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Abstract During mid-Cretaceous Oceanic Anoxic Event 2, significant increase of atmospheric carbon dioxide concentrations from the eruption of the large igneous provinces is hypothesized to have induced a humid climate and an elevation in nutrient runoff from continents to the oceans, resulting in oxygen depletion in the ocean. However, hitherto there is limited insight into the driving factors of Oceanic Anoxic Event 2 from the Pacific and Asian continental margins, even though the former and the latter were the largest ocean and landmass at that time. Here, a multiproxy analysis for the Oceanic Anoxic Event 2 interval of the Yezo Group –deposited on northwestern Pacific along the active Asian continental margin– is interpretated to identify seven volcanic pulses, five of which may have elevated humidity, weathering intensity, and vegetational change in the eastern margin of Asia. Moreover, oxygen depletion occurred simultaneously in the northwest Pacific. Given that these environmental changes in the eastern margin of Asia were penecontemporaneous with the global carbon burial intervals during Oceanic Anoxic Event 2, the elevated nutrient supply from the Asian continental margin to the Pacific Ocean may have, in part, contributed to the worldwide depletion of oxygen of the ocean during Oceanic Anoxic Event 2.

Antiferromagnetic (AFM) materials have attracted attention for device applications due to the absence of the stray field and high-frequency response. To integrate AFM materials into magnetic devices, the understanding of the interfacial effect between AFM and ferromagnetic (FM) materials is required. In particular, magnetization dynamics and magnetic damping are critical phenomena to be elucidated since they govern magnetization switching, spin-wave propagation, etc. Although a conventional method for studying the interfacial effects is stacking materials, the approach may cause unfavorable factors. To get insight into the dynamic properties at the AFM and FM interfaces, we have focused on B2-ordered FeRh, showing the first-order phase transition from the AFM to FM states, since the coexistence of AFM and FM domains occurs during transitions, which is an ideal platform for studying interfacial effects. For this study, we have studied ferromagnetic resonance (FMR) of FeRh thin films during the AFM–FM phase transition as a function of temperature. From the FMR measurements, we characterize the temperature dependence of the effective Gilbert damping constant αeff. We find that αeff decreases with increasing temperature, indicating that the temperature variation of the effective Gilbert damping constant originates from the exchange interaction between the AFM and FM domains in the film and/or AFM domains as a spin sink.

Cobalt-nickel nanoparticles (Co-Ni-NPs) show promising electrochemical performance in oxygen and hydrogen evolution reactions (OER and HER) due to their physicochemical properties such as electronic configuration and great electrochemical stability. Therefore, developing new economically and environmentally friendly methods of synthesizing Co-Ni-NPs has become a practical requirement. Co-Ni-NPs were produced by employing the liquid-phase reduction method. Nickel and cobalt sulfate solutions in hydrazine monohydrate with various mixing ratios were used as raw materials. Nickel plays an important role in the nucleation process via increasing the reduction reaction rate throughout the formation of Co-Ni-NPs. Furthermore, the acceleration of the Co-Ni-NPs formation process may be attributed to the partial dissolution of Ni(OH)2 in the presence of N2H4 and/or citrate-anions and the formation of the Ni-N2H4 or Ni-Cit complexes in contrast to Co(OH)2.

Cobalt nanoparticles were produced by employing the liquid-phase reduction method and hydrazine. The effect of citric acid additives on the formation and growth mechanism of cobalt nanoparticles was investigated using polarization methods. The cobalt nanoparticles produced in 0.2 M cobalt sulfate and 5 M hydrazine at 298 K had a spherical shape with a diameter of 400 nm. The dendritic nanoparticles formed with the decreasing of hydrazine concentration at 298 K. On the other hand, dendritic large particles are confirmed at 353 K. It was confirmed that the reduction reaction progressed with the addition of citric acid, and a hexagonal close-packed (εCo) phase was formed.

