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AbstractInsurers are the largest institutional investors of corporate bonds. However, a standard theory of insurance markets, in which insurers maximize firm value subject to regulatory or risk constraints, predicts no allocation to corporate bonds. We resolve this puzzle in an equilibrium asset pricing model with leverage-constrained households and institutional investors. Insurers have relatively cheap access to leverage through their underwriting activity. They hold a leveraged portfolio of low-beta assets in equilibrium, relaxing other investors’ leverage constraints. The model explains recent empirical findings on insurers’ portfolio choice and its impact on asset prices. (JEL G11, G12, G22, G23)

CYP105A1 from Streptomyces griseolusconverts vitamin D3 to its biologically active form, 1α,25-dihydroxy vitamin D3. R73A/R84A mutation enhanced the 1α- and 25-hydroxylation activity for vitamin D3, while M239A mutation generated the 1α-hydroxylation activity for vitamin D2. In this study, the stability of six CYP105A1 enzymes, including 5 variants (R73A/R84A, M239A, R73A/R84A/M239A (=TriA), TriA/E90A, and TriA/E90D), was examined. Circular dichroism analysis revealed that M239A markedly reduces the enzyme stability. Protein fluorescence analysis disclosed that these mutations, especially M239A, induce large changes in the local conformation around Trp residues. Strong stabilizing effect of glycerol was observed. Nondenaturing PAGE analysis showed that CYP105A1 enzymes are prone to self-association. Fluorescence analysis using a hydrophobic probe 8-anilino-1-naphthalenesulfonic acid suggested that M239A mutation enhances self-association and that E90A and E90D mutations, in cooperation with M239A, accelerate self-association with little effect on the stability.Graphical AbstractM239A mutation of CYP105A1 reduced stability and enhanced self-association. Both E90A and E90D, together with M239A, accelerated self-association without effect on stability.

In recent years, laser-driven neutron sources have attracted attention for their applications such as nondestructive analysis and the production of medical radioisotopes. One of the efficient neutron production methods is the use of the 9Be(d, n)10B reaction on a beryllium target with deuterons accelerated by laser–plasma interactions, since this is an exothermic reaction. For efficient deuteron acceleration, we have developed a formation system for solid deuterium targets. A millimeter thick solid deuterium target can be formed with the system. Before the laser shot, the solid deuterium target in the laser chamber can be mechanically moved to the laser irradiation point. We have demonstrated deuteron acceleration by the LFEX laser, and a highly pure deuteron pulse with energies of up to 6.2 MeV was measured with a Thomson parabola ion spectrometer.

Here, we present an overview on the recent progress in the development of the laser-driven neutron source (LDNS) and nuclear resonance absorption (NRA) imaging at the Institute of Laser Engineering (ILE), Osaka University. The LDNS is unique because the number of neutrons per micro pulse is very large, and the source size and the pulse width are small. Consequently, extensive research and development of LDNSs is going on around the world. In this paper, a typical neutron generation process by the laser-driven ion beam, called the pitcher–catcher scheme, is described. The characteristics of the LDNS are compared with those of the accelerator-driven neutron source (ADNS), and unique application of the LDNS, such as NRA imaging, is presented. In the LDNS, NRA imaging is possible with a relatively short beam line in comparison with that of the ADNS since the neutron pulse width and the source size of the LDNS are small. Future prospects in research and development of NRA imaging with the LDNS at ILE Osaka University are also described.

Coastal wetlands are highly sensitive to changes occurring at the coastline. It is critically important to determine region‐specific projections for these areas due to their specificities and vulnerabilities to climate change. This work aimed to value the impacts of recent climate changes at West Africa Sahara coastland, southern Morocco, at Khnifiss Lagoon. We have applied a combined approach using remote sensing techniques and environmental reconstructions based on high‐resolution analysis of sediment cores, covering the current warm period. Remote sensing highlighted changes to the lagoon inlet, accompanied by a greater meandering character of the tidal channels. As a response, the sediment cores have recorded a predominant vegetation substitution due to changes in the tidal limit, and an increase in organic carbon accumulation was observed. For the current climatology, during positive phases of the North Atlantic Oscillation, winds reaching the coast strengthen in an east‐to‐west direction. In the Khnifiss Lagoon, whose inlet is dominated by the ebb tide, the intensity and direction of the winds on the coast at surface level modifies its connection to the ocean by increasing sediment transport toward the interior of the lagoon. Locally biological responses to wind intensification, and possibly sea‐level rise, exemplify the lagoon sensitivity to large‐scale processes. Coastal vegetated wetlands are considered to be highly dynamic environments. However, we expect a loss of the upper tidal vegetation due to boundary conditions limiting the accommodation space in this arid environment in a possible future scenario of continuously inland tidal line displacement.

