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Thiyl radicals are important reactive sulfur species and can cause cis to trans isomerization on unsaturated fatty acids. However, biocompatible strategies for the controlled generation of thiyl radicals are still lacking. In this work, we report the study of a series of naphthacyl-derived thioethers as photo-triggered thiyl radical precursors. Tertiary naphthacyl thioether was identified to be a suitable template that could be used to produce both aryl and alkyl thiyl radicals under ultraviolet (UV) light or sunlight. The effective cis-to trans-isomerization of unsaturated fatty acid models (methyl oleate, methyl linoleate) and a natural phospholipid (cardiolipin) using these photo-triggered substrates was demonstrated. This reaction was also proved to proceed effectively in cells to produce thiyl radicals and subsequent fatty acid isomerization. Additionally, the most promising thiyl radical precursor showed antiviral activity in a pseudotyped virus model, likely due to disrupting viral lipid membranes upon UV activation. These findings highlight the potential of thiyl radicals for both biochemical and antiviral applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Site-selective cleavage of the peptide backbone in proteins is an important class of post-translational modification (PTM) in nature. However, the organic chemistry for such site-selective peptide bond cleavages has yet to be fully explored. Herein, we report cysteine S -formylation as a means of selective protein backbone cleavage. We developed N -formyl sulfonylanilide as a cysteine-selective formylation reagent for peptides and proteins. Upon S -formylation with the reagent, the amide bond adjacent to the S -formylated cysteine is cleaved by hydrolysis under neutral aqueous conditions. Formylation probes bearing a protein ligand enabled the affinity-based selective cleavage of the target proteins not only in the test tube but also under biorelevant conditions such as in crude cell lysate and on the cell surface. These results demonstrate the high biocompatibility of this protein cleavage technology. A proof-of-concept study of cleavage-induced protein activation further demonstrates its utility as a platform for the functional regulation of proteins by artificial PTM.

Purpose: Controversy remains about the ideal construct for certain olecranon fractures. The purpose of this study was to compare cost-effectiveness with the value driven outcomes tool between fixation strategies of olecranon fractures., Methods: All surgically treated isolated proximal ulna fractures (CPT code 24,685) at a level 1 trauma center from 2013 to 2023 were retrospectively reviewed. Patients with concomitant radial/ulnar shaft fractures and ligamentous elbow injuries requiring repair were excluded. Demographics, outcomes, initial, downstream (costs secondary to index surgery), and combined cost were compared between plate andintramedullary (IM) screw constructs. Costs included charges to the hospital from facility, implant, supply, pharmacy, imaging, and other service use., Results: 102 patients with average age of 51 were included: 84 olecranon-specific plates and18 IM screws. Average follow-up was 14.62 ± 16.79 months. There were differences in CCI (p = 0.006). Plate initial and combined cost was significantly greater than an IM screw (1.26x, p = 0.007; 1.49x, p = 0.009, respectively). Using IM screws for reference and controlling for demographics and fracture patterns, treatment with a plate was more expensive at downstream and combined total cost (56.28x, p = 0.04;76.73x, p = 0.03, respectively)., Conclusion: Olecranon plate fixation is associated with increased downstream and overall cost to the healthcare system. When indicated, other forms of fixation should be considered due to lower costs while still maintaining satisfactory outcomes., Competing Interests: Declarations. Conflict of interests: The authors report no conflicts of interest specifically relevant to this study. Individual sources of potential conflict are as follows: Mau, Thorne, Yoo, Soule, Nelson, Torrez, Amick, Gates, Sato, Marchand have nothing to report., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Schizophrenia is a psychiatric disorder characterized by cognitive dysfunctions. These dysfunctions significantly impact the daily lives of schizophrenic patients, yet effective interventions remain scarce. In this study, we explored the effects of two enriched housing types-cognitive and physical-on cognitive dysfunctions in a rat model of schizophrenia. Male neonatal Wistar-Imamichi rats were administered MK-801, a noncompetitive NMDAR antagonist, twice daily from postnatal day (PND) 7 to PND 20. Physical enrichment ameliorated memory deficits in both object and place recognition tests, while cognitive enrichment primarily improved object recognition performance. Our findings suggest that exercise therapy could be a potential approach to address cognitive dysfunctions in schizophrenia patients., Competing Interests: Conflict of Interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tumor lysis syndrome (TLS) is a fatal complication associated with chemotherapy. We herein report a case of TLS in a 73-year-old woman with metastatic BRAF V600E mutated colon cancer after she received combined treatment with cetuximab and encorafenib. The serum uric acid, urea nitrogen, and creatinine levels were elevated on day four of the first cycle. The fibrin degradation product (FDP) and D-dimer levels were also high. Diuresis and rasburicase were initiated for TLS, and the laboratory data all normalized on day 8. Thus, the possibility of TLS being induced by targeted drugs in patients with solid tumors, including colorectal cancer, must not be overlooked.