To develop voltage-controlled magnetization switching technologies for spintronics applications, a highly (422)-oriented Co 2 FeSi layer on top of the piezoelectric PMN-PT(011) is experimentally demonstrated by inserting a vanadium (V) ultra-thin layer. The strength of the growth-induced magnetic anisotropy of the (422)-oriented Co 2 FeSi layers can be artificially controlled by tuning the thicknesses of the inserted V and the grown Co 2 FeSi layers. As a result, a giant converse magnetoelectric effect (over 10 -5 s m -1 ) and a non-volatile binary state at zero electric field are simultaneously achieved in the (422)-oriented Co 2 FeSi/V/PMN-PT(011) multiferroic heterostructure. This study leads to a way toward magnetoresistive random-access-memory (MRAM) with a low power writing technology., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: In the phase 3 EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, cemiplimab significantly improved overall survival (OS) versus chemotherapy for patients with recurrent or metastatic cervical cancer who progressed after first-line platinum-based chemotherapy. We present a post hoc subgroup analysis of patients enrolled in Japan., Methods: Patients were enrolled regardless of programmed cell death-ligand 1 status and randomized 1:1 to cemiplimab 350 mg intravenously every 3 weeks or investigator's choice  single-agent chemotherapy for up to 96 weeks. Primary endpoint was OS. Key secondary endpoints were progression-free survival (PFS) and objective response rate (ORR)., Results: Overall, 608 patients were randomized, of whom 56 (9.2%) were in Japan (cemiplimab, n = 29; chemotherapy, n = 27). The median (range) duration of follow-up was 13.6 (6.0-25.3) versus 18.2 (6.0-38.2) months for patients in Japan and for the overall population, respectively. Median OS (95% confidence interval [CI]) was 8.4 (7.0-not evaluable) and 9.4 (5.4-14.9) months for cemiplimab versus chemotherapy (hazard ratio [HR]: 0.86; 95% CI: 0.43-1.68). Median PFS (95% CI) was 4.0 (1.4-8.2) versus 3.7 (1.8-4.2) months with cemiplimab and chemotherapy (HR: 0.90; 95% CI: 0.50-1.61), respectively. ORR was 17.2% for cemiplimab and 7.4% for chemotherapy (odds ratio, 2.47; 95% CI, 0.44-13.99). Incidence of treatment-emergent adverse events at any grade was 79.3% for cemiplimab and 100% for chemotherapy. Grade ≥3 adverse events were 37.9% versus 66.7% with cemiplimab and chemotherapy, respectively., Discussion: While acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6-month shorter median duration of follow-up versus the overall study population., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Anterior knee pain due to patellar maltracking following total knee arthroplasty (TKA) reduces patients' satisfaction. This study aimed to determine the patellofemoral pressure (PFP) in patients with favorable patellar tracking (FT) and impaired patellar tracking (IT) following TKA, the factors causing patellar maltracking, and the effect of lateral retinacular release (LRR) on patients with IT., Methods: Forty-four patients with varus knee osteoarthritis undergoing cruciate-retaining TKA were enrolled. After component implantation, patients with a separation of ≥ 2 mm of the patellar medial facet from the medial femoral trochlea throughout knee range of motion were classified into the IT group; meanwhile, the others were classified into the FT group. PFP was measured intraoperatively in three phases: (1) with the resurfaced patella (RP); (2) with the resurfaced patella and knee (RPK); and (3) when LRR was performed in IT (post-LRR). The PFPs at 0°, 90°, 120°, and 135° knee flexion were compared between FT and IT using the Mann-Whitney U test. Pairwise comparison of the PFP in IT between RPK and post-LRR was performed using the Wilcoxon signed-rank test. Correlations between PFP and pre- and postoperative radiographic parameters, such as hip-knee-ankle angle, lateral distal femoral angle, medial proximal tibial angle, anterior femoral offset, Insall-Salvati ratio (ISR), patellar tilt, and patellar resection angle (PRA), were evaluated using Spearman's rank correlation coefficients., Results: High lateral PFP in the knee flexion position led to patellar maltracking. Patients with IT (n = 24) had higher lateral and lower medial PFP than did patients with FT (n = 20) at 90°, 120°, and 135° knee flexion in RP and RPK. LRR in IT reduced the lateral PFP in the knee flexion position. PRA and ISR were correlated with the lateral PFP at no less than 90° in RP and RPK., Conclusions: This study demonstrated that internal rotational patellar resection, which resulted in a thick medial patellar remnant and a thin lateral counterpart, and patella alta were the causative factors of high lateral PFP, which induced patellar maltracking after TKA. Surgeons should avoid internal rotational patellar resection to achieve FT and perform LRR in patients with patellar maltracking., (© 2024. The Author(s).)

