐year‐old Japanese man with severe hypocalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia was referred to the gastroenterology and hepatology department our university hospital for severe diarrhea and abdominal pain. Based on clinical symptoms and biochemical and endoscopic findings, Crohn’s disease, intestinal Behçet’s disease, and intestinal tuberculosis were considered as differential diagnoses, but a final diagnosis was not reached. Prednisolone, azathioprine, and metronidazole were administered, and no apparent electrolyte abnormality was observed at the patient’s admission to our hospital. On the 80th hospital day, marked hypocalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia were noted and prolonged, despite daily supplementation with Ca and inorganic P. At his consultation with our department, we observed decreased fractional excretion of Ca, tubular reabsorption of phosphate, fractional excretion of K, and fractional excretion of Mg, suggesting the depletion of vitamin D and extrarenal wasting of K and Mg. The patient’s serum Ca and inorganic P were quickly elevated in response to treatment with an active form of vitamin D, and his serum levels of K and Mg were restored to the normal range by an intravenous administration of K and Mg. A vitamin D deficiency is not rare in inflammatory bowel disease and is caused primarily by the decreased intestinal absorption of vitamin D. In the management of electrolyte imbalances in patients with inflammatory bowel disease, clinicians must consider the possible development of vitamin D deficiency-related disorders. Conclusion Vitamin D deficiency in entero-Behçet’s disease leads to severe hypocalcemia and hypophosphatemia, highlighting the importance of awareness in management.

Background: Oral immunotherapy (OIT) can ameliorate cow's milk allergy (CMA); however, the achievement of sustained unresponsiveness (SU) is challenging. Regarding the pathogenesis of CMA, recent studies have shown the importance of gut microbiota (Mb) and fecal water-soluble metabolites (WSMs), which prompted us to determine the change in clinical and gut environmental factors important for acquiring SU after OIT for CMA. Methods: We conducted an ancillary cohort study of a multicenter randomized, parallel-group, delayed-start design study on 32 school-age children with IgE-mediated CMA who underwent OIT for 13 months. We defined SU as the ability to consume cow's milk exceeding the target dose in a double-blind placebo-controlled food challenge after OIT followed by a 2-week-avoidance. We longitudinally collected 175 fecal specimens and clustered the microbiome and metabolome data into 29 Mb- and 12 WSM-modules. Results: During OIT, immunological factors improved in all participants. However, of the 32 participants, 4 withdrew because of adverse events, and only 7 were judged SU. Gut environmental factors shifted during OIT, but only in the beginning, and returned to the baseline at the end. Of these factors, milk- and casein-specific IgE and the Bifidobacterium-dominant module were associated with SU (milk- and casein-specific IgE; OR for 10 kUA/L increments, 0.67 and 0.66; 95%CI, 0.41–0.93 and 0.42–0.90; Bifidobacterium-dominant module; OR for 0.01 increments, 1.40; 95%CI, 1.10–2.03), and these associations were observed until the end of OIT. Conclusions: In this study, we identified the clinical and gut environmental factors associated with SU acquisition in CM-OIT.

Introduction Early diagnosis of patients with urolithiasis or hypouricemia owing to inborn errors of hypoxanthine metabolism is important in preventing renal failure or drug‐induced toxicity. Case presentation We identified three patients with xanthinuria using gas chromatography/mass spectrometry‐based urine metabolomics: a 72‐year‐old male with bladder stone, a severe hypouricemic 59‐year‐old female with type 2 diabetes mellitus, and an 8‐year and 9‐month‐old female who was first discovered to harbor a mutation in the xanthine dehydrogenase gene using whole‐exome sequencing, but had a normal molybdenum cofactor sulfurase gene. Hydantoin‐5‐propionate was detected in the first and third patients but not in the second, suggesting that the first and second patients had type I and II xanthinuria, respectively. Conclusion Gas chromatography/mass spectrometry‐based metabolomics can be used for undiagnosed patients with xanthinuria, identification of the type of xanthinuria without allopurinol loading, and the quick functional evaluation of mutations in the xanthinuria‐related genes.