This retrospective study aimed to kinematically classify mandibular movements collected during Temporomandibular Disorders (TMD) treatment, employing Fourier transformation (FT), Principal Component Analysis (PCA), and K-means clustering (k-means), and to investigate their correlation with symptoms of pain-related TMD. The study included five TMD participants diagnosed with myalgia (age: 39-86 years, with an SD of 18.96) and three healthy participants (age: 32-42 years, with an SD of 5.13) with no stomatognathic problems. TMD participants underwent tailored treatment for their symptoms, and their maximum unassisted mouth opening (MMO) was recorded randomly with a motion capture system (ARCUS digma II, Kavo, Biberach, Germany) at multiple time points. MMO for healthy participants served as a control. The dataset comprising 28 trials, was transferred to the AnyBody Modeling System (AnyBody Technology, Aalborg, Denmark) to extract joint angle time series, which were then transformed into Fourier series. Subsequently, PCA and k-means clustering were conducted. Two clusters were identified: Cluster 1, predominantly composed of symptomatic trials, and Cluster 2, mainly consisting of asymptomatic trials. Distinct transition pathways between the clusters were observed among participants, corresponding to the alleviation of pain-related symptoms during TMD treatment. These findings suggest that this approach has potential as an effective tool for diagnosing and assessing TMD by identifying symptomatic kinematic patterns and tracking temporal changes in mandibular movement. Despite the small dataset, these results suggest promise for a novel functional assessment method for TMD based on kinematic features., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The overexpression of Polo-like kinase 1 (PLK1) is associated with poor clinical outcomes in various malignancies, making it an attractive target for anticancer therapies. Although recent studies suggest PLK1's involvement in homologous recombination (HR), the impact of its overexpression on HR remains unclear. In this study, we investigated the effect of PLK1 overexpression on HR using bioinformatics and experimental approaches. Analyzing The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) datasets with the Homologous Recombination Deficiency (HRD) score, we found a positive correlation between PLK1 expression and HRD score, indicating that increased PLK1 expression suppresses HR. To validate these findings, we performed cell line-based experiments, demonstrating that PLK1 overexpression attenuates RAD51 focus formation and HR, as measured by ASHRA in T47D cells. Since HR-deficient cells are hypersensitive to PARP inhibitors, we further confirmed that PLK1 overexpression increases sensitivity to PARP inhibitors, both in CCLE dataset analysis and experiments using T47D cells. Additionally, we found that the effects of PLK1 overexpression on HR suppression and increased PARP inhibitor sensitivity were mitigated by either a PLK1 kinase inhibitor or the kinase-dead mutant [T210A]. This suggests that PLK1's impact on HR and PARP inhibitor sensitivity is mediated through its kinase activity. Moreover, analysis of clinical ovarian cancer samples revealed that higher PLK1 expression correlates with increased sensitivity to PARP inhibitors. Our results suggest that PLK1 overexpression suppresses homologous recombination, leading to enhanced sensitivity to PARP inhibition, presenting a potential therapeutic strategy for targeting cancers with overexpression of PLK1., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Catalysts for Claisen rearrangement have been intensively studied to overcome the need for high temperature. However, previous studies have encountered challenges, such as the need for heating, a long reaction time, and/or the need for equivalent amounts of catalyst. In this study, we introduce an effective electrogenerated boron-based Lewis acid catalyst for the aromatic Claisen rearrangement, which proceeds in a few minutes at ambient temperature. Generation of the electrogenerated Lewis acid catalyst is discussed based on NMR analysis and DFT calculations.

Connecting two small molecules, such as ligands, fluorophores, or lipids, together via a linker with amide bonds is a widely used strategy to generate synthetic bifunctional molecules for various biological and biomedical applications. Such bifunctional molecules have been used in live-cell experiments under the assumption that they should be stable in cells. However, we recently found that a membrane-targeting bifunctional molecule, composed of a lipopeptide and the small-molecule ligand trimethoprim, referred to as mgcTMP, underwent amide-bond cleavage in mammalian cells. In this work, we first identified γ-secretase as the major protease degrading mgcTMP in cells. We next investigated the intracellular degradation of several different types of amide-linked bifunctional compounds and found that N -terminally fatty acid-conjugated small molecules are susceptible to γ-secretase-mediated amide-bond cleavage. In contrast, amide-linked bifunctional molecules composed of two small molecules, such as ligands and hydrophobic groups, which lack lipid modification, did not undergo intracellular degradation. These findings highlight a previously overlooked consideration for the development and application of lipid-based bifunctional molecules in chemical biology research.

Purpose This study aimed to clarify which positions are beneficial for patients with pathological lung diseases, such as acute respiratory distress syndrome, by obtaining lung ventilation and deformable vector field (DVF) images using Deformable Image Registration (DIR). Methods Thirteen healthy volunteers (5 female, 8 male) provided informed consent to participate to observe changes in normal lungs. DIR imaging was processed using the B-spline algorithm to obtain BH-CTVI (inhale, exhale) in four body positions (supine, prone, right lateral, left lateral) using DIR-based breath-hold CT ventilation imaging (BH-CTVI). DVF imaging was created through DIR-based BH-CTVI, which obtained the displacement vector from expiration to inspiration for each lung lobe. Results In the DIR images for each body position, the areas with Jacobian values in the 75th percentile or higher, indicating highly functional areas, were distributed on the side of the patient in contact with the ground. DVF images showed the abdominal displacement vector to be oriented from dorsal to ventral in the supine position. However, in the prone position, the displacement vectors were nearly parallel to the ground, directed from head to feet, indicating that lung motion was unaffected by gravity. Conclusion We demonstrated that the prone position allows for lung ventilation with the least gravitational load compared with the supine, right lateral decubitus, and left lateral decubitus positions, based on a comparison of DIR-based BH-CTVI when the positions were converted. It is important to include the evaluation of DVF images, in addition to ventilation images, when assessing lung function using DIR-based BH-CTVI., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Medical Ethics Committee of Fujieda Municipal General Hospital issued approval P FY21 6. Radiation was administered to the human body, but its effects were minimized as much as possible. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Amano et al.)