Aim: To investigate changes in the clinical characteristics of patients who abused benzodiazepine receptor agonists (BZRA) or over-the-counter (OTC) drugs before and after COVID-19 based on the 2018 and 2022 data of the "Nationwide Psychiatric Hospital (NPH) Survey on Drug-related Psychiatric Disorders.", Method: A total of 446 and 155 cases, and 435 and 273 cases, who mainly abused BZRAs or OTC drugs, respectively, were extracted from the database of the two NPH Surveys. Demographic variables, education, employment, criminal record, drug use during the previous year, psychiatric diagnosis, and types of abused drugs were compared between 2018 and 2022., Result: A comparison of BZRA abusers revealed a decreased number of users during the previous year and an increase in the comorbidity rate of other disorders (F3 and F4 in ICD-10) in 2022. Etizolam, flunitrazepam, triazolam, and zolpidem were used most in both years, with an increase in zolpidem and a decrease in triazolam in 2022. A comparison of OTC drug abusers revealed a higher proportion of women and young patients in 2022. An increase in the comorbidity rate of F3 and F9 and a significant increase in the use of dextromethorphan products were observed in 2022, although codeine products were in the majority in both years., Conclusion: By comparing NPH Surveys before and after the COVID-19 pandemic, both BZRA abusers and OTC drug abusers present complex pathologies, requiring tailor-made treatment. The younger OTC drug abusers were particularly evident among women, and the abuse of dextromethorphan-containing OTC drugs has increased alarmingly., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Objective: To examine the clinical characteristics of over-the-counter (OTC) drug abusers in psychiatric practice in Japan., Method: We examined the attributes, ICD-10 subcategory, and comorbid mental disorders of patients who mainly abuse OTC products and compared the clinical characteristics of single product and multiple products abusers, using the database of the "2022 Nationwide Mental Hospital Survey of Drug-related Disorders.", Results: Among the 2468 subjects included in this survey, 273 (11.1%) used OTC products as main drugs. Of these, 209 (78.3%) and 58 (21.7%) were classified into the single product group and the multiple products group, respectively. Six were excluded for unknown ingredients. By comparing these groups, we found that many of the multiple products group consisted of young women who were recently treated for drug problems. Many subjects in the group also had a short treatment period. No differences were observed between the groups regarding the ICD-10 F1 subcategory, but many subjects in the multiple products group fulfilled the criteria of F6 "disorders of adult personality and behavior.", Conclusion: OTC products are easily accessible drugs of abuse for young women in Japan. The results of this study indicate the necessity to reconsider the educational approach for preventing drug abuse, which has focused on illicit drugs. The study also indicates that some OTC products, which contain ingredients banned overseas due to their harmful effects, are still sold in Japan and that abusers for those products exist. Measures by the government are considered urgently needed., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Objective: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician's choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis., Methods: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis., Results: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1-43.0) months. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49-1.10) and 0.64 (0.44-0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45-1.02) and 0.61 (0.41-0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3-5, 74% and 72%), respectively., Conclusion: Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC., Trial Registration: ClinicalTrials.gov Identifier: NCT03517449., Competing Interests: Kan Yonemori has received lecture fees from Eisai, Pfizer, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR pharma, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), Boeringer Ingelheim, Ono, Daiichi-Sankyo, Bayer, Jansen, Sanofi, and AstraZeneca; is a member of the advisory board for Eisai, AstraZeneca, Sanofi, Genmab, Gilead, OncXerna, Takeda, Novartis, and MSD; research funding from MSD, Daiichi-Sankyo, Merck Biopharma, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe; and is principle investigator for MSD, Daiichi-Sankyo, AstraZeneca, Taiho, Merk Biopharma, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boeringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: An unstable trochanteric femoral fracture is a serious injury, with a 1-year mortality rate of 5.4% to 24.9%, for which there is currently no standard treatment method. The lag screw insertion site is one of the primary contact areas between the cortical bone and an intramedullary nail. We hypothesized that a posterolateral fracture causes intramedullary nail instability when the posterolateral fracture line interferes with lag screw insertion. The purpose of the present study was to investigate the effect of posterolateral fracture line morphology on intramedullary nail stability by simulating unstable trochanteric femoral fractures with a posterolateral fracture fragment., Methods: Eighteen custom-made synthetic osteoporotic bone samples were used in the present study. Nine samples had a posterolateral fracture line interfering with the lag screw insertion hole (Fracture A), and the other 9 had a fracture line 10 mm away from the hole (Fracture B). Cyclic loading (750 N) was applied to the femoral head 1,500 times. Movement of the end cap attached to the intramedullary nail was recorded. The amplitudes of motion in the coronal plane (coronal swing motion), sagittal plane (sagittal swing motion), and axial plane (total swing motion) were evaluated. The change in the neck-shaft angle was evaluated on photographs that were made before and after the test. Medial cortical displacement was measured before and after the test., Results: Two Fracture-A samples were excluded because the amplitude of sagittal swing motion was too large. The mean values for coronal, sagittal, and total swing motion were 1.13 ± 0.28 mm and 0.51 ± 0.09 mm (p < 0.001), 0.50 ± 0.12 mm and 0.46 ± 0.09 mm (p = 0.46), and 1.24 ± 0.24 mm and 0.69 ± 0.11 mm (p < 0.001) for Fractures A and B, respectively. The mean neck-shaft angle change was -8.29° ± 2.69° and -3.56° ± 2.35° for Fractures A and B, respectively (p = 0.002). The mean displacement of the medial cortex was 0.38 ± 1.12 mm and 0.12 ± 0.37 mm for Fractures A and B, respectively (p = 0.57)., Conclusions: This study showed that an unstable trochanteric femoral fracture with a posterolateral fracture line that interferes with the lag screw insertion holes is a risk factor for increased intramedullary nail instability., Competing Interests: Disclosure: This study was funded by Teijin Nakashima Medical Co., Ltd. (the manufacturer of the intramedullary nails used in the study), and also partly supported by a Grant-in-Aid for Scientific Research (19K18471) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a Grant-in-Aid for Research (2213035) from Nagoya City University. The Article Processing Charge for open access publication was funded by Teijin Nakashima Medical Co., Ltd. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A601)., (Copyright © 2024 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Premelanosome protein (PMEL), a melanocyte-specific glycoprotein, has an essential role in melanosome maturation, assembling amyloid fibrils for melanin deposition. PMEL undergoes several post-translational modifications, including N- and O-glycosylations, which are associated with proper melanosome development. C-mannosylation is a rare type of protein glycosylation at a tryptophan residue that might regulate the secretion and localization of proteins. PMEL has one putative C-mannosylation site in its core amyloid fragment (CAF); however, there is no report focusing on C-mannosylation of PMEL. To investigate this, we expressed recombinant PMEL in SK-MEL-28 human melanoma cells and purified the protein. Mass spectrometry analyses demonstrated that human PMEL is C-mannosylated at multiple tryptophan residues in its CAF and N-terminal fragment (NTF). In addition to the W 153 or W 156 residue (CAF), which lies in the consensus sequence for C-mannosylation, the W 104 residue (NTF) was C-mannosylated without the consensus sequence. To determine the effects of the modifications, we deleted the PMEL gene by using CRISPR/Cas9 technology and re-expressed wild-type or C-mannosylation-defective mutants of PMEL, in which the C-mannosylated tryptophan was replaced with a phenylalanine residue (WF mutation), in SK-MEL-28 cells. Importantly, fibril-containing melanosomes were significantly decreased in W104F mutant PMEL-re-expressing cells compared with wild-type PMEL, observed using transmission electron microscopy. Furthermore, western blot and immunofluorescence analysis suggested that the W104F mutation may cause mild endoplasmic reticulumretention, possibly associated with early misfolding, and lysosomal misaggregation, thus reducing functional fibril formation. Our results demonstrate that C-mannosylation of PMEL is required for proper melanosome development by regulating PMEL-derived fibril formation., (© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: R2* relaxometry and quantitative susceptibility mapping can be combined to distinguish between microstructural changes and iron deposition in white matter. Here, we aimed to explore microstructural changes in the white matter associated with clinical presentations such as cognitive impairment in patients with idiopathic normal-pressure hydrocephalus (iNPH) using R2* relaxometry analysis in combination with quantitative susceptibility mapping., Methods: We evaluated 16 patients clinically diagnosed with possible or probable iNPH and 18 matched healthy controls (HC) who were chosen based on similarity in age and sex. R2* and quantitative susceptibility mapping were compared using voxel-wise and atlas-based one-way analysis of covariance (ANCOVA). Finally, partial correlation analyses were performed to assess the relationship between R2* and clinical presentations., Results: R2* was lower in some white matter regions, including the bilateral superior longitudinal fascicle and sagittal stratum, in the iNPH group compared to the HC group. The voxel-based quantitative susceptibility mapping results did not differ between the groups. The atlas-based group comparisons yielded negative mean susceptibility values in almost all brain regions, indicating no clear paramagnetic iron deposition in the white matter of any subject. R2* and cognitive performance scores between the left superior longitudinal fasciculus (SLF) and right sagittal stratum (SS) were positively correlated. In addition to that, R2* and gait disturbance scores between left SS were negatively correlated., Conclusion: Our analysis highlights the microstructural changes without iron deposition in the SLF and SS, and their association with cognitive impairment and gait disturbance in patients with iNPH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kano, Uchida, Kan, Sakurai, Kobayashi, Seko, Mizutani, Usami, Takada and Matsukawa.)

