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During mucosal injury, intestinal immune cells play a crucial role in eliminating invading bacteria. However, as the excessive accumulation of immune cells promotes inflammation and delays tissue repair, it is essential to identify the mechanism that limits the infiltration of immune cells to the mucosal-luminal interface. Cholesterol sulfate (CS) is the lipid product of the sulfotransferase SULT2B1 and suppresses immune reactions by inhibiting DOCK2-mediated Rac activation. In this study, we aimed to elucidate the physiological role of CS in the intestinal tract. We found that, in the small intestine and colon, CS is predominantly produced in the epithelial cells close to the lumen. While dextran sodium sulfate (DSS)-induced colitis was exacerbated in Sult2b1-deficient mice with increased prevalence of neutrophils, the elimination of either neutrophils or intestinal bacteria in Sult2b1-deficient mice attenuated disease development. Similar results were obtained when the Dock2 was genetically deleted in Sult2b1-deficient mice. In addition, we also show that indomethacin-induced ulcer formation in the small intestine was exacerbated in Sult2b1-deficient mice and was ameliorated by CS administration. Thus, our results uncover that CS acts on inflammatory neutrophils, and prevents excessive gut inflammation by inhibiting the Rac activator DOCK2. The administration of CS may be a novel therapeutic strategy for inflammatory bowel disease and non-steroidal anti-inflammatory drug-induced ulcers.

We visualized macrophages engulfing cholesterol crystals from spontaneously ruptured aortic plaques sampled by angioscopy. Docosahexaenoic acid cholesterol ester (DHA-CE) was demonstrated by imaging mass spectrometry. DHA-CE is reported to be produced by macrophages against inflammation. Activities of macrophages against atherosclerosis inside plaques was shown from spontaneously ruptured aortic plaques in situ. LEARNING OBJECTIVES: Activities of macrophages such as engulfing cholesterol crystals and producing docosahexaenoic acid cholesterol ester were shown from spontaneously ruptured aortic plaques in situ.

Supplementary Material 2

Supplemental material, sj-pdf-2-imr-10.1177_03000605231173319 for Real-world retrospective review of monotherapy following platinum-based chemotherapy for metastatic urothelial cancer by Hideaki Uchida, Daisuke Obinata, Shogo Takada, Tsuyoshi Yoshizawa, Junichi Mochida, Kenya Yamaguchi and Satoru Takahashi in Journal of International Medical Research

Additional file 3. Fig. S3: Correlation of the best ALP and CRP response to abiraterone with docetaxel and cabazitaxel.

Supplemental material, sj-pdf-1-imr-10.1177_03000605231173319 for Real-world retrospective review of monotherapy following platinum-based chemotherapy for metastatic urothelial cancer by Hideaki Uchida, Daisuke Obinata, Shogo Takada, Tsuyoshi Yoshizawa, Junichi Mochida, Kenya Yamaguchi and Satoru Takahashi in Journal of International Medical Research

Supplemental material, sj-pdf-2-imr-10.1177_03000605231173319 for Real-world retrospective review of monotherapy following platinum-based chemotherapy for metastatic urothelial cancer by Hideaki Uchida, Daisuke Obinata, Shogo Takada, Tsuyoshi Yoshizawa, Junichi Mochida, Kenya Yamaguchi and Satoru Takahashi in Journal of International Medical Research

Additional file 2. Fig. S2: Clinical course of a representative case treated with docetaxel, abiraterone, and cabazitaxel. A 54-year-old man was referred for a prostate biopsy due to a high PSA level. Prostate cancer with a Gleason score of 4 + 4 + = 8 was diagnosed by prostate biopsy. Imaging studies showed bone and multiple lymph node metastases. After treatment with CAB, including bicalutamide and flutamide, he developed CRPC and was treated with docetaxel. However, the patient had side effects from docetaxel and was switched to abiraterone. Due to PSA rising on abiraterone, he was switched to cabazitaxel, and PSA has been slowly declining since then. During the disease course, lymph node metastases continued to shrink, and bone metastases did not worsen on imaging.