We aimed to survey the status of tolvaptan administration in routine clinical practice since the approval of a novel indication for treating syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in Japan. Data from a population of 3,152 patients aged ≥18 years and diagnosed with SIADH between July 1, 2020 and June 30, 2021 were extracted from a Japanese database. Tolvaptan was administered to 586 patients while 2,566 patients were followed up without tolvaptan. In the tolvaptan-treated group, the standard initial doses were 3.75 mg and 7.5 mg in 290 (49.5%) and 250 (42.7%) patients, respectively. The dose was increased in 112 (38.6%) and 71 (28.4%) and decreased in 8 (2.8%) and 46 (18.4%) of patients with 3.75 and 7.5 mg initial doses, respectively. Of the total 586 SIADH patients treated with tolvaptan, serum sodium concentrations were analyzed in 60 patients. In both treatment groups of 3.75 and 7.5 mg initial doses, the serum sodium concentration was elevated from the second day of treatment and reached 135 mEq/L on the fourth day, which was maintained for 2 weeks. Rapid correction of hyponatremia (>10 mEq/L increase in serum sodium concentration over 1 day or >18 mEq/L increase over 2 days) occurred in 26.7% patients with a 7.5 mg initial dose (4 of 15 patients) but not in the patients with a 3.75 mg initial dose (n = 16), suggesting that an initial dose of 3.75 mg of tolvaptan may be a better choice for the safe and proper correction of hyponatremia.

Aim: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Pemafibrate, a selective peroxisome-proliferator-activated receptor α modulator (SPPARMα), has been reported to ameliorate liver function among patients with dyslipidemia. However, there are not many reports of the clinical effects of pemafibrate. This study aims to summarize the experience of using pemafibrate and analyze the effects on liver function in patients with dyslipidemia. Methods: One hundred twelve cases of hyperlipidemia receiving pemafibrate 0.2 mg/day were retrospectively enrolled in this study. Age, gender, BMI, complications, concomitant medications, serum parameters (TG, HDL-C, LDL-C, AST, ALT, γGTP, ALP, platelets, M2BPGi, Cre, eGFR, HbA1c, blood glucose level at any time) were investigated and evaluated. Results: Pemafibrate administration significantly improved serum TG and HDL-C, but not in LDL-C. Serum AST, ALT, γGTP, and ALP were also significantly improved. The fib-4 index, a liver fibrosis score, did not significantly change, but M2-BPGi, an index of fibrosis, significantly decreased. No correlation was observed between each lipid parameter and ALT, and ALT decreased independently of the lipid parameters. Conclusions: As we expected, pemafibrate demonstrated a lipid-improving effect without adversely affecting hepatic and renal functions. An unexpected finding was the decrease in ALT that was independent of lipid parameters.

Objective: To make an initial assessment of the correlation between immersive virtual reality–based (ILBT) line bisection testing and paper-and-pencil–based line bisection (PLBT) testing in healthy subjects. Design: Diagnostic study. Setting: Research laboratory. Participants: Twenty healthy adults (51.5 [11.0] years old, 55% women; N=20). Interventions: Participants underwent an ILBT and a conventional PLBT in near space (NS) and more distant space (MDS). Correlations between the ILBT and PLBT, deviation rates in the NS and MDS, horizontal gaze distribution, and presence of virtual reality sickness (VRS) were evaluated. Main Outcome Measures: Correlation between the deviation rates of the PLBT and ILBT. Results: There was no significant correlation between the ILBT and PLBT for evaluating the deviation rate of the line bisection test (LBT). There was no significant difference in the deviation rate of the LBTs between the NS and MDS, but there was a significant difference in the horizontal line-of-sight distribution. VRS was not observed as an adverse event. Conclusions: In healthy adult subjects, our results suggested that there was no significant correlation between the deviation rates of the ILBT and PLBT. We also found that the ILBT is a useful and safe method for evaluating the horizontal line-of-sight distribution and percentage deviation of line segments from the center in the NS and MDS without inducing VRS.