We describe the wiring technique and evaluate the radiographic and clinical outcomes of treatment with a pin and wire system (PWS) for comminuted patella fractures. From June 2013 to October 2018, 33 patients with comminuted patella fractures were treated using a PWS. Open reduction and internal fixation was performed with multiple pins and a wire. All patients were allowed full weight bearing without a brace. Radiographs were obtained to evaluate bone union, implant breakage, back-out of pins, and intra-articular gaps and step-off. Clinical outcomes and postoperative complications were assessed at final follow-up examination. All fractures were united. Thirteen cable wires in 13 patients were partially broken without displacement of fracture at an average of 7.4 months (range, 1-19 months) postoperatively. The average preoperative, postoperative, and final follow-up intra-articular gap and step-off were 11.7 mm, 0.5 mm, and 0.03 mm and 6.6 mm, 0.4 mm, and 0.2 mm, respectively. The average postoperative pin displacement was 0.1 mm (range, 0-0.8 mm). Deep infection was not observed after the surgery. The implant removal rate was 21% (7 of 33). Among these, the symptomatic implant removal rate was 9% (3 of 33). Additionally, 3 of 7 patients with implant removal had broken wires. The average flexion and extension of knee joints were 139.7° (range, 120°-150°) and -0.9° (range, -10° to 0°), respectively. A PWS prevents back-out of the pins and reduces intra-articular gaps and step-off distances to acceptable levels, even if the cable wire is partially broken. Therefore, a PWS is a good treatment option for comminuted patella fractures. [ Orthopedics . 2023;46(5):291-296.].