Additional file 1. Fig. S1: Therapeutic drug sequencing is shown. Each drug was switched to the next at the discretion of the attending physician based on PSA elevation, progression on imaging, and side effects.

Supplementary Material 1

Supplementary Material 1: Additional file 1: Single-cell RNA-sequencing analysis of healthy mature mouse kidney.

Hereditary spastic paraplegias (HSPs) are rare neurological disorders caused by degeneration of the corticospinal tract. Among the 79 causative genes involved in HSPs, variants in SPAST on chromosome 2p22, which encodes the microtubule-severing protein spastin, are responsible for spastic paraplegia type 4 (SPG4), the most common form of HSPs. SPG4 is characterized by a clinically pure phenotype that is associated with restricted involvement of the corticospinal tract; however, it is often accompanied by additional neurological symptoms such as epilepsy and cognitive impairment. There are few reports regarding the clinical course and treatment of epilepsy associated with SPG4. We describe a 21-year-old male patient with progressive weakness and spasticity of the lower limbs since infancy, which was complicated by epilepsy and cognitive impairment. Magnetic resonance imaging of the brain showed right hippocampal atrophy before the onset of epilepsy. Genetic analysis revealed a novel missense variant (NM_014946.4:c.1330G>C, p.Asp444His) in the SPAST gene. At the age of 13, the patient developed focal epilepsy, characterized by focal onset seizures that were preceded by a sensation of chest tightness. Carbamazepine, levetiracetam, and zonisamide were ineffective in controlling the seizures; however, the use of lacosamide in combination with lamotrigine and valproate was highly effective in improving the seizure symptoms and led to the patient being seizure free for at least 2 years. In conclusion, the missense variant in SPAST may cause a complex SPG4 phenotype accompanied by epilepsy and cognitive impairment, suggesting that the clinical manifestations of this condition do not confine to the motor system.

Total body irradiation (TBI) with ovarian shielding is expected to preserve fertility among hematopoietic stem cell transplant (HSCT) patients with myeloablative TBI-based regimens. However, the radiation dose to the ovaries that preserves ovarian function in TBI remains poorly understood. Furthermore, it is uncertain whether the dose to the shielded organs is associated with relapse risk. Here, we retrospectively evaluated the relationship between fertility and the dose to the ovaries, and between relapse risk and the dose to the pelvic bones. A total of 20 patients (median age, 23 years) with standard-risk hematologic diseases were included. Median follow-up duration was 31.9 months. The TBI prescribed dose was 12 Gy in six fractions for three days. Patients' ovaries were shielded with cylinder-type lead blocks. The dose-volume parameters (D98% and Dmean) in the ovaries and the pelvic bones were extracted from the dose-volume histogram (DVH). The mean ovary Dmean for all patients was 2.4 Gy, and 18 patients recovered menstruation (90%). The mean ovary Dmean for patients with menstrual recovery and without recovery were 2.4 Gy and 2.4 Gy, respectively, with no significant difference (P = 0.998). Hematological relapse was observed in five patients. The mean pelvis Dmean and pelvis D98% for relapse and non-relapse patients were 11.6 Gy and 11.7 Gy and 5.6 Gy and 5.3 Gy, respectively. Both parameters showed no significant difference (P = 0.827, 0.807). In conclusion, TBI with ovarian shielding reduced the radiation dose to the ovaries to 2.4 Gy, and preserved fertility without increasing the risk of relapse.

