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Although there is growing evidence of the efficacy of carbon-ion radiotherapy (CIRT) for locally advanced cervical adenocarcinoma, reports on combined treatment with CIRT and image-guided brachytherapy (IGBT) are scarce. We retrospectively analyzed patients with International Federation of Gynecology and Obstetrics (2008) stage II–IVA locally advanced cervical adenocarcinoma who received combined scanning CIRT (sCIRT) and IGBT between April 2019 and March 2022. sCIRT consisted of whole-pelvic irradiation with 36 Gy (relative biological effectiveness [RBE]) in 12 fractions and subsequent local boost irradiation with 19.2 Gy (RBE) in 4 fractions. Three sessions of IGBT were administered after completion of sCIRT. Concurrent chemotherapy using weekly cisplatin (40 mg/m2/week) was also administered. Efficacy, toxicity and dose–volume parameters were analyzed. Fifteen patients were included in the analysis. The median follow-up period was 25 months. The 2-year overall survival, progression-free survival and local control rates were 92.3% (95% confidence interval [CI] = 77.8–100%), 52.5% (95% CI = 26.9–78.1%) and 84.8% (95% CI = 65.2–100%), respectively. Neither severe acute toxicity necessitating treatment cessation nor grade 3 or higher late toxicity were observed. The sigmoid D2cm3of the patient who developed grade 2 late sigmoid hemorrhage was 65.6 Gy, which exceeded the standard deviation and target dose. The combination of sCIRT and IGBT for locally advanced cervical adenocarcinoma showed acceptable efficacy and safety. Further large-scale and long-term studies are warranted to confirm the efficacy and safety of this treatment.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of aggressive extranodal large B-cell lymphoma characterized by the selective growth of lymphoma cells within the lumina of blood vessels, particularly capillaries. IVLBCL lacks mass formation, and its diagnosis can be challenging. We analyzed the utility of insulin-like growth factor II mRNA-binding protein 3 (IMP3) immunohistochemistry for IVLBCL diagnosis in various organs. Double staining with paired box 5 (PAX5) was performed for validation. Overall, 152 pathological specimens (111 positive and 41 negative for IVLBCL) obtained from 88 patients with a diagnosis of IVLBCL were stained for IMP3 and IMP3/PAX5. As negative controls, 40 pathology specimens from 38 patients with no history of IVLBCL or other B-cell lymphomas were stained for IMP3, which comprised 31 benign pathological specimens from 29 patients in whom malignancy was suspected, 7 cases of appendicitis with intravascular and/or intralymphatic lymphoid proliferations, and 2 cases of intravascular natural killer/T-cell lymphoma. All mononuclear cells with cytoplasmic staining were considered positive for IMP3 expression, but expression restricted to germinal center B cells was excluded from evaluation. All 111 IVLBCL pathological specimens were positive for IMP3 and IMP3/PAX5. In addition, 11 of the 41 specimens originally diagnosed as IVLBCL-negative showed IMP3/PAX5 double-positive cells, raising the suspicion of IVLBCL. However, of the 40 negative control samples, IMP3-positive non–germinal center B cells were detected in only 2 samples (P= 0.0131) and no intravascular IMP3-positive B cells suspicious for IVLBCL were identified. Altogether, IMP3 immunohistochemistry is a highly sensitive marker of IVLBCL and can be a helpful adjunct for IVLBCL diagnosis.

ABSTRACTIntroductionRecombinant viral-based gene therapy products, such as those incorporating adeno-associated viruses (AAVs), fall under the category of genetically modified organisms (GMOs). The European Union (EU) countries and Japan must obtain environmental risk assessment (ERA) approval for the use of GMOs before starting any clinical trials. It has been reported that the development of GMO-containing products in these two regions encounters several regulatory obstacles due to the longer regulatory procedures and document preparation for ERA.Areas coveredIn this article, we comparatively analyzed the ERA document requirements in the EU and Japan for AAV-based recombinant medicinal products to highlight the differences in the context of potential future attempts of convergence. Additionally, we analyzed non-clinical and clinical shedding data requirements, which are key components of ERA reviews in the EU and Japan. Lastly, we compared the containment measures to minimize the spread of GMOs in the environment in the EU and Japan.Expert opinionBased on our comparative analysis, we present several policy recommendations of standardizing and simplifying the application materials and procedures for the ERA regulations on GMOs in the EU and Japan in the mid-, and long-term timeframe to achieve global regulatory convergence.