Verticillium dahliae is a soilborne fungal pathogen that causes disease on many economically important crops. Based on the resistance or susceptibility of differential cultivars in tomato, isolates of V. dahliae are divided into three races. Avirulence ( avr ) genes within the genomes of the three races have also been identified. However, the functional role of the avr gene in race 3 isolates of V. dahliae has not been characterized. In this study, bioinformatics analysis showed that VdR3e, a cysteine-rich secreted protein encoded by the gene characterizing race 3 in V. dahliae , was likely obtained by horizontal gene transfer from the fungal genus Bipolaris . We demonstrate that VdR3e causes cell death by triggering multiple defense responses. In addition, VdR3e localized at the periphery of the plant cell and triggered immunity depending on its subcellular localization and the cell membrane receptor BAK1. Furthermore, VdR3e is a virulence factor and shows differential pathogenicity in race 3-resistant and -susceptible hosts. These results suggest that VdR3e is a virulence factor that can also interact with BAK1 as a pathogen-associated molecular pattern (PAMP) to trigger immune responses. IMPORTANCE Based on the gene-for-gene model, research on the function of avirulence genes and resistance genes has had an unparalleled impact on breeding for resistance in most crops against individual pathogens. The soilborne fungal pathogen, Verticillium dahliae, is a major pathogen on many economically important crops. Currently, avr genes of the three races in V. dahliae have been identified, but the function of avr gene representing race 3 has not been described. We investigated the characteristics of VdR3e-mediated immunity and demonstrated that VdR3e acts as a PAMP to activate a variety of plant defense responses and induce plant cell death. We also demonstrated that the role of VdR3e in pathogenicity was host dependent. This is the first study to describe the immune and virulence functions of the avr gene from race 3 in V. dahliae, and we provide support for the identification of genes mediating resistance against race 3., Competing Interests: The authors declare no conflict of interest.

The development of BCR::ABL1 tyrosine kinase inhibitors (TKIs), such as dasatinib, has dramatically improved survival in cases of chronic myeloid leukaemia (CML). However, the development of resistance to BCR::ABL1 TKIs is a clinical problem. BCR::ABL1 TKI resistance is known to have BCR::ABL1-dependent or BCR::ABL1-independent mechanisms, but the mechanism of BCR::ABL1 independence is not well understood. In the present study, we investigated the mechanism of BCR::ABL1-independent dasatinib resistance. The expression and activation level of genes or proteins were evaluated using array CGH, real time PCR, or western blot analysis. Gene expression was modulated using siRNA-mediated knockdown. Cell survival was assessed by using trypan blue dye method. We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Hydroxyapatite (HA) augments are used to treat trochanteric femoral fractures. However, the efficacy of HA augmentation has not been fully described in trochanteric femoral fracture surgery. In total, 85 patients were enrolled in the present study; all had trochanteric femoral fractures between January 2016 and October 2020, 45 with HA (HA group) and 40 without HA (N group). The intraoperative lag screw insertion torque was directly measured and the amount of lag screw telescoping with and without HA augmentation after surgery was analyzed. Maximum lag screw insertion torque (max-torque), bone mineral density in the opposite femoral neck (n-BMD), tip apex distance (TAD) of the lag screw, radiographic findings including fracture union, the amounts of lag screw telescoping and occurrence of complications were evaluated. A total of 12 patients were excluded if they were aged under 60 years old, had ipsilateral surgery and disorders in the hip joint, TAD of the lag screw ≥26 mm on postoperative radiographs and had measurement errors. A total of 73 fractures could be analyzed: HA group (n=36) and N group (n=37). Max-torque/n-BMD ratios were higher in the HA group compared with in the N group (7.23±2.71 vs. 5.93±1.91 g/cm 2 ·N·m; P=0.04). The amounts of lag screw telescoping in the HA group were smaller compared with the N group (1.41±2.00 vs. 2.58±2.34; P=0.05). Evaluation of screw insertion torque showed maximum screw insertion torque correlated well with n-BMD in both groups, HA (R=0.57; P<0.01) and N group (R=0.64; P<0.01). No correlation was found between maximum screw insertion torque and TAD in both groups, HA (R=-0.10; P=0.62) and N group (R=0.02; P=0.93). All fractures were radiographically united without any complications. These results support the effectiveness of HA augmentation, indicating higher resistance against rotational instability and reduced lag screw telescoping in trochanteric femoral fracture treatment., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Background: Forged unsintered hydroxyapatite and poly l-lactic acid ( F-u-HA/PLLA) screw is bioactivite, bioabsorbable, and radiopaque with high mechanical strength. Its efficacy has been previously demonstrated in the treatment of lateral humeral condylar, lateral tibial condylar, ankle, and patellar fractures. However, studies on its efficacy in treatment of calcaneal fractures is lacking. This study aimed to compare the postoperative results of F-u-HA/PLLA screw fixation and locking plate fixation for intra-articular calcaneal fractures., Methods: From January 2013 to December 2019, 47 closed intra-articular fractures treated with either F-u-HA/PLLA screws (group S, 18 feet in 17 patients) or locking plates (group P, 29 feet in 28 patients) in a single trauma center were retrospectively reviewed. The sinus tarsi approach was used in both groups. The time to bone union, step-off, varus deformity, Bohler's angle, and width and height of the calcaneus were assessed after surgery. Ankle joint range of motion (ROM) and postoperative complications were also assessed., Results: All fractures were successfully treated. The Kaplan-Meier curves of the two groups showed similar trends. The log-rank test showed no significant difference in the time to bone union between the two groups (p = 0.48). In the Cox proportional hazards model adjusted for preoperative width and Bohler's angle, the hazard ratio for bone union was not statistically significant (HR: 1.13, 95%CI: 0.50-2.56, p = 0.78). Other variables included step-off (group S: 2.0 vs group P: 2.2 mm, p = 0.84), varus deformity (2.0° vs. 3.0°, p = 0.7), Gissane's angle (103.5° vs 104.0°, p = 0.84), width (38.0 vs 34.8 mm, p = 0.12), height (42.1 vs 44.0 mm, p = 0.07), and ankle ROM degrees (dorsal flexion, 20.0° vs. 20.0°, p = 0.13; plantar flexion 40.0° vs 40.0°, p = 0.56), which were not significantly different between groups P and S. The Bohler's angle was smaller in group S than in group P (20.5° vs 27.0°, p < 0.01). No skin necrosis or infection was observed in either group., Conclusion: Postoperative results of F-u-HA/PLLA screw fixation using the sinus tarsi approach for intra-articular calcaneal fractures were as good as those of locking plate fixation., Competing Interests: The authors declare no competing interests., (© 2023 The Authors. Published by Elsevier Ltd.)