大気球シンポジウム 2022年度（2022年11月7-8日. ハイブリッド開催（JAXA相模原キャンパス& オンライン)), Balloon Symposium 2022 (November 7-8, 2022. Hybrid(in-person & online) Conference (Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency (JAXA)(ISAS)), Sagamihara, Kanagawa Japan, 資料番号: SA6000177020, レポート番号: isas22-sbs-020

大気球シンポジウム 2022年度（2022年11月7-8日. ハイブリッド開催（JAXA相模原キャンパス& オンライン)), Balloon Symposium 2022 (November 7-8, 2022. Hybrid(in-person & online) Conference (Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency (JAXA)(ISAS)), Sagamihara, Kanagawa Japan, 著者人数: 42名, 資料番号: SA6000177018, レポート番号: isas22-sbs-018

大気球シンポジウム 2022年度（2022年11月7-8日. ハイブリッド開催（JAXA相模原キャンパス& オンライン)), Balloon Symposium 2022 (November 7-8, 2022. Hybrid(in-person & online) Conference (Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency (JAXA)(ISAS)), Sagamihara, Kanagawa Japan, 著者人数: 42名, 資料番号: SA6000177019, レポート番号: isas22-sbs-019

大気球シンポジウム 2022年度（2022年11月7-8日. ハイブリッド開催（JAXA相模原キャンパス& オンライン)), Balloon Symposium 2022 (November 7-8, 2022. Hybrid(in-person & online) Conference (Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency (JAXA)(ISAS)), Sagamihara, Kanagawa Japan, 著者人数: 46名, 資料番号: SA6000177017, レポート番号: isas22-sbs-017

大気球シンポジウム 2022年度（2022年11月7-8日. ハイブリッド開催（JAXA相模原キャンパス& オンライン)), Balloon Symposium 2022 (November 7-8, 2022. Hybrid(in-person & online) Conference (Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency (JAXA)(ISAS)), Sagamihara, Kanagawa Japan, 著者人数: 42名, 資料番号: SA6000177021, レポート番号: isas22-sbs-021

The challenge for medical schools in Japan is to develop research activities for innovation. This study aimed at analyzing the connection between the research output of “promising researchers” (next-generation leaders in terms of research activity) and their supervisors' past research activities to identify those factors that impact researchers' performance. Activity was analyzed from the viewpoints of productivity, coauthorship networks, and research impact using a novel index called the Research Diversity Index (REDi) that quantifies crossdisciplinarity. Research funding, which has not yet been fully utilized in correlation studies of the characteristics of authors, was also considered in this study. For the promising researchers extracted using betweenness centrality scores within coauthorship networks, there were diachronic correlations between the records of the promising researchers and those of their supervisors. Supervisor leadership as measured by the number of last-authored publications and extent of networking had a positive effect on the promising researchers productivity. Supervisors' research style of integrating knowledge from multiple fields, as measured by REDi, was negatively correlated with the publication impact of promising researchers, suggesting that REDi is useful as a novel indicator of research quality not being captured by existing indices. It was also noted that establishing an academic presence through extensive collaborations could be advantageous for obtaining research funding, especially from top-down government programs. The possible implications of this study for promoting research activities are the importance of incorporating new doctorates into research groups at an early stage and that of promoting interinstitutional, crossdisciplinary collaborations.Classification codeMSC: 62P10 Applications of statistics to biology and medical sciences; meta-analysis.JEL: Z1Z10 Cultural Economics • Economic Sociology • Economic Anthropology- General.

Clarification of the criteria for managing animal health is essential to increase the reliability of experiments and ensure transparency in animal welfare. For experiments performed in space, there is no consensus on how to care for animals owing to technical issues, launch mass limitation, and human resources. Some biological processes in mammals, such as musculoskeletal or immune processes, are altered in the space environment, and mice in space can be used to simulate morbid states, such as senescence acceleration. Thus, there is a need to establish a novel evaluation method and evaluation criteria to monitor animal health. Here, we report a novel method to evaluate the health of mice in space through a video downlink in a series of space experiments using the Multiple Artificial-gravity Research System (MARS). This method was found to be more useful in evaluating animal health in space than observations and body weight changes of the same live mice following their return to Earth. We also developed criteria to evaluate health status via a video downlink. These criteria, with “Fur condition” and “Respiratory” as key items, provided information on the daily changes in the health status of mice and helped to identify malfunctions at an early stage. Our method and criteria led to the success of our missions, and they will help establish appropriate rules for space experiments in the future.