Inactivation of the Hippo tumor suppressive pathway is frequently observed in mesothelioma, which leads to the activation of YAP and TAZ (YAP/TAZ) transcriptional coactivators. YAP/TAZ form complexes with TEAD family members, DNA-binding proteins, to activate transcription, which promotes cancer cell growth and proliferation. Recently developed TEAD inhibitors exhibit antitumor activity by inhibiting the formation of the transcription complex through binding to TEAD; however, the antitumor activity of TEAD inhibitors against mesothelioma remains to be fully elucidated. Here, we show that the TEAD inhibitor K-975 acts as a pan-TEAD inhibitor and selectively inhibits the binding of TEAD-binding proteins, especially YAP/TAZ, in mesothelioma cells. In studies using a panel of mesothelioma cell lines, K-975 showed a significant growth inhibitory effect on Hippo-inactivated mesothelioma cells, but some of these cell lines exhibited primary resistance to K-975. Differential gene expression analysis revealed that cells resistant to K-975 exhibited activation of MYC signaling in the presence of K-975, and cells overexpressed with MYC showed strong drug resistance, both in vitro and in vivo. Our study revealed the features of a subset of mesothelioma cells that proliferate in a TEAD-independent manner and provides important insights for the successful development of therapeutic strategies for mesothelioma with Hippo pathway inactivation.

Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoic acid and α-eleostearic acid (ESA), induced GPX4 degradation, generation of mitochondrial reactive oxygen species (ROS) and lipid peroxides, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549 cells, which were suppressed by either pharmacological blockade of CMA or genetic deletion of LAMP2A, a crucial molecule for CMA. Mitochondrial ROS were sufficient and necessary for CMA-dependent GPX4 degradation. Oral administration of an ESA-rich oil attenuated xenograft tumor growth of wild-type, but not that of LAMP2A-deficient HT1080 cells, accompanied by increased lipid peroxidation, GPX4 degradation and cell death. Our study establishes mitochondria as the key target of CFAs to trigger lipid peroxidation and GPX4 degradation, providing insight into ferroptosis-based cancer therapy., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All animal experiments were approved by the ethics committee of Tohoku University (approval number: 2022PhA-008). All procedures were performed in accordance with the Guidelines for Animal Experiments of Tohoku University and the Japanese Government Animal Protection and Management Law. All authors checked the study and agreed to participate in the manuscript. Consent for publication: All authors checked the study and agreed., (© 2024. The Author(s).)

Objective: To compare outcomes after ankle fracture fixation between those receiving formal physical therapy (PT) vs. no formal PT and those with high vs. low PROMIS anxiety score (AS), and to evaluate the effect of PT in the setting of PROMIS AS scores., Design: Retrospective cohort study., Setting: Level 1 trauma center., Patient Selection Criteria: Patients aged > 18 undergoing isolated ankle fracture (OTA/AO 44A, 44B, 44C) fixation with documented PROMIS scores postoperatively.Outcome Measures and Comparisons: The post-operative PROMIS physical function (PF) and pain interference (PI) were compared between patients receiving formal PT vs. no PT and those with baseline high vs. low PROMIS AS scores. A sub-analysis was performed between patients with low anxiety and no PT (LANP) vs. low anxiety with PT (LAP) vs. high anxiety and no PT (HANP), and high anxiety with PT (HAP)., Results: A total of 161 patients, 111 females (68.9%), with an average age of 46 years (range: 72), were included in this study: 127 PT, 34 no PT, 88 low anxiety, and 73 high anxiety. PT did not yield any significant differences in PROMIS PF (44.9 PT vs 42.6 no PT, p=0.180) or PI (53.5 PT vs 54.4 no PT, p=0.656) at final follow-up. At final follow-up, high anxiety patients had similar PROMIS PF (43.0) vs. low anxiety patients (45.5, p=0.088), but significantly worse PROMIS PI scores (51.5 vs. 56.7, respectively; p=0.001). Univariate analysis demonstrated a significant difference in age between high and low anxiety patients and was thus selected as a control variable in the analysis of HANP, HAP, LANP, and LAP. After controlling for age, pairwise comparisons of estimated PROMIS PF scores at final follow-up were significantly lower for HANP (39.0) than HAP (43.9, p=0.05), LANP (45.1, p=0.05), and LAP patients (45.9, p=0.04). Final PROMIS PI scores were significantly worse for HANP (59.1) and HAP (56.5) when compared to LANP (51.3, p=0.021 vs HANP, p=0.049 vs HAP) and LAP (51.3, p=0.005 vs HANP, p=0.004 vs HAP) groups ., Conclusion: Patients with high anxiety who undergo isolated ankle fracture fixation perform worse regarding PROMIS PI irrespective of PT status. However, some patients with high anxiety may benefit from formal PT referral to maximize their functional outcomes., Level of Evidence: Level III, Prognostic., Competing Interests: Potential Conflicts of Interest and Funding Sources: This study was not funded. The authors have no relevant specifically relevant to this study. Individual sources of potential conflict are as follows: Dong, Mau, Soule, Sato, Thorne, and Marchand – None Higgins – DePuy Synthes: Paid consultant, DePuy, A Johnson & Johnson Company: IP royalties, Globus Medical: Paid consultant, Imagen: Paid consultant, NT nPhase: Stock or stock Options, Orthogrid: Stock or stock Options, Osteocentric: Stock or stock Options. Orthopaedic Trauma Association: Board member Rothberg - AO North America – Paid Lecturer Haller – NewClip Technics - Paid consultant; AO North America – Paid lecturer; Orthopaedic Trauma Association - Board or committee memberConflicts of Interest and Funding Sources: This study was not funded. TH is a paid consultant for De Puy, Synthes, Globus Medical, and Imagen; receives honoraria from A Johnson & Johnson company; possesses stock in NT nPhase, Orthogrid, and Osteocentric; is also a board member for the Orthopaedic Trauma Association. DR is a paid lecturer for AO North America. JH is a paid consultant for NewClip Technics; is a paid lecturer for AO North America; is a board member for the Orthopaedic Trauma Association. For the remaining authors, none are declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Sutimlimab, a complement inhibitor, has recently been approved in Japan for treating cold agglutinin disease (CAD). We report the safety and efficacy of sutimlimab in Japanese patients with CAD who completed a global phase 3 clinical trial (CARDINAL/CADENZA: 26-week treatment with 1-2 years of open-label extension [OLE] periods) and subsequently participated in the Japanese OLE study. Patients with a recent history of blood transfusion (CARDINAL, n = 3) and those without (CADENZA, n = 4) were analyzed (71.4% female; median [range] baseline age: 70 [46-83] years). For CARDINAL/CADENZA, the treatment duration (median [range]) was 140.9 (104.9-157.3) weeks, and the cessation period was 70 (61-133) weeks. For the Japanese OLE study, the treatment duration was 47.1 (15.1-49.1) weeks. Three (42.9%) patients experienced treatment-related and treatment-emergent adverse events (TEAEs): injection site erythema, cystitis bacterial, viral infection, and blood pressure increased during CARDINAL/CADENZA. One (14.3%) patient experienced one treatment-related TEAE (urinary tract infection) during the Japanese OLE study. One patient died of renal failure, considered unrelated to sutimlimab, that was exacerbated by hepatorenal syndrome due to liver cirrhosis and bacterial peritonitis, in addition to CKD. Hemoglobin and bilirubin levels improved during treatment but deteriorated after withdrawal and recovered on retreatment. Sutimlimab was well tolerated over a median of 3.8 years, with no new safety concerns identified during retreatment., Competing Interests: Declarations. Conflict of interest: YM received research grants from Sanofi K.K., Pfizer Japan Inc., Novartis Pharma K.K., Kissei Pharmaceutical Co., Ltd., Argenx Japan K.K., Novo Nordisk Pharma Ltd., CSL Behring K.K., BioMarin Pharmaceutical Japan K.K., Chugai Pharmaceutical Co., Ltd., and Janssen Pharmaceutical K.K. and received lecture fees from Sanofi K.K., Asahi Kasei Medical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Alexion Pharmaceuticals, Inc., Kissei Pharmaceutical Co. Ltd., and Kyowa Kirin Co., Ltd. and participated in advisory boards held by Sanofi K.K. and Pfizer Japan Inc and was involved in consultancy for Argenx Japan K.K., Zenyaku Holdings Co., Ltd., and Kissei Pharmaceutical Co., Ltd. YO received research grants from Mochida Pharmaceutical Co., Ltd., Fortrea Japan Inc., Janssen Pharmaceutical K.K., FUJIFILM K.K., AbbVie GK., and Otsuka Pharmaceutical Co., Ltd. and received honoraria/payment from Novartis Pharma K.K, Chugai Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., AstraZeneca K.K., Daiichi Sankyo Co., Ltd., and AbbVie GK. JN received honoraria or lecture fee from Swedish Orphan Biovitrum Japan K.K, Alexion Pharmaceuticals, Inc., Roche Diagnostics K.K., Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., BioCryst Pharmaceuticals, Inc., and Sanofi K.K. MN and OK are employees at Sanofi K.K. and ST was employee at Sanofi K.K at the time when the Japan OLE study was conducted and the data were analyzed. ES and MY have no conflict of interest to declare., (© 2024. The Author(s).)