"Akahoya" is a volcanic soil classified as a special soil deposited in Kyushu, Japan. Many of its properties are not yet clearly understood. We found that Akahoya had the potential to adsorb bacteria in cattle feces, which prompted us to investigate its material properties and perform experiments to comprehensively evaluate its adsorption performance for various fine particles such as acidic and basic dyes, NO x /SO x gas, and phosphoric acid ions, in addition to bacteria. Akahoya had a very high specific surface area owing to the large number of nanometer-sized pores in its structure; it exhibited a high adsorption capacity for both NO 2 and SO 2 . Regarding the zeta potential of Akahoya, the point of zero charge was approximately pH 7.0. The surface potential had a significant effect on the adsorption of acidic and basic dyes. Akahoya had a very high cation exchange capacity when the sample surface was negatively charged and a high anion exchange capacity when the sample surface was positively charged. Akahoya also exhibited a relatively high adsorption capacity for phosphoric acid because of its high level of Al 2 O 3 , and the immersion liquid had a very high Al ion concentration. Finally, filtration tests were performed on Escherichia coli suspension using a column filled with Akahoya or another volcanic soil sample. The results confirmed that the Escherichia coli adhered on the Akahoya sample. The results of the Escherichia coli release test, after the filtration test, suggested that this adhesion to Akahoya could be phosphorus-mediated.

Benzoquinone derivatives (BQDs) are hybridized inside activated carbon (AC) pores via gas-phase adsorption to prepare electrochemical capacitor materials. In this study, 2 mmol of BQDs are hybridized with 1 g of AC. The hybridization of alkylbenzoquinones (ABQs) with AC enhances the volumetric capacitances of the hybrids from 117 to 201 F cm -3 at 0.05 A g -1 and the capacitances are retained up to 73% at 10 A g -1 . Meanwhile, the volumetric capacitances are increased to 163 F cm -3 at 0.05 A g -1 by the hybridization of halobenzoquinones (HBQs) and the capacitance retentions at 0.05 A g -1 are ∼62%, which are higher than that of AC (46%). The results of electrochemical measurements suggest that HBQs exist as agglomerates while ABQs are finely dispersed inside the pores. The ABQs have good contact with the conductive carbon pore surface compared to the HBQs. Consequently, most of the ABQ molecules undergo reversible redox reactions ( i.e. , high utilization efficiencies), and a large contact area facilitates charge transfer at the large contact interface, thereby endowing the hybrids of ABQs with fast charging and discharging characteristics. HBQ molecules can be finely dispersed by liquid-phase adsorption, but the finely dispersed HBQ molecules are mobile inside the pores at room temperature and gradually form agglomerates. The difference in the existing form of BQDs is explained by the dominant interaction affecting the BQD molecules. ABQs have a strong interaction with the carbon pore surface while the intermolecular interaction is dominant for HBQs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m 2  + cisplatin 50 mg/m 2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD-L1 combined positive score (CPS) ≥1, all-comers, and PD-L1 CPS ≥10. Fifty-seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD-L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16-0.77]), all-comers (n = 57; 0.45 [0.22-0.90]), and patients with PD-L1 CPS ≥10 (n = 25; 0.36 [0.12-1.07]). HRs (95% CI) for OS were 0.38 (0.14-1.01), 0.41 (0.17-1.00), and 0.37 (0.10-1.30), respectively. Incidence of grade 3-5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE-826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Study 309/KEYNOTE-775 is a phase 3 open-label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with progression after platinum-based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression-free survival (PFS) and overall survival (OS) in all-comers (ie, regardless of mismatch repair [MMR] status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m 2 Q3W or paclitaxel 80 mg/m 2 QW [3 weeks on/1 week off]). Primary endpoints were PFS by blinded independent central review per RECIST version 1.1 and OS. One hundred four patients were randomized in Japan (data cutoff, October 26, 2020; median follow-up, 11.8 [range, 1.1-26.9] months). Hazard ratios (HRs) for PFS with lenvatinib plus pembrolizumab versus TPC were 1.04 (95% CI, 0.63-1.73) in patients with pMMR and 0.81 (0.50-1.31) in all-comers. Hazard ratios for OS were 0.74 (0.41-1.34) with pMMR and 0.59 (0.33-1.04) for all-comers. Adverse events were manageable and led to discontinuation of one/both study drugs in 36.5% of patients in the lenvatinib plus pembrolizumab group versus 7.8% in the TPC group. Similar to the global Study 309/KEYNOTE-775 results, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum-based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A pyrene dimer (PYD) is synthesized by electrochemical oxidation via homocoupling of pyrene (PY) inside the pores of MgO-templated mesoporous carbons without any metal catalysts or organic solvents. The resulting MgO-C/PYD hybrids can be used as high-performance aqueous electrochemical capacitor electrodes due to the reversible redox property of PYD and large contact area between the hybridized PYD and conductive carbon surfaces, which enable rapid charge transfer at the large contact interface. In our previous study, PY was considered to polymerize through electrochemical oxidation, and activated carbon with the pore sizes of ∼4 nm was used as a porous carbon substrate. In this study, the MgO-templated carbons have the average pore sizes of 5, 10, and 30 nm, and their large mesopore volumes can accommodate a large amount of PYD for enhancing the capacitance. To develop high-performance electrochemical capacitors, the dependence of the capacitance enhancement and the capacitance retention on the amount of PY and the pore sizes of MgO-templated carbons are studied. It is found that mesopores are necessary for fast charging/discharging, but the capacitance retention and capacitance enhancement decrease with increasing the mesopore sizes and the amount of PY due to the decreased utilization ratio of PY., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