ABSTRACTPurposeDistributional changes of beta subunit 3 (SCN3B) and alpha subunit 7 (SCN7A) proteins of voltage-gated sodium channel proteins were investigated in the periodontal ligament (PDL) after experimental tooth movement to understand their roles in pain transmission and bone remodelling during orthodontic tooth movement.Materials and methodsImmunohistochemical staining for SCN; SCN and tartrate-resistant acid phosphatase (TRAP); and SCN, calcitonin gene-related peptide (CGRP), and TRAP were performed on the PDL in the first molar teeth of mice at 1–14 days after experimental tooth movement.ResultsIn intact animals, the PDL of the first molar tooth had only a few SCN3B-immunoreactive (−IR) nerve fibres. At 5 days, however, SCN3B-IR nerve fibres significantly increased in the compression area of the PDL. SCN3B-IR nerve fibres were occasionally detected in the vicinity of TRAP-positive multinuclear cells within the resorption lacunae. These nerve fibres appeared to contain CGRP-immunoreactivity. At 7–14 days after tooth movement, SCN3B-IR nerve fibres decreased in the compression area and were infrequent in both compression and tension areas. In contrast, SCN7A-IR nerve fibres decreased in the compression area after the experimental tooth movement.ConclusionsExperimental tooth movement changed the distribution of SCNs in the PDL. SCN3B may be associated with nociceptive transmission and regulate activity of osteoclasts through release of CGRP from sensory nerve endings during orthodontic tooth movement.

Point defects dictate various physical, chemical, and optoelectronic properties of two-dimensional (2D) materials, and therefore, a rudimentary understanding of the formation and spatial distribution of point defects is a key to advancement in 2D material-based nanotechnology. In this work, we performed the demonstration to directly probe the point defects in 2H-MoTe2monolayers that are tactically exposed to (i) 200 °C-vacuum-annealing and (ii) 532 nm-laser-illumination; and accordingly, we utilize a deep learning algorithm to classify and quantify the generated point defects. We discovered that tellurium-related defects are mainly generated in both 2H-MoTe2samples; but interestingly, 200 °C-vacuum-annealing and 532 nm-laser-illumination modulate a strong n-type and strong p-type 2H-MoTe2,respectively. While 200 °C-vacuum-annealing generates tellurium vacancies or tellurium adatoms, 532 nm-laser-illumination prompts oxygen atoms to be adsorbed/chemisorbed at tellurium vacancies, giving rise to the p-type characteristic. This work significantly advances the current understanding of point defect engineering in 2H-MoTe2monolayers and other 2D materials, which is critical for developing nanoscale devices with desired functionality.

Point defects often appear in two-dimensional (2D) materials and are mostly correlated with physical phenomena. The direct visualisation of point defects, followed by statistical inspection, is the most promising way to harness structure-modulated 2D materials. Here, we introduce a deep learning-based platform to identify the point defects in 2H-MoTe2: synergy of unit cell detection and defect classification. These processes demonstrate that segmenting the detected hexagonal cell into two unit cells elaborately cropped the unit cells: further separating a unit cell input into the Te2/Mo column part remarkably increased the defect classification accuracies. The concentrations of identified point defects were 7.16 × 1020cm2of Te monovacancies, 4.38 × 1019cm2of Te divacancies and 1.46 × 1019cm2of Mo monovacancies generated during an exfoliation process for TEM sample-preparation. These revealed defects correspond to the n-type character mainly originating from Te monovacancies, statistically. Our deep learning-oriented platform combined with atomic structural imaging provides the most intuitive and precise way to analyse point defects and, consequently, insight into the defect-property correlation based on deep learning in 2D materials.