Aim: This study aimed to comprehensively assess the incidence of immune-related adverse events (irAEs) and the detection systems in place for patients with liver cancer undergoing treatment with immune checkpoint inhibitors (ICIs), using a self-administered anonymous questionnaire. The questionnaire was designed to gather crucial insights into the management of irAEs in these patients., Methods: A self-administered anonymous questionnaire was sent to 456 liver disease collaborative base hospitals and cancer care coordination base hospitals in Japan., Results: Responses were received from 112 facilities, indicating a response rate of 25%. The region with the highest response rate was Kanto (22%, 24 sites), followed by Kyushu (19%, 21 sites), Chubu (14%, 15 sites), and Kinki (14%, 15 sites). The number of patients with hepatocellular carcinoma (HCC) who received ICI treatment varied, with a mean ± SD of 20.4 ± 19.4 cases per year per facility. The number of full-time physicians who provided ICI treatment for HCC was 4.2 ± 3.3 (mean ± SD), ranging from 0 to 24 per facility. Of these, the majority included hepatologists and oncologists, whose numbers were 3.3 ± 2.4 (mean ± SD) (range, 0-11) and 0.8 ± 1.0 (0-3), respectively. Gastroenterologists and internal medicine specialists participated in the treatment at some facilities., Conclusions: The survey results revealed that physicians administered ICI therapy for an average of 20 HCC cases per institution, with more than 17 types of irAEs reported. The most common irAEs were hepatic dysfunction, followed by thyroid dysfunction, skin disorders, interstitial pneumonia, and renal dysfunction., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Extracellular vesicles (EVs) play important roles in intercellular communication in various biological events. In particular, EVs released from cancer cells have attracted special attention. Although it has been reported that cancer-associated glycosphingolipids play important roles in the enhancement of malignant properties of cancer cells, the presence, behavior, and roles of glycosphingolipids in EVs have not been elucidated. Recently, we reported crucial roles of EVs expressing gangliosides, GD2, and/or GD3 in the enhancement of cancer properties in malignant melanomas and gliomas. However, how EVs containing cancer-associated glycosphingolipids play their roles has not been reported to date. Here, we studied spatio-temporal mechanisms for GD3/GD2-containing EVs released from gliomas in the actions toward target cells. Proteome analyses of EVs with/without GD3/GD2 revealed an equally high concentration of integrin isoforms in both GD3/GD2+ and GD3/GD2- EVs. PKH26-labeled EVs attached, invaded, and distributed to/in the target cells within 1 h. GD3/GD2 formed molecular complexes with integrins on EVs as elucidated by immunoprecipitation/immunoblotting and immunocytostaining. The addition of antibodies reactive with GD3, GD2, or integrins resulted in the suppression of the enhancing effects of EVs in the cell adhesion assay. The addition of GD3/GD2 + EVs to GD3/GD2- cells clearly increased the phosphorylation levels of the PDGF receptor, FAK, and Erk1/2 in immunoblotting, suggesting GD3/GD2+ EVs activate the signaling pathway in the target cells within 15 min after addition. Anti-ganglioside antibodies clearly blocked signaling with EVs. In conclusion, EVs released from GD3/GD2-expressing glioma cells enhance cancer phenotypes and malignant signals via the cluster formation of integrins and GD3/GD2 on EVs, leading to the regulation of the cancer microenvironment.