It is difficult to identify patients with isolated dizziness caused by cerebrovascular events. The estimated risk of cerebrovascular events in isolated dizziness patients is not completely understood. We aimed to evaluate the association of the finger-to-nose test (FNT) in diagnosing cerebrovascular events in isolated dizziness patients in emergency departments (EDs). We combined 2 datasets from a single center for consecutive isolated dizziness patients, with the same inclusion and exclusion criteria. Those who met any of the following criteria were excluded: no FNT data, age < 16 years, and psychological trauma. The primary outcome was cerebrovascular event, which was defined as cerebral stroke due to cerebral infarction, cerebral hemorrhage, vertebral artery dissection, or transient ischemic attack. In the combined dataset, there were 357 patients complaining of isolated dizziness and 31 cerebrovascular events. After adjusted by 5 previously reported risk factors for cerebrovascular event, (age, hypertension, hyperlipidemia, diabetes mellitus, nystagmus), a multivariable logistic model analysis showed that the existence of FNT abnormalities was significantly associated with cerebrovascular events (odds ratio, 25.3; 95% confidence interval, 7.3-88.2; p < 0.001). There was a significant increase in predictive accuracy, with an AUC increase of 0.116 in the in a ROC analysis (p = 0.023). The existence of FNT abnormalities is considered as a strong risk factor that could be useful for predicting cerebrovascular events in isolated dizziness patients. We recommend the FNT for screening isolated dizziness patients in EDs to judge whether they need to undergo further diagnostic evaluation., Competing Interests: We declare that we have no conflicts of interest.

Background: The oxygen extraction fraction (OEF) has been applied to identify ischemic penumbral tissue, but is difficult to use in an urgent care setting. This study aimed to investigate whether an OEF map generated via magnetic resonance quantitative susceptibility mapping (QSM) could help identify the ischemic penumbra in patients with acute ischemic stroke., Materials and Methods: This prospective imaging study included 21 patients with large anterior circulation vessel occlusion who were admitted <24 h after stroke onset and 21 age-matched healthy controls. We identified the ischemic penumbra as the region with a Tmax of >6 s during dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) and calculated the perfusion-core mismatch ratio between the ischemic penumbra and infarct core volumes. The OEF values were measured based on magnetic susceptibility differences between the venous structures and brain tissues using rapid QSM acquisition. Volumes with increased OEF values were compared to the ischemic penumbra volumes using an anatomical template., Results: Eleven patients had a perfusion-core mismatch ratio of ≥1.8, and reperfusion therapy was recommended. In these patients, the volumes with increased OEF values of >51.5%, which was defined using the anterior circulation territory OEF values from the 21 healthy controls, were positively correlated with the ischemic penumbra volumes ( r = 0.636, 95% CI: 0.059 to 0.895, P = 0.035) and inversely correlated with the 30-day change in the National Institutes of Health Stroke Scale scores ( r = -0.624, 95% CI: -0.891 to -0.039, P = 0.041)., Conclusion: Tissue volumes with increased OEF values could predict ischemic penumbra volumes based on DSC-MRI, highlighting the potential of the QSM-derived OEF map as a penumbra biomarker to guide treatment selection in patients with acute ischemic stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Uchida, Kan, Inoue, Oomura, Shibata, Kano, Kuno, Usami, Takada, Yamada, Kudo and Matsukawa.)