Global warming has become an urgent issue, and heat-stress protective materials should be developed to manage human life and animal husbandry. Here, thermoprotective effects of Weizmannia coagulans SANK70258, a thermostable probiotic lactic acid bacterium, are investigated using a broiler model in an artificial thermal climate facility. Probiotic exposure significantly enhances their growth even under heat-stress. Based on the characteristic omics data selected using machine learning (random forest and XGBoost), structural equations and causal inference for broiler growth under heat-stress estimate the strong relationship with pyridoxal involved in the reduction of hepatic oxalic acid, which is responsible for cold sensitivity. It is also estimated that faecal Pseudomonas, which can reduce pyridoxal, is reduced by probiotic exposure, and has a negative causal effect on growth. Thus, these observations suggest a novel probiotic aspect of W. coagulans that modulates the mechanism of heat tolerance related to the cold sensitivity.

Background:. Recently, cosmetic surgeons in Japan have used social media to advertise their procedures. We analyzed the influence of social and other media on patients’ motivation to visit our clinic using the aggregated results of a questionnaire distributed to our cosmetic surgery group. Methods:. We obtained the data of 146,108 patients from our database between September 2018 and February 2023. To understand changes in patient motivation over time, patient motivation was compared between the opening (September 2018–February 2020), growth (March 2020–August 2021), and expansion (September 2021–February 2023) periods. Results:. Most patients were motivated to visit clinics by the internet (53.7%) and Instagram (17.3%). Between the opening and growth periods, the internet [odds ratio (OR) 1.28; 95% confidence interval (CI), 1.14–1.43] and referrals (OR, 1.48; 95% CI, 1.08–2.01) significantly increased. Between the opening and expansion periods, there was a significant increase in TV (OR, 4.86; 95% CI, 3.09–7.65) and TikTok use (OR, 24.9; 95% CI, 3.50–177.0). There was more variability in the motivation to visit our clinic during the expansion period than during the other periods, and patients’ motivation differed by procedure and region. In addition, TikTok was used primarily by patients in their late teens and early twenties, whereas TV was used by those in their twenties and forties. YouTube, referrals, and review websites were distributed bimodally. Conclusions:. Patients choose information from various media sources. To attract more patients to our clinics, it is important to disseminate information on both the internet and social media.

Autologous-engineered artificial tissues constitute an ideal alternative for radical surgery in terms of natural anticoagulation, self-repair, tissue regeneration, and the possibility of growth. Previously, we focused on the development and practical application of artificial tissues using “in-body tissue architecture (iBTA)”, a technique that uses living bodies as bioreactors. This study aimed to further develop iBTA by fabricating tissues with diverse shapes and evaluating their physical properties. Although the breaking strength increased with tissue thickness, the nominal breaking stress increased with thinner tissues. By carving narrow grooves on the outer periphery of an inner core with narrow grooves, we fabricated approximately 2.2 m long cord-shaped tissues and net-shaped tissues with various designs. By assembling the two inner cores inside the branched stainless-steel pipes, a large graft with branching was successfully fabricated, and its aortic arch replacement was conducted in a donor goat without causing damage. In conclusion, by applying iBTA technology, we have made it possible, for the first time, to create tissues of various shapes and designs that are difficult using existing tissue-engineering techniques. Thicker iBTA-induced tissues exhibited higher rupture strength; however, rupture stress was inversely proportional to thickness. These findings broaden the range of iBTA-induced tissue applications.