Abstract: Aggregating and sharing the metadata of flux observation sites results in a strong collaboration among various fields of study. Such data sharing will also be a part of the future design of a tower flux observation network in Asia. The aim of this review is to comprehend the state of tower flux observation sites in Asia. There are 109 tower flux observation sites in Asia including 51 forest sites. There are more new sites under construction in Asia than in America and Europe. These sites range from the taiga in Siberia to the rainforest in Southeast Asia, and from the equatorial to polar Koeppen climate zones. There are many highly humid areas in Asia, not only at low latitudes but also at middle latitudes. This climate condition has developed unique vegetation such as lucidophyllous (evergreen broadleaf) forest, which is distributed in warm areas with high precipitation in the growing season. However, there are only a few observations taking place in lucidophyllous forest. Rice paddy fields are also unique land cover in Asia. It is important to accumulate long-term data for rice fields with their management records, because plant activity depends highly on both climate conditions and land-use management. Flux data, especially net ecosystem exchange and related elements, are used for widespread studies not only within the flux-research community but also in other fields of study, for example remote sensing. At present, however, both the quantity and quality of the data are not sufficient for these studies. Regarding the quantity, there are many recently established sites that have not published data yet; regarding quality, flux data include uncertainties caused by methodological problems. Flux researchers are required not only to obtain flux data but also to improve their quality. Meanwhile, data users must understand there are still uncertainties in flux data.

Abstract: Measurement of soil CO2 concentrations is important for investigating the dynamics and diffusion of CO2 in soil. In this study, we developed a small CO2 analyzer for measuring in situ-soil CO2 concentrations. The CO2 analyzer consists of a module containing an infrared CO2 gas sensor, a temperature sensor, and a relative humidity sensor. These sensors are installed in a protective box with an air vent, which is suitable for burying in the soil. The output response time of the CO2 analyzer was 349 s, as evaluated from the phase lag after input of known CO2 concentrations. This response time is short enough to measure soil CO2 concentrations, because variations in concentration are slower than the response time of the analyzer. In a field test, we used the CO2 analyzer to measure soil CO2 concentrations at five depths (0–50 cm) over 2.5 months. While the CO2 concentration generally increased with depth, the amplitude of the variation in CO2 concentration decreased with depth. The phase lag of the variations in soil CO2 concentration also increased with depth, as did soil temperature. The tests confirm that the CO2 analyzer is applicable to continuous monitoring of soil CO2 concentrations.

The human bone marrow (BM) niche sustains hematopoiesis throughout life. We present a method for generating complex BM-like organoids (BMOs) from human induced pluripotent stem cells (iPSCs). BMOs consist of key cell types that self-organize into spatially defined three-dimensional structures mimicking cellular, structural and molecular characteristics of the hematopoietic microenvironment. Functional properties of BMOs include the presence of an in vivo-like vascular network, the presence of multipotent mesenchymal stem/progenitor cells, the support of neutrophil differentiation and responsiveness to inflammatory stimuli. Single-cell RNA sequencing revealed a heterocellular composition including the presence of a hematopoietic stem/progenitor (HSPC) cluster expressing genes of fetal HSCs. BMO-derived HSPCs also exhibited lymphoid potential and a subset demonstrated transient engraftment potential upon xenotransplantation in mice. We show that the BMOs could enable the modeling of hematopoietic developmental aspects and inborn errors of hematopoiesis, as shown for human VPS45 deficiency. Thus, iPSC-derived BMOs serve as a physiologically relevant in vitro model of the human BM microenvironment to study hematopoietic development and BM diseases.

ABSTRACTPurposeLong-term post-treatment stability should be a crucial objective of orthodontic treatment. This article reports the treatment of an adult Class II patient using orthodontic miniscrews as anchorage for maxillary dentition distalization. The main purpose of this report was to examine whether long-term retention was effective for maintaining the obtained optimal occlusion.Materials and methodsThe patient was a 26.5-year-old female diagnosed with skeletal Class I jaw relationship, low angle, Class II molar relationship, maxillary and mandibular anterior crowding, and excessive overjet. To correct the crowding and molar relationship, the maxillary lateral dentition was moved distally using miniscrews. After active treatment, wrap-around retainers were provided to be worn for 10 years.ResultsA normal overjet and overbite, Class I molar relationship, and rigid intercuspation were achieved after active treatment. From pre-treatment to post-treatment, the right and left maxillary molars moved distally with slight intrusion and buccal movement. At the 10-year retention, the maxillary and mandibular molars remained almost unchanged. The maxillary intercanine and maxillary and mandibular intermolar widths increased during active treatment, and remained almost unchanged after active treatment.ConclusionAn optimal occlusion and harmonious facial profile were obtained and maintained for an extended period using maxillary dentition distalization with miniscrews as anchorage.