The production of cyclic amines, which are vital to the pharmaceutical industry, relies on energy-intensive thermochemical hydrogenation. Herein, we demonstrate the electrocatalytic hydrogenation of nitrogen-containing aromatic compounds, specifically pyridine, at ambient temperature and pressure via a membrane electrode assembly with an anion-exchange membrane. We synthesized piperidine using a carbon-supported rhodium catalyst, achieving a current density of 25 mA cm -2 and a current efficiency of 99% under a circular flow until 5 F mol -1 . Quantitative conversion of pyridine into piperidine with 98% yield was observed after passing 9 F mol -1 , corresponding to 65% of current efficiency. The reduction of Rh oxides on the catalyst surface was crucial for catalysis. The Rh(0) surface interacts moderately with piperidine, decreasing the energy required for the rate-determining desorption step. The proposed process is applicable to other nitrogen-containing aromatic compounds and could be efficiently scaled up. This method presents clear advantages over traditional high-temperature and high-pressure thermochemical catalytic processes.

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Urinary tract infections caused by Aerococcus urinae have rarely been reported in children, and the clinical characteristics remain unclear. We reviewed medical records of children whose urine cultures grew A. urinae (≥10 4  CFU/mL) at a tertiary children's hospital in Tokyo, Japan. We found 17 pediatric patients in a review of 22,769 urine cultures between June 2006 and May 2022. The median age of 17 patients was 10.7 years (IQR 8-13 years), and males represented 76.5 % of the patients. Sixteen patients (94.1 %) had underlying urological conditions (neurogenic bladder, vesicoureteral reflux, urethral stenosis, bladder exstrophy, or urinary catheterization). The chief symptoms were fever (35.3 %), malodorous urine (23.5 %), nausea (11.8 %), and back pain (5.9 %). Ten patients were asymptomatic. Pyelonephritis was diagnosed in five male patients. All of them had underlying abnormal conditions of the bladder, and two had malodorous urine. All patients had favorable outcomes after 10-14 days of ampicillin/amoxicillin-based antimicrobial therapy., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Vici syndrome (VICIS) is a congenital disorder characterized by agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive. This study aimed to elucidate the number of patients with VICIS, its clinical characteristics and relevant genetic information in Japan., Methods: After developing diagnostic criteria for VICIS, we conducted a nationwide questionnaire-based survey of VICIS in Japan. In the initial survey, we investigated the number of VICIS patients who fulfilled definite or probable criteria. The second survey was used to obtain detailed clinical and genetic information of VICIS from institutions that responded to the initial survey., Results: Clinical information was available for 15 patients (12 definite, three probable). As of October 2023, nine patients (60%) were alive and six (40%) had died. All patients presented with developmental delay, agenesis of the corpus callosum, elevated serum aspartate/alanine aminotransferase, hypopigmentation and hypotonia. Developmental delay was profound. Most patients developed recurrent infection, high-arched palate, epilepsy, failure to thrive, and microcephaly. Cardiomyopathy and cataracts, both initially described as principal features in VICIS, were notably uncommon in our study. Based on the information collected, all 14 patients for whom information was available received home medical care: 11 (79%) received tube feeding, three (21%) required noninvasive ventilation, four (29%) required tracheostomy, and four (29%) required home subcutaneous immunoglobulin administration., Conclusion: This study revealed for the first time the nationwide status of patients with VICIS in Japan. The mortality rate of patients with VICIS is as high as 40%, and almost all VICIS patients require various forms of home medical care, necessitating comprehensive management. Additionally, we identified one adult patient, underscoring the need for comprehensive medical management extending into adulthood for patients with VICIS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Problem: What is the effect of SR-16234 (SR), a selective estrogen receptor (ER) modulator, on human endometriotic stromal cells (ESCs)?, Method of Study: Endometriotic tissues were obtained from 21 patients undergoing laparoscopic surgery for ovarian endometriomas (OEs). Normal eutopic endometrium during the luteal phase was obtained from 18 patients without endometriosis. ESCs isolated from OEs and normal eutopic endometrial stromal cells (NESCs) were cultured with SR and subsequently exposed to tumor necrosis factor (TNF)-α. After 48 h of incubation, the effect of SR on cell proliferation was evaluated by the WST-8 assay. The gene expressions of inflammatory and pain-related factors, including interleukin (IL)-6, IL-8, cyclooxygenase (COX)-2, transient receptor potential vanilloid (TRPV)1, ESR1, and ESR2, were evaluated by real-time RT-PCR. The phosphorylation of Inhibitor κBα (IκBα), extracellular signal-regulated kinase (ERK)1/2, and Protein Kinase B (AKT) were evaluated by western blot analysis. ILs, prostaglandin (PG) E2, and intranuclear p65 syntheses were assessed by ELISA., Results: SR treatment repressed TNF-α-induced proliferation by 20% in ESCs but not　NESCs. SR also reduced IL-6, IL-8, COX-2, TRPV1, ESR1, and ESR2 mRNA expressions and ILs protein, and PGE2 synthesis in ESCs, whereas in NESCs, only TRPV1 mRNA expression was decreased. SR suppressed TNF-α-induced phosphorylated IκBα levels by approximately 50%, and intranuclear p65 protein was reduced by 30% compared to addition of only TNF-α in ESCs. However, SR did not affect the phosphorylation of AKT and ERK1/2., Conclusions: SR appears to be a potential therapeutic agent for endometriosis by suppressing inflammatory and pain-related factor expressions by inhibiting the nuclear factor-kappa B pathway., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To identify the predictive factors of first hospitalization and associated variables to the main causes of hospitalizations in lupus patients from a Latin American cohort., Methods: The first hospitalization after entry into the cohort during these patients' follow-up due to either lupus disease activity and/or infection was examined. Clinical and therapeutic variables were those occurring prior to the first hospitalization. Descriptive statistical tests, multivariable logistic, and Cox regression models were performed., Results: 1341 individuals were included in this analysis; 1200 (89.5%) were women. Their median and interquartile range (IQR) age at diagnosis were 27 (20-37) years and their median and IQR follow up time were 27.5 (4.7-62.2) months. A total of 456 (34.0%) patients were hospitalized; 344 (75.4%), 85 (18.6%) and 27 (5.9%) for disease activity, infections, or both, respectively. The predictors of the first hospitalization regardless of its cause were: medium (HR 2.03(1.27-3.24); p = 0.0028) and low (HR 2.42(1.55-3.79); p < 0.0001) socioeconomic status, serosal (HR 1.32(1.07-1.62); p = 0.0074) and renal (HR 1.50(1.23-1.82); p < 0.0001) involvement. Antimalarial (AM) use (HR 0.61(0.50-0.74); p < 0.0001) and achieving remission (HR 0.80(0.65-0.97); p = 0.0300) were negative predictors., Conclusions: The first hospitalization was associated with worse socioeconomic status and serosal and renal involvement. Conversely, AM use and achieving remission were associated with a lower risk of hospitalizations., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AO, US, EA and FZ are Janssen Pharmaceutical Companies employees.