Steller sea lions (SSLs) migrate to the Hokkaido coast to spend the winter there, leading to conflicts arising with fishermen over herring. This study analyzed the trends in the SSLs’ use of a haulout as a rest site under human pressure. From January to March in 2017, 2018, and 2019, we recorded the SSL behavior at the haulout site off Otaru City, Hokkaido, for 24 h a day using a fixed-point video recorder. We investigated three years of data to analyze the relationships between the SSL behaviors (attendance/landing–entry timings/remaining on land) and herring caught. We also monitored the SSL behaviors during changes in weather conditions and under human pressure. Throughout the three years, the SSLs used the haulout site during harsher weather or under human pressure. In 2017 and 2018, there was a correlation between the herring caught and the maximum number of SSLs on the haulout, but not in 2019. The number of SSLs on the haulout increased from evening to night; most individuals entered the water in the morning. The SSLs probably return to the water around sunrise not only for foraging but also to avoid anthropogenic pressure. The damage caused to the herring fishery by the SSLs was severe, but it is also clear that human pressure changed their behavior in response.

ABSTRACTEvidence has accumulated that gut microbiota and its metabolites, in particular the short-chain fatty acid propionate, are significant contributors to the pathogenesis of a variety of diseases. However, little is known regarding its impact on pediatric bronchial asthma, one of the most common allergic diseases in childhood. This study aimed to elucidate whether, and if so how, intestinal propionate during lactation is involved in the development of bronchial asthma. We found that propionate intake through breast milk during the lactation period resulted in a significant reduction of airway inflammation in the offspring in a murine house dust mite-induced asthma model. Moreover, GPR41 was the propionate receptor involved in suppressing this asthmatic phenotype, likely through the upregulation of Toll-like receptors. In translational studies in a human birth cohort, we found that fecal propionate was decreased one month after birth in the group that later developed bronchial asthma. These findings indicate an important role for propionate in regulating immune function to prevent the pathogenesis of bronchial asthma in childhood.

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients’ serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.

Background:. Recently, cosmetic surgery demand has increased due to the spread of promotional social media in Japan. However, understanding the overall landscape remains difficult due to many clinics with varied procedure options. To understand the current trends and status of cosmetic surgery in Japan, we analyzed large-scale data from a group of clinics throughout the country. Methods:. We analyzed data from 152,457 patients in our database. The periods from September 2018 to August 2021 and September 2021 to February 2023 were defined as the first and second periods, respectively, and the statuses of procedures were compared between the two. Results:. Eye procedures were the most common (23.6%), followed by face-lifts (19.5%) and dark circles under the eyes (10.4%). Between the first and second periods, the number of procedures in the second period (128,898 cases) was overwhelmingly higher than that in the first period (23,559 cases). Orbital fat removal for dark circles under the eyes significantly increased (OR 2.97, 95%CI 2.78–3.17); procedures in provincial cities significantly increased (Kinki/Chugoku/Shikoku: OR 2.21, 95%CI 2.08–2.36); and procedures for patients with occupations where appearance is considered important, such as nightlife businesses or being a celebrity, decreased (celebrity: OR 0.44, 95%CI 0.38–0.51, nightlife business: OR 0.58, 95%CI 0.53–0.62). Conclusions:. In Japan, cosmetic surgery has become increasingly common in recent years, and the trend has been changing over time. In the future, it will be important to organize and enhance our large-scale database to disseminate more accurate and useful information.

Polyetheretherketone (PEEK) is an important super engineering plastic utilized in industries owing to its thermal stability and mechanical strength, however, its robustness hinders chemical recycling. Here, the authors report the depolymerization of insoluble PEEK using sulfur nucleophiles via carbon–oxygen bond cleavage and then treatment with organic halides to form various dithiofunctionalized benzophenones and hydroquinone monomers.