The high temperature superconductor (HTS) dual-band bandpass filter (DB-BPF) has been developed for microwave intermediate frequency (IF) signals (8--12 GHz) of a multi-frequency millimeter-wave atmospheric spectrometer. The HTS DB-BPF consists of 6-pole and 12-pole BPFs with an 8.348 GHz center frequency and 0.27 GHz band width and an 11.156 GHz center frequency and 1.46 GHz band width, respectively. The HTS DB-BPF was fabricated using YBa2Cu3Oy thin films on R-Al2O3 substrate. Fabricated DB-BPF is evaluated by experiment and simulation with good agreement. We started the long-term monitoring of atmospheric molecular species using DB-BPF at Syowa station in Antarctica.

ABSTRACTPurposeThis article aims to showcase the effects and benefits of a multidisciplinary treatment approach incorporating orthodontics in adult patients with jaw deformities and partially edentulous jaws. We present a case of a skeletal Class III patient with partially edentulous jaws treated through a combination of surgical-orthodontic and prosthetic procedures.Materials and MethodsA 49-year-old female patient sought treatment at our clinic for prosthetic care post root cyst extraction and improvement of her mandibular protrusion. She presented with a skeletal Class III malocclusion, facial asymmetry, maxillary distal extension defect, and mandibular intercalary defect.ResultsThe patient underwent preoperative treatment with multi-bracket appliances to correct dental decompensation of the mandibular incisors and upright the mandibular molars. Subsequently, she underwent a bilateral sagittal split ramus osteotomy, with the mandibular setback of 8 mm on the right side and 4 mm on the left side. Prior to surgery, treatment dentures were fabricated for the defect, and post-surgery, these dentures, along with an occlusal splint, were secured with intermaxillary fixation screws and the remaining teeth. The interdental space in the mandibular anterior teeth was closed by postoperative treatment. The preoperative treatment lasted for 7 months, the hospital stay was 14 days, and the postoperative treatment continued for 6 months.ConclusionThe successful treatment of this patient with jaw deformity and a partially edentulous jaw was achieved through the collaborative efforts of orthodontics, oral surgery, and prosthodontics departments.

Purpose: The significance of thyroglobulin antibodies (TgAbs) and thyroid peroxidase antibodies (TPOAbs) in Graves’ disease (GD) remains unclear. Therefore, this study aimed to clarify the clinical significance of TgAbs and TPOAbs in GD. Methods: A total of 442 patients with GD were recruited and divided into four groups based on TgAb and TPOAb positivity. Their clinical parameters and the characteristics of the groups were compared. Cox proportional hazard regression analysis was performed to assess risk factors for GD remission. Results: The free triiodothyronine (FT3) level was significantly higher in groups positive for TgAbs and TPOAbs than in the other groups. The FT3 to free thyroxine (FT4) (FT3/FT4) ratio was significantly higher and thyrotropin-stimulating hormone (TSH) receptor antibodies (TRAbs) were significantly lower in the TgAb+/TPOAb− group. Time to FT4 recovery was significantly shorter for groups negative for TPOAbs, whereas time to TSH recovery was significantly longer for groups positive for TPOAbs. Cox proportional hazard regression analysis revealed that TgAb positivity, prolonged treatment duration with antithyroid drugs, and Graves’ ophthalmopathy treated with methylprednisolone were significantly associated with GD remission and that a smoking history, elevated FT3/FT4 ratio, and treatment with propylthiouracil hindered GD remission. Conclusion: The contributions of TgAbs and TPOAbs to GD pathogenesis differ. Patients positive for TgAbs develop GD with lower TRAb titers and undergo earlier remission than those negative for TgAbs. Patients positive for TPOAbs develop GD with high TRAb titers and need a long time to achieve remission.

Graphite intercalation compounds (GICs) are formed by inserting various atoms and molecules between the layers of graphite. Among these GICs, five structures have been reported wherein a single atom M was intercalated into graphite. Here, the formation energies of the GICs with these crystal structures and various M were investigated using a van der Waals density functional method. Consequently, we found the stable GICs for M = Sc, Y, Fr, and Ra, which are yet to be reported. Furthermore, we found that Ra-GICs have the possibility to exhibit a superconductivity of Tc∼ 0.07 K and that Sc- and Y-GICs have the possibility to exhibit the charge density wave, due to the strong interaction of the electron and lattice. This insight provides further understanding of how intercalants and graphite interact with each other in GICs that exhibit unique physical properties. The calculated formation energies of experimentally reported ones showed a good agreement with the experimentally reported stabilities, which provides insights into the synthesizing mechanism of GICs including the new ones.