Background: Segmental absence of intestinal musculature (SAIM) is a partial defect of intestinal muscularis propria without diverticulum. Many reports indicate that the increase in intestinal pressure caused by enemas or endoscopic examinations leads to bowel perforation, but there are few reports involving malignant tumors. Moreover, few reports have had good outcomes after performing one-stage intestinal anastomosis., Case Presentation: A 60-year-old male came to the office with right-side abdominal pain, and was diagnosed with acute generalized peritonitis caused by ascending colon perforation. Emergency laparotomy was performed, and oval and smooth perforation at the ascending colon was observed, which caused ascites with feces. In addition, there was a tumor on the distal side. The terminal ileum was not dilated, so the cause of the perforation was more likely the SAIM-related thin intestinal wall rather than increased internal intestinal pressure due to obstruction of the tumor. Therefore, a right hemicolectomy with functional end-to-end anastomosis (FEEA) between the ascending colon and ileum was performed, rather than creating a stoma. On pathological examination, the resected bowel segments had a partial defect of intestinal muscularis propria around the perforation, leading to the diagnosis of SAIM. The patient had a favorable postoperative course without anastomotic issues and was discharged safely., Conclusions: This case implies that initial intestinal anastomosis can be performed without creating a stoma when SAIM is suspected from the shape of the perforation and proximal intestine. This case report suggests surgeons should keep SAIM in mind during operations for colon perforations., (© 2024. The Author(s).)

Background/objectives: Health-related quality of life (HRQoL) is critical in patients with hepatocellular carcinoma (HCC). It has become a key endpoint in the evaluation of new therapies, including atezolizumab + bevacizumab (Atezo + Bev) therapy., Methods: This study explored the factors associated with treatment efficacy, treatment duration, and overall survival (OS) in patients with advanced HCC undergoing Atezo + Bev therapy. We included 58 consecutive patients with HCC receiving Atezo + Bev from 19 November 2020, to 28 December 2023, who were followed up until the end of the study or death. We analyzed the relationships between baseline characteristics, adverse events (AEs), and HRQoL and efficacy, OS, and treatment duration., Results: The demographic (older men) and baseline characteristics (Child-Pugh score of 5, Barcelona Clinic Liver Cancer Stage C) were consistent with those of previous studies. The treatment demonstrated promising efficacy with a disease control rate of 71.2%, but HRQoL scores in five functional domains and seven symptoms worsened significantly within the first 3 months. Notably, better baseline cognitive and physical function scores and absence of severe (grade ≥ 2) hypoalbuminemia were associated with an improved objective response rate, longer treatment duration, and better OS., Conclusions: These findings underscore the importance of monitoring and managing treatment-related AEs and maintaining the HRQoL. They also highlight the crucial and reassuring role of multidisciplinary care in enhancing treatment outcomes in this cohort.

Introduction: Neurolymphomatosis (NL) is a rare condition characterized by the infiltration of malignant lymphoma cells into the peripheral nervous system. The optimal treatment for NL remains unclear, and patients with secondary NL have a poor prognosis. Although early recognition of NL may contribute to successful treatment, the predictive factors for secondary NL are yet to be established., Case Presentation: Here, we present our investigation on the predictive factors for secondary NL, and report two cases of secondary NL with a literature review. We analyzed chromosomal abnormalities in patients with secondary NL and found a common deletion of chromosome 10 and add(11)(p11). The chromosomal abnormalities might be a predictive factor for secondary NL; therefore, confirmation of chromosomal abnormalities can possibly give a hint for early detect of secondary NL. Prompt histopathological examination or imaging techniques can lead to early diagnosis of secondary NL in patients with diffuse large B-cell lymphoma (DLBCL)., Conclusion: When neurological symptoms manifest in patients with DLBCL and there are chromosomal abnormalities, the possible development of secondary NL should be considered., Competing Interests: The authors state that they have no conflict of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Not available.