Biotubes are autologous tubular tissues developed within a patient’s body through in-body tissue architecture, and they demonstrate high potential for early clinical application as a vascular replacement. In this pilot study, we used large animals to perform implantation experiments in preparation for preclinical testing of Biotube. The biological response after Biotube implantation was histologically evaluated. The designed Biotubes (length: 50 cm, internal diameter: 4 mm, and wall thickness: 0.85 mm) were obtained by embedding molds on the backs of six goats for a predetermined period (1–5 months). The same goats underwent bypass surgery on the carotid arteries using Biotubes (average length: 12 cm). After implantation, echocardiography was used to periodically monitor patency and blood flow velocity. The maximum observation period was 6 months, and tissue analysis was conducted after graft removal, including the anastomosis. All molds generated Biotubes that exceeded the tensile strength of normal goat carotid arteries, and eight randomly selected Biotubes were implanted. Thrombotic occlusion occurred immediately postoperatively (1 tube) if anticoagulation was insufficient, and two tubes, with insufficient Biotube strength (2 months without aneurysm formation. The spots far from the anastomosis became stenosed within 3 months (3 tubes) when Biotubes had a wide intensity distribution, but the shape of the remaining two tubes remained unchanged for 6 months. The entire length of the bypass region was walled with an αSMA-positive cell layer, and an endothelial cell layer covered most of the lumen at 2 months. Complete endothelial laying of the luminal surface was obtained at 3 months after implantation, and a vascular wall structure similar to that of native blood vessels was formed, which was maintained even at 6 months. The stenosis was indicated to be caused by fibrin adhesion on the luminal surface, migration of repair macrophages, and granulation formation due to the overproliferation of αSMA-positive fibroblasts. We revealed the importance of Biotubes that are homogeneous, demonstrate a tensile strength > 5 N, and are implanted under appropriate antithrombotic conditions to achieve long-term patency of Biotube. Further, we clarified the Biotube regeneration process and the mechanism of stenosis. Finally, we obtained the necessary conditions for a confirmatory implant study planned shortly.

Notch signaling is conserved in C. elegans, Drosophila, and mammals. Among the four NOTCH genes in humans, NOTCH1, NOTCH2, and NOTCH3 are known to cause monogenic hereditary disorders. Most NOTCH-related disorders are congenital and caused by a gain or loss of Notch signaling activity. In contrast, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling. Pathophysiological processes following mutant N3ECD accumulation have been intensively investigated; however, the process leading to N3ECD accumulation and its association with canonical NOTCH3 signaling remain unknown. We reviewed the progress in clarifying the pathophysiological process involving mutant NOTCH3.

Human cord blood–endothelial progenitor cells (hCB-EPCs) isolated from the human umbilical cord can be used to repair damaged arteries. In this study, we used an animal model with pathological changes that mimics artery wall damage caused by stent retrievers in humans. We injected hCB-EPCs to investigate their effect on endothelial hyperplasia and dysfunction during intimal repair. Four groups were established based on the length of reperfusion (3 and 28 days), as well as the presence or absence of hCB-EPC therapy. Damage to the internal carotid artery was evaluated by hematoxylin-eosin and immunohistochemical staining. Stroke volume was not significantly different between non-EPC and EPC groups although EPC treatment alleviated intimal hyperplasia 28 days after intimal damage. Vascular endothelial growth factor (VEGF) and eNOS expression were significantly higher in the EPC-treated group than in the non-EPC group 3 days after intimal damage. In addition, MMP9 and 4HNE expression in the EPC-treated group was significantly lower than in the non-EPC group. Ultimately, this study found that venous transplantation of hCB-EPCs could inhibit neointimal hyperplasia, alleviate endothelial dysfunction, suppress intimal inflammation, and reduce oxidative stress during healing of intimal damage.

We report 2 cases of reversible cerebral vasoconstriction syndrome (RCVS) associated with postpartum. In case 1, a 26-year-old woman developed sudden-onset headache, nausea, and vomiting 1 h after an uncomplicated vaginal delivery. In case 2, a 27-year-old woman developed generalized seizures 9 days after an uncomplicated vaginal delivery. In both cases, initial angiographic studies showed no significant vasoconstriction; however, repeat studies revealed reversible vasoconstriction. Serial magnetic resonance imaging (MRI) revealed transient brain lesions during 6 months. RCVS remains poorly characterized, misdiagnosed, and under-recognized. Serial MRI and magnetic resonance angiographic findings may contribute to diagnosis of RCVS.

iPSCs from three endangered avian species (including Okinawa rail, Japanese ptarmigan, and Blakiston’s fish owl) are developed and characterized as a potential resource for their conservation.