The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover 2 novel human genetic defects in signal recognition particle receptor alpha (SRPRA) and SRP19, constituents of the mammalian cotranslational targeting machinery, and characterize their roles in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the SRP genes, HAX1, and ELANE, and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP deficiency on neutrophil granulocyte development. In a heterologous cell–based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking, and homeostasis are critically important for the differentiation of neutrophil granulocytes.

•SRPRAand SRP19are novel genes affected in congenital neutropenia and essential for granule protein processing.•Comparative proteomics in neutrophils of patients with defects in SRPRA, SRP19, SRP54, HAX1, and ELANE reveal genotype-specific alterations.

Faults are rarely completely smooth, with topographic undulations coming from the distribution of asperities along the fault surface. Understanding the effects of fault surface topography on fault strength and earthquake source properties has been limited due to a lack of in situ observations in the field. Here we use simulated earthquake cycles on metre-scale laboratory faults to show the effects of the degree of fault topographic heterogeneity, especially on macroscopic peak strength represented by the shear force required to commence macroscopic failure. Our results demonstrate that the less heterogeneous fault is weaker, due to its lower macroscopic peak strength, and produces a larger stress drop on average than the more heterogeneous fault. Rupture along the less heterogeneous fault tends to propagate at subshear speed while the more heterogeneous fault accommodates a wider range of rupture speeds, including slow slip and supershear rupture. These results reveal how fault topographic heterogeneity affects macroscopic peak strength at rupture initiation and stress drop during rupture propagation, which has important implications for understanding natural faults and earthquakes.

BackgroundSeveral genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS.MethodsWe enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS.ResultsThree novel loci were significantly associated with the survival of patients with sporadic ALS—FGF1at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10−9), THSD7Aat 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10−8) and LRP1at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10−8). FGF1and THSD7Avariants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1and THSD7Awas partially disrupted. The rs60565245 was not associated with LRP1mRNA expression.ConclusionsWe identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1and THSD7Aand the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

Diamond Blackfan anemia (DBA) is a chronic congenital form of erythrocytic hypoplasia in which erythroid precursor cell levels are low. DBA reflects ribosomal dysfunction and is accompanied by hematopoietic cell apoptosis, anemia, and various somatic symptoms. We report the characteristic symptoms of the craniofacial region and the orthodontic treatments of two DBA cases. Case 1 was a 12-year-old female. The typical physical and facial characteristics of DBA were lacking. On initial examination, she exhibited a skeletal Class II jaw and end to end molar relationships and a large overjet. An edgewise appliance was placed after extraction of the first maxillary premolars. After 3 years and 11 months, an appropriate overjet and overbite, rigid intercuspation, and an acceptable profile were evident without any clinical adverse effects. Case 2 was a 13-year-old female. She exhibited a skeletal Class I jaw relationship, a spaced dental arch, the maxillofacial dysplasia characteristic of Binder syndrome, hypoplasia of the right mandibular condyle, and labial protrusions of the maxillary and mandibular incisors. We placed an edgewise appliance and after 1 year and 7 months, the occlusion was optimal in the absence of any adverse effects. Our two DBA cases exhibited a broad spectrum of physical and dentofacial symptoms. Patients with DBA are often prescribed combined steroid/bisphosphonate therapies. Both agents are likely to affect alveolar bone remodeling after tooth extraction and orthodontic tooth movement. Careful consideration of medication with reference to various dentofacial characteristics is necessary.

In recent years, it has become clear that the cytotoxicity of γ-irradiation of cells is increased under microgravity conditions. However, there has been no study of the effect of the gravity vector direction, rather than the magnitude, on γ-ray-induced cytotoxicity. Therefore, in this study, we inverted cultures of human bronchial epithelium BEAS-2B cells and human lung cancer A549 cells in order to change the gravity vector direction by 180° with respect to the cells and observed the cellular response to radiation in this state. We found that cells in inverted culture showed increased irradiation-induced production of reactive oxygen species and decreased expression of the antioxidant protein thioredoxin-1 compared to cells in normal culture. Furthermore, the DNA damage response was delayed in γ-irradiated cells in inverted culture, and the number of unrepaired DNA sites was increased, compared to irradiated cells in normal culture. γ-Ray-induced cell death and the number of G2-M arrested cells were increased in inverted culture, in accordance with the decreased capacity for DNA repair. Our findings suggest that the gravity vector direction, as well as its magnitude, alters the cellular response to radiation.