Introduction: Microsoft Kinect V2 ® (Kinect) is a peripheral device of Xbox ® and acquires information such as depth, posture, and skeleton definition. In this study, we investigated whether Kinect can be used for human gait analysis., Methods: Ten healthy volunteers walked 20 trials, and each walk was recorded by a Kinect and infrared- and marker-based-motion capture system. Pearson's correlation and overall agreement with a method of meta-analysis of Pearson's correlation coefficient were used to assess the reliability of each parameter, including gait velocity, gait cycle time, step length, hip and knee joint angle, ground contact time of foot, and max ankle velocity. Hip and knee angles in one gait cycle were calculated in Kinect and motion capture groups., Results: The coefficients of correlation for gait velocity (r = 0.92), step length (r = 0.81) were regarded as strong reliability. Gait cycle time (r = 0.65), minimum flexion angle of hip joint (r = 0.68) were regarded as moderate reliability. The maximum flexion angle of the hip joint (r = 0.43) and maximum flexion angle of the knee joint (r = 0.54) were regarded as fair reliability. Minimum flexion angle of knee joint (r = 0.23), ground contact time of foot (r = 0.23), and maximum ankle velocity (r = 0.22) were regarded as poor reliability. The method of meta-analysis revealed that participants with small hip and knee flexion angles tended to have poor correlations in maximum flexion angle of hip and knee joints. Similar trajectories of hip and knee angles were observed in Kinect and motion capture groups., Conclusions: Our results strongly suggest that Kinect could be a reliable device for evaluating gait parameters, including gait velocity, gait cycle time, step length, minimum flexion angle of the hip joint, and maximum flexion angle of the knee joint., (© The Authors, published by EDP Sciences, 2022.)

Verticillium dahliae is a widespread soilborne fungus that causes Verticillium wilt on numerous economically important plant species. In tomato, until now, three races have been characterized based on the response of differential cultivars to V. dahliae, but the genetic basis of race divergence in V. dahliae remains undetermined. To investigate the genetic basis of race divergence, we sequenced the genomes of two race 2 strains and four race 3 strains for comparative analyses with two known race 1 genomes. The genetic basis of race divergence was described by the pathogenicity-related genes among the three races, orthologue analyses, and genomic structural variations. Global comparative genomics showed that chromosomal rearrangements are not the only source of race divergence and that race 3 should be split into two genotypes based on orthologue clustering. Lineage-specific regions (LSRs), frequently observed between genomes of the three races, encode several predicted secreted proteins that potentially function as suppressors of immunity triggered by known effectors. These likely contribute to the virulence of the three races. Two genes in particular that can act as markers for race 2 and race 3 ( VdR2e and VdR3e , respectively) contribute to virulence on tomato, and the latter acts as an avirulence factor of race 3. We elucidated the genetic basis of race divergence through global comparative genomics and identified secreted proteins in LSRs that could potentially play critical roles in the differential virulence among the races in V. dahliae. IMPORTANCE Deciphering the gene-for-gene relationships during host-pathogen interactions is the basis of modern plant resistance breeding. In the Verticillium dahliae-tomato pathosystem, two races (races 1 and 2) and their corresponding avirulence ( Avr ) genes have been identified, but strains that lack these two Avr genes exist in nature. In this system, race 3 has been described, but the corresponding Avr gene has not been identified. We de novo -sequenced genomes of six strains and identified secreted proteins within the lineage-specific regions (LSRs) distributed among the genomes of the three races that could potentially function as manipulators of host immunity. One of the LSR genes, VdR3e , was confirmed as the Avr gene for race 3. The results indicate that differences in transcriptional regulation may contribute to race differentiation. This is the first study to describe these differences and elucidate roles of secreted proteins in LSRs that play roles in race differentiation.

To protect against COVID-19, SARS-CoV-2 vaccines have been widely used. Besides anaphylaxis, some less severe adverse effects may occur at higher frequencies. It remains unclear whether present or past histories of allergic diseases exert effects on local and systemic reactions. We conducted a questionnaire survey among workers in our hospital. We analyzed the adverse effects occurring after the first and second doses of the Pfizer-BioNTech vaccine in 955 subjects. The presence or absence of local injection reactions and systemic reactions (headache, fatigability, fever, muscle pain, and joint pain) was questioned. The intensities of these reactions were graded on a scale of 0-4 (except fever) or 0-2 (fever). The allergic diseases that we focused on were bronchial asthma, atopic dermatitis, food allergy, pollinosis, and hand eczema. For the systemic reactions, fatigability after the first dose tended to be more severe in the bronchial asthma than in the non-allergic group. Headache, joint pain, and fever tended to be more severe in the food allergy than in the non-allergic group after the second dose. For the local skin reactions, atopic dermatitis subjects tended to show rather less severe local skin reactions after the second dose. The results contribute to the guidelines for the care of individuals with different allergy histories, so that they may safely receive their vaccine.