Low birthweight (LBW) increases the risk of adult-onset diseases, including kidney diseases, with intergenerational consequences; however, the underlying mechanisms and effective interventions are unclear. To examine the cross-generational effects of LBW, we established an LBW mouse model through reduced uterine perfusion pressure (RUPP) and investigated the therapeutic potential of tadalafil, a phosphodiesterase 5 inhibitor, on LBW-associated consequences. RUPP-pups (R1) had lower fetal and birth weights, delayed renal development, and fewer glomeruli than Sham-pups. In adulthood, R1 mice exhibited persistently fewer glomeruli and elevated blood pressure, while Tadalafil-R1 mice showed reduced hypertension in both sexes and improved renal pathological changes in males. Additionally, pregnant R1 mice displayed inadequate gestational liver hypertrophy, impaired hepatic purine metabolism, and diminished placental angiogenesis, resulting in fetal growth restriction in the subsequent generation. These findings underscore the lasting impact of LBW on adult health and future generations and suggest tadalafil's potential to mitigate LBW-associated risks., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 The Author(s).)

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of maternal UBE3A. The major cause of AS is a maternal deletion in 15q11.2-q13, and the minor causes are a UBE3A mutation, uniparental disomy (UPD), and imprinting defect (ID). Previous reports suggest that all patients with AS exhibit developmental delay, movement or balance disorders, behavioral characteristics, and speech impairment. In contrast, a substantial number of AS patients with a UBE3A mutation, UPD, or ID were reported not to show these consistent features and to show age-dependent changes in their features. In this study, we investigated 134 patients with AS, including 57 patients with a UBE3A mutation and 48 patients with UPD or ID. Although developmental delay was present in all patients, 20% of patients with AS caused by UPD or ID did not exhibit movement or balance disorders. Differences were also seen in hypopigmentation and seizures, depending on the causes. Moreover, patients with a UBE3A mutation, UPD, or ID tended to show fewer of the specific phenotypes depending on their age. In particular, in patients with UPD or ID, easily provoked laughter and hyperactivity tended to become more pronounced as they aged. Therefore, the clinical features of AS based on cause and age should be understood, and genetic testing should not be limited to patients with the typical clinical features of AS., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/aim: Patients with triple-negative breast cancer (TNBC) who obtain a pathological complete response (pCR) after neoadjuvant chemotherapy have an improved prognosis. Lymphocyte-predominant breast cancer is more likely to respond to neoadjuvant chemotherapy. Here, we investigated the correlation between tumor-infiltrating lymphocytes (TILs) in pre-treatment biopsy specimens from patients with TNBC in relation to response to NAC., Patients and Methods: The level of infiltration by immune cells expressing immune cell lineage surface markers (CD8, CD4, CD19, CD14, CD11c, and CD11b) in biopsy specimens from 52 patients with TNBC was examined using multispectral immunofluorescent labelling., Results: The level of CD8-positive TILs was significantly higher in patients with a pCR (p=0.045). The Cox proportional hazard model confirmed that lymph node involvement was associated with poorer disease-free survival (p=0.008). A high level of CD8-positive TILs was related to significantly prolonged disease-free survival in patients with node-positive TNBC (p=0.018)., Conclusion: Assessing infiltration by CD8-positive TILs in the primary tumor is a useful biomarker to predict pCR and improved outcome in patients with node-positive TNBC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Interprofessional education (IPE) can cultivate competencies in multidisciplinary collaboration for patient safety, and both face-to-face and online IPE programs have recently been introduced. This study aimed to elucidate the effects of the online IPE program on undergraduate students after the coronavirus disease 2019 pandemic., Methods: The difference-in-differences method was used to assess undergraduate students in the Schools of Medicine and Health Sciences and in the Faculty of Pharmacy at Takasaki University of Health and Welfare who participated in IPE programs at Gunma University (face-to-face IPE was implemented in 2019 and online IPE in 2020). We distributed a questionnaire that included modified versions of the Attitudes Toward Health Care Teams Scale (ATHCTS) and the Teamwork Attitudes Questionnaire (T-TAQ) to evaluate attitudes toward health-care teams and collaboration for patient safety, respectively, and then compared the differences., Results: The mean score on the "team efficiency" subscale of the ATHCTS in the online IPE program was significantly lower than that in the face-to-face IPE program. Scores on the T-TAQ in two categories, "mutual support" and "communication", were significantly higher in the online IPE program, which suggests that it may have a similar effect on students learning collaborative practice for patient safety. However, due to technological difficulties, the online IPE program reduced the educational effects for "team efficiency". The improvements in "mutual support" and "communication" seen in the online IPE program, suggest its necessity for collaborative practice for patient safety., Conclusion: These findings suggest that an online IPE program for patient safety may provide better education effects as a whole, but efforts are needed to minimize the associated technological difficulties., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024 Nozaki et al.)