As glucocorticoids induce muscle atrophy during the treatment course of polymyositis (PM), novel therapeutic strategy is awaited that suppresses muscle inflammation but retains muscle strength. We recently found that injured muscle fibres in PM undergo FASLG‐mediated necroptosis, a form of regulated cell death accompanied by release of pro‐inflammatory mediators, contributes to accelerate muscle inflammation and muscle weakness. Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists have pleiotropic actions including anti‐inflammatory effects, prevention of muscle atrophy, and inhibition of cell death, in addition to anti‐diabetic effect. We aimed in this study to examine the role of GLP‐1R in PM and the effect of a GLP‐1R agonist on in vivoand in vitromodels of PM. Muscle specimens of PM patients and a murine model of PM, C protein‐induced myositis (CIM), were examined for the expression of GLP‐1R. The effect of PF1801, a GLP‐1R agonist, on CIM was evaluated in monotherapy or in combination with prednisolone (PSL). As an in vitromodel of PM, C2C12‐derived myotubes were treated with FASLG to induce necroptosis. The effect of PF1801 on this model was analysed. GLP‐1R was expressed on the inflamed muscle fibres of PM and CIM. The treatment of CIM with PF1801 in monotherapy (PF) or in combination with PSL (PF + PSL) suppressed CIM‐induced muscle weakness (grip strength, mean ± SD (g); PF 227 ± 6.0 (P< 0.01), PF + PSL 224 ± 8.5 (P< 0.01), Vehicle 162 ± 6.0) and decrease in cross‐sectional area of muscle fibres (mean ± SD (μm2); PF 1896 ± 144 (P< 0.05), PF + PSL 2018 ± 445 (P< 0.01), Vehicle 1349 ± 199) as well as the severity of histological inflammation scores (median, interquartile range; PF 0.0, 0.0–0.5 (P< 0.05), PF + PSL 0.0, 0.0–0.0 (P< 0.01), Vehicle 1.9, 1.3–3.3). PF1801 decreased the levels of inflammatory mediators such as TNFα, IL‐6, and HMGB1 in the serum of CIM. PF1801 inhibited necroptosis of the myotubes in an AMP‐activated protein kinase (AMPK)‐dependent manner. PF1801 activated AMPK and decreased the expression of PGAM5, a mitochondrial protein, which was crucial for necroptosis of the myotubes. PF1801 promoted the degradation of PGAM5 through ubiquitin‐proteasome activity. Furthermore, PF1801 suppressed FASLG‐induced reactive oxygen species (ROS) accumulation in myotubes, also crucial for the execution of necroptosis, thorough up‐regulating the antioxidant molecules including Nfe2l2, Hmox1, Gclm, and Nqo1. GLP‐1R agonist could be a novel therapy for PM that recovers muscle weakness and suppresses muscle inflammation through inhi biting muscle fibre necroptosis.

As both physiological and psychological factors influence age-associated declines in older people, the development of drug therapy with multifaceted effects is required. To investigate the utility of ninjin'yoeito (NYT) against geriatric syndromes, we evaluated the effects of NYT on age-related declines in old C57BL/6 mice (88-week-old) as a preclinical model of frailty progression. Here, we showed that NYT reversed the decline of rectal temperature in old mice and also improved forelimb grip strength compared with that in the old control group without affecting skeletal muscle loss. Moreover, NYT significantly increased the duration of grooming after a sucrose solution was sprayed, which reflected self-care motivation. Finally, we revealed the antioxidant effects of NYT using a cell-free assay. These results suggest that NYT can improve both physiological and psychological declines associated with aging, and the mechanism may include antioxidant effects. NYT may have potential utility for maintaining the health of older people.Graphical AbstractNinjin'yoeito (NYT) can improve both physiological and psychological declines associated with aging in old C57BL/6J mice.