The eye lens of vertebrates is composed of fibre cells in which all membrane-bound organelles undergo degradation during terminal differentiation to form an organelle-free zone. The mechanism that underlies this large-scale organelle degradation remains largely unknown, although it has previously been shown to be independent of macroautophagy. Here we report that phospholipases in the PLAAT (phospholipase A/acyltransferase,also known as HRASLS) family-Plaat1 (also known as Hrasls) in zebrafish and PLAAT3 (also known as HRASLS3, PLA2G16, H-rev107 or AdPLA) in mice-are essential for the degradation of lens organelles such as mitochondria, the endoplasmic reticulum and lysosomes. Plaat1 and PLAAT3 translocate from the cytosol to various organelles immediately before organelle degradation, in a process that requires their C-terminal transmembrane domain. The translocation of Plaat1 to organelles depends on the differentiation of fibre cells and damage to organelle membranes, both of which are mediated by Hsf4. After the translocation of Plaat1 or PLAAT3 to membranes, the phospholipase induces extensive organelle rupture that is followed by complete degradation. Organelle degradation by PLAAT-family phospholipases is essential for achieving an optimal transparency and refractive function of the lens. These findings expand our understanding of intracellular organelle degradation and provide insights into the mechanism by which vertebrates acquired transparent lenses.

Gender and menopause influence the severity and development manner of nonalcoholic steatohepatitis (NASH). Male p62/Sqstm1 and nuclear factor E2-related factor-2 (p62 and Nrf2) double-knockout (DKO) mice exhibit severe steatohepatitis caused by hyperphagia-induced obesity, overload of lipopolysaccharide (LPS) into the liver, and potentiation of the inflammatory response in Kupffer cells. However, the pathogenetic phenotype of steatohepatitis in female DKO mice remains unknown. Phenotypic changes of steatohepatitis in DKO mice were compared in terms of gender differences. Compared with DKO male mice, DKO female mice exhibited later onset of steatohepatitis with obesity after 30 weeks of age, as well as milder severity of hepatic inflammation and fibrosis. Serum estradiol was higher in female than male mice, with levels increasing up to 30 weeks of age before decreasing until 50 weeks of age (corresponding to the post-menopausal period). Fecal and serum LPS were lower in female mice than male mice, and inflammatory signaling in the liver was attenuated in female compared with male mice. Correlating with LPS levels, the composition of intestinal microbiota in female mice was different from male mice. Gender differences were observed for the development of steatohepatitis in DKO mice. Low-grade inflammatory hit in the liver under in vivo conditions of high estradiol may be attributable to the milder pathological features of steatohepatitis in female mice.

Additional file 1. This table shows all the transcription factors listed in DoRothEA that have an association with JAGGED1 as their target gene. SNAI2 (SLUG), SOX2, and SOX13 had DoRothEA levels of A, B, and C, respectively. The other 32 transcription factors had DoRothEA levels of D. The line number indicates the corresponding positions in DoRothEA.

Supplemental material, sj-pdf-1-imr-10.1177_03000605221106434 for Tension-free vaginal mesh for patients with pelvic organ prolapse: mid-term functional outcomes by Daisuke Obinata, Kenya Yamaguchi, Sho Hashimoto, Tsuyoshi Yoshizawa, Junichi Mochida and Satoru Takahashi in Journal of International Medical Research

Supplemental material, sj-pdf-1-imr-10.1177_03000605221106434 for Tension-free vaginal mesh for patients with pelvic organ prolapse: mid-term functional outcomes by Daisuke Obinata, Kenya Yamaguchi, Sho Hashimoto, Tsuyoshi Yoshizawa, Junichi Mochida and Satoru Takahashi in Journal of International Medical Research

Additional file 1: Supplemental Table 1. Odds ratios of maternal pre-pregnancy body mass index in the complete dataset (n = 84,366).