地方における小児重症外傷患者の診療体制を明らかにし，集約化の課題を抽出するため，2016年から2020年までに小児集中治療室（pediatric intensive care unit: PICU）に入室した15歳以下の小児外傷患者を対象とした。診療録を用いて後方視的に検討を行い，対象は113例，injury severity score >15の症例は55例（48.6%），probability of survival ≦ 50%の症例は2例（1.8%）であった。外傷部位は，頭頸部が最多の57例（50.4%），多発外傷は13例（11.5%）であった。搬送手段は，救急車・ドクターカーによる陸路搬送とドクターヘリ・防災ヘリによる空路搬送の2群間において搬送距離の分布に有意差のあるばらつきがあった。搬送距離が40kmを超える症例が空路搬送では11例（55.0%），陸路搬送でも14例（19.5%）あった。陸路搬送の14例のうち12例は空路搬送の運行時間外であった。地方で小児重症外傷患者を集約化しても症例数は少なく，同時に空路搬送が不可能な状況では陸路での長距離搬送をせざるを得ない症例があった。集約化の方法に関して，搬送方法を含めた診療体制の整備が必要であることが示唆された。 To elucidate the medical care system for pediatric patients with severe trauma in local communities and identify problems associated with the consolidation of their care. The study included patients with severe trauma aged ≤15 years who were in the pediatric intensive care unit from 2016 to 2020. The status of patients’ care was retrospectively examined using medical records. Among 113 patients, 55 (48.6%) had an injury severity score of >15 and two (1.8%) had a survival probability of ≤50%. We investigated the mode of transportation by categorizing the various modes into two groups: overland and air transportation. The results showed a significant degree of variation with respect to transport distance. Patients transported more than 40 km included 11 (55.0%) who were transported by air and 14 (19.5%) who were transported overland. Among 14 patients who were transported ground, 12 were transported when air transportation was unavailable. Even when patients with severe trauma in local communities are consolidated, the number of patients is small. Furthermore, some patients were transported ground for long distances owing to the unavailability of air transportation. This finding suggests that it would be necessary to revise the medical care system, including modes of transportation, to consolidate patients.

AbstractAmong 1,770 healthcare workers serving in high-risk care areas for coronavirus disease 2019 (COVID-19), 39 (2.2%) were seropositive. Exposure to severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in the community was associated with being seropositive. Job or unit type and percentage of time working with COVID-19 patients were not associated with positive antibody tests.

The accurate measurement of the 3D dose distribution of carbon-ion beams is essential for safe carbon-ion therapy. Although ionization chambers scanned in a water tank or air are conventionally used for this purpose, these measurement methods are time-consuming. We thus developed a rapid 3D dose-measurement tool that employs a silver-activated zinc sulfide (ZnS) scintillator with lower linear energy transfer (LET) dependence than gadolinium-based (Gd) scintillators; this tool enables the measurement of carbon-ion beams with small corrections. A ZnS scintillator sheet was placed vertical to the beam axis and installed in a shaded box. Scintillation images produced by incident carbon-ions were reflected with a mirror and captured with a charge-coupled device (CCD) camera. A 290 MeV/nucleon mono-energetic beam and spread-out Bragg peak (SOBP) carbon-ion passive beams were delivered at the Gunma University Heavy Ion Medical Center. A water tank was installed above the scintillator with the water level remotely adjusted to the measurement depth. Images were recorded at various water depths and stacked in the depth direction to create 3D scintillation images. Depth and lateral profiles were analyzed from the images. The ZnS-scintillator-measured depth profile agreed with the depth dose measured using an ionization chamber, outperforming the conventional Gd-based scintillator. Measurements were realized with smaller corrections for a carbon-ion beam with a higher LET than a proton. Lateral profiles at the entrance and the Bragg peak depths could be measured with this tool. The proposed method would make it possible to rapidly perform 3D dose-distribution measurements of carbon-ion beams with smaller quenching corrections.