Background/aim: The local immune response in colorectal cancer is closely related to prognosis and therapeutic efficacy. In this study, histological analyses were performed to determine the phenotype of tumor-infiltrating lymphocytes (TILs) and their infiltration in the stromal and intratumoral regions, aiming to elucidate their interactions and prognostic effects., Patients and Methods: Multiplex fluorescent labeling was performed using surgically resected colorectal cancer specimens to investigate the infiltration of CD45RO (+) TILs, which exhibit cytotoxicity, and subsets of CD4 (+) TILs, identified by their characteristic transcription factor expression., Results: The degree of CD45RO (+) TIL infiltration in the entire observation field or stromal area was not associated with prognosis. However, a high degree of infiltration in the tumor nest (intratumoral area) was significantly associated with a favorable prognosis. CD4 (+) TILs and their subsets were not associated with prognosis. However, stratified analyses revealed that a high degree of infiltration of stromal CD4 (+) TILs and the subsets T helper (Th)1, Th2, Th17, and regulatory T cells is necessary for the association between high intratumoral CD45RO (+) TIL infiltration and favorable prognosis., Conclusion: A sufficient degree of infiltration of stromal CD4 (+) TIL subsets is required for intratumoral CD45RO (+) TILs to exert toxicity against cancer cells. This highlights the significance of stromal immune reactions in achieving effective cytotoxic immune responses in the intratumoral area and demonstrates the critical role of the spatial distribution pattern of TILs in exerting their functions., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Bullous pemphigoid (BP), an autoimmune bullous dermatosis, occurs predominantly in older individuals. Nemolizumab, a humanized monoclonal antibody against the interleukin (IL)-31 receptor A, is used to treat severe atopic dermatitis (AD) in Japan. However, it can cause several adverse events, such as exacerbation of AD, erythema, and eosinophilia. Herein, we describe a case of prurigo-type AD developing BP after nemolizumab administration. A 62-year-old man with prurigo-type AD and asthma presented with serious, refractory itching. After nemolizumab injection, his pruritus was relieved for 2 days. However, on day 3, erythema with blisters and erosions suddenly appeared throughout his body. Pathological examination showed typical BP and the patient's serum anti-BP180-NC16a antibody level was 882.5 U/mL. Oral prednisolone (PSL) was initiated and nemolizumab was never used again. Despite high-dose PSL, new blisters continued to develop, with a rapid elevation of anti-BP180-NC16a antibodies to 6930 U/mL. Adding high-dose cyclosporine and intravenous gamma globulin reduced new blister formation after 9 weeks, and PSL and cyclosporine were gradually tapered. Dupilumab, an anti-IL-4 receptor antibody, was initiated after 16 weeks, resulting in continued remission without PSL and cyclosporine. The sudden occurrence of BP in this case suggested that the patient had occult BP before the nemolizumab initiation and that nemolizumab exacerbated BP and made it overt. Blocking the IL-31 pathway may exacerbate inflammation in AD or BP, resulting in the acceleration of blister formation. This may be countered by blocking the IL-4/13 pathway with dupilumab. To our knowledge, this is the first case of nemolizumab-exacerbated BP., (© 2024 Japanese Dermatological Association.)

Background: Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRβ. TH activates lipid metabolism via THRβ, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRβ have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide., Methods: We developed a TH analog, ZTA-261, by modifying the existing THRβ-selective agonists GC-1 and GC-24. To determine the THRβ-selectivity of ZTA-261, an in vitro radiolabeled TH displacement assay was conducted. ZTA-261 was intraperitoneally injected into a mouse model of high-fat diet-induced obesity, and its effectiveness in reducing body weight and visceral fat, and improving lipid metabolism was assessed. In addition, its toxicity in the liver, heart, and bone was evaluated., Results: ZTA-261 is more selective towards THRβ than GC-1. Although ZTA-261 is less effective in reducing body weight and visceral fat than GC-1, it is as effective as GC-1 in reducing the levels of serum and liver lipids. These effects are mediated by the same pathway as that of T 3 , a natural TH, as evidenced by similar changes in the expression of TH-induced and lipid metabolism-related genes. The bone, cardiac, and hepatotoxicity of ZTA-261 are significantly lower than those of GC-1., Conclusions: ZTA-261, a highly selective and less toxic THRβ agonist, has the potential to be used as a drug for treating diseases related to lipid metabolism., (© 2024. The Author(s).)

To regulate the effective photon energy with a constant tube voltage and to perform enhanced K-edge x-ray imaging, we built a prototype fully digitalized triple-energy x-ray computed tomography (TECT) scanner utilizing beam hardening. An object on the turntable is irradiated by a 0.1-mm-focus x-ray tube at 1.4-time-magnification. 720 raw radiograms are obtained using a flat panel detector, and 512 tomograms are reconstructed. With an increasing digital amplification factor, the gray raw-density projections obtained using low-energy-photon absorption disappeared at a constant maximum raw density, and the effective energy was increased by x-ray beam hardening. TECT was performed at digital amplifier factors below 3.0, and the effective energy increased with increasing amplification factors. In particular, fine blood vessels were visible using gadolinium-K-edge CT., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

An electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines using a proton-exchange membrane (PEM) reactor was developed. Cyanoarenes were then reduced to the corresponding benzylamines at room temperature in the presence of ethyl phosphate. The reduction of nitroarenes proceeded at room temperature, and a variety of anilines were obtained. The quinoline reduction was efficiently promoted by adding a catalytic amount of p -toluenesulfonic acid (PTSA) or pyridinium p -toluenesulfonate (PPTS). Pyridine was also reduced to piperidine in the presence of PTSA., (Copyright © 2024, Mitsudo et al.)

Staphylococcus aureus, a Gram-positive bacterium, causes inflammatory skin diseases, such as atopic dermatitis, and serious systemic diseases, such as sepsis. In the skin and nasal environment, peptidoglycan (PGN)-degrading enzymes, including lysozyme and lysostaphin, affects S. aureus PGN. However, the effects of PGN-degrading enzymes on the acute innate immune-inducing activity of S. aureus have not yet been investigated. In this study, we demonstrated that PGN-degrading enzymes induce acute silkworm hemolymph melanization by S. aureus. Insoluble fractions of S. aureus treated with lysozyme, lysostaphin, or both enzymes, were prepared. Melanization of the silkworm hemolymph caused by the injection of these insoluble fractions was higher than that of S. aureus without enzyme treatment. These results suggest that structural changes in S. aureus PGN caused by PGN-degrading enzymes affect the acute innate immune response in silkworms.

This case of PJRT shows negative linking on ventriculoatrial intervals after atrial differential pacing. Interpreting the results of atrial differential pacing may be challenging in cases where the pacing site affects retrograde conduction or when retrograde conduction is unstable., Competing Interests: Authors declare no conflict of interests for this article., (© 2024 The Author(s). Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)