Supplemental material, sj-docx-1-cpc-10.1177_10556656221128425 for Null Association Between Isolated Orofacial Clefts and Sleep Duration: A Cohort Study From the Japan Environment and Children's Study by Yukihiro Sato, Eiji Yoshioka and Yasuaki Saijo, Yasuhito Kato, Ken Nagaya, Satoru Takahashi, Yoshiya Ito, Sumitaka Kobayashi, Yu Ait Bamai, Keiko Yamazaki, Sachiko Itoh, Chihiro Miyashita, Atsuko Ikeda-Araki, Reiko Kishi, in The Cleft Palate-Craniofacial Journal

Additional file 1: Figure S1. Adductome maps of rats at 52 weeks. The relative peak areas and the number of peaks are given for each group. There were no significant differences in either peak area or the number of peaks between any of the groups. No adducts specific to any of the treated groups were found.

Asami Nagaoka-Takatori,1 Madoka Ishii,1 Koremasa Hayama,1 Daisuke Obinata,2 Kenya Yamaguchi,2 Satoru Takahashi,2 Hideki Fujita1 1Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, 173-8610, Japan; 2Department of Urology, Nihon University School of Medicine, Tokyo, 173-8610, JapanCorrespondence: Hideki FujitaDivision of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, JapanTel +81-3-3972-8111 (ext. 2502)Fax +81-3-5995-9841Email fujita.hideki@nihon-u.ac.jpAbstract: A 50-year-old Japanese woman presented with a 4-day history of multiple purpura on her extremities and myalgia. She had been receiving nivolumab therapy for stage IV renal cell carcinoma for 18 months. Nivolumab was temporarily discontinued due to liver dysfunction and resumed 3 months before. Biopsy specimen revealed leukocytoclastic vasculitis, and direct immunofluorescence showed deposition of IgA and C3 in the vessel walls of the upper dermis. Based on these findings, a diagnosis of IgA vasculitis was made. She was treated with  20 mg/day of  oral prednisolone, which resulted in the complete disappearance of purpura and myalgia. Although the patient needed temporary cessation of nivolumab therapy, she experienced no recurrence of purpura or myalgia, and the dose of prednisolone was gradually tapered to 5 mg/day. Although nivolumab can lead to various immune-related adverse events, vasculitis is rare. To the best of our knowledge, this is the second case of IgA vasculitis during nivolumab therapy.Keywords: immune checkpoint inhibitors, leukocytoclastic vasculitis, PD-1, purpura

大気球シンポジウム 2021年度（2021年11月1-2日. オンライン開催), Balloon Symposium 2021 (November 1-2, 2021. Online Meeting), PDF再処理の為、2023年3月24日に差替, 資料番号: SA6000166026, レポート番号: isas21-sbs-026

大気球シンポジウム 2021年度（2021年11月1-2日. オンライン開催), Balloon Symposium 2021 (November 1-2, 2021. Online Meeting), 著者人数: 40名PDF再処理の為、2023年3月24日に差替, 資料番号: SA6000166025, レポート番号: isas21-sbs-025

大気球シンポジウム 2021年度（2021年11月1-2日. オンライン開催), Balloon Symposium 2021 (November 1-2, 2021. Online Meeting), 著者人数: 40名PDF再処理の為、2023年3月24日に差替, 資料番号: SA6000166024, レポート番号: isas21-sbs-024

An amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP mice. The mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption., An amino acid exchange (P209L) in the human co-chaperone BAG3 gives rise to severe childhood restrictive cardiomyopathy. Here the authors describe humanized transgenic mouse models which phenocopy the disease and provide insight into the pathogenic mechanisms.