A labscale continuous CO2capture system for coal-fired power plants with amine-impregnated solid sorbents was optimized using process simulation. The system comprises three-column fixed-bed sorbents, and a steam-aided vacuum swing absorption (SA-VSA) was used as the CO2capture/recovery process. The simulation was performed using Aspen Adsorption V10. First, the effect of three sensitive parameters, namely, regeneration steam volume, rinsing time, and feed-gas moisture, was simulated and the obtained results were compared with the experimental values. As a result, the simulated values agreed well with those of the experimentals. After the reliability of the simulator has been demonstrated, a cycle time and each process time was optimized by the simulation. As a result, the potential for further reduction of the regeneration heat without lowering the amount of CO2capture was measured by simulation. Finally, the simulation-suggested process was experimentally confirmed and then optimized with 540 s of cycle time, which successfully demonstrated a minimum regeneration heat of 1.2 GJ/t-CO2(not including electric energy of vacuum pump) with high recovery rate (≥90%), purity (≥99%), and continuous CO2capturing. Therefore, this simulation-based optimization technique would be useful for optimizing the CO2capture process with an amine-impregnated solid sorbent.

The movement of the small ribosomal subunit (30S) relative to the large ribosomal subunit (50S) during translation is widely known, but many molecular details and roles of rRNA and proteins in this process are still undefined, especially in solution models. The functional relationship of modified nucleotides to ribosome activity is one such enigma. To better understand ribosome dynamics and the influence of modified nucleotides on such processes, the focus of this work was helix 69 of 23S rRNA, which contains three pseudouridine residues in its loop region. Ribosome probing experiments with dimethylsulfate revealed that specific base accessibilities and individual nucleotide conformations in helix 69 are influenced differently by pH, temperature, magnesium, and the presence of pseudouridine modifications.

A series of efficient adsorbents for CO2capture was prepared by a wet-impregnation method. Mesostructured cellular silica foam (MF) was selected as a support and modified with a mixture of tetraethylenepentamine (TEPA) and imidazoles (Ims) to improve the initial and working CO2-adsorption capacity. The heat of adsorption was also evaluated. The impact of different amines and the adsorption temperature on CO2-adsorption performance was investigated. Some Ims showed a synergistic effect with TEPA regarding adsorption/desorption performance. Impregnating MF with such Ims and TEPA increased CO2-adsorption performance and decreased the heat of absorption compared with those obtained for MF impregnated only with TEPA. MF modified with 30 wt % 4-methylimidazole and 40 wt % TEPA exhibited a high first-pass CO2adsorption capacity of 4.88 mmol/g at 100 kPa and 40 °C. Following vacuum regeneration, a working capacity of 4.15 mmol/g was observed for the same conditions.

Technology to visualize small prostate cancers is urgently needed because of the difficulty of discriminating prostate cancer from normal tissue with the naked eye, and a fluorescence imaging method would be advantageous. Here, we describe the design and synthesis of a fluorogenic probe (Ac–KQLR–HMRG) that is activated by hepsin and matriptase (proteases over-expressed in prostate cancer). Ac–KQLR–HMRG exhibited significant turn-on fluorogenicity in the presence of hepsin (180-fold) and matriptase (80-fold) and allowed specific fluorescence imaging of various prostate cancer cell line in vitro. In addition, the probe enabled rapid imaging (within 1–10 min) of small prostate cancer nodules in mouse models of disseminated peritoneal tumor and orthotopic tumor.

It is important to select reliable tools that archers should use in archery competitions. For this reason, we focused on the arrows among the tools and developed a shooting machine for selecting arrows. It is important to imitate the movement of the right finger to release the arrow and the forward movement of the bow after the arrow is released. Therefore, these factors were considered when designing the machine. In this study, a shooting experiment was conducted in which the shooting cycle of twelve ends of six arrows was repeated five times (one end is defined as six arrows). Next, using the data from the impact points on the target, specific arrows with a large dispersion were identified. Cluster analysis was then conducted to identify the arrows that showed a high similarity distribution. Based on the above results, we were able to identify arrows with the most flaws and select arrows that archers should use. The results indicate the effectiveness of the method of selecting reliable arrows by rejecting flawed arrows.

Despite the recent advances in the life sciences and the remarkable investment in drug discovery research, the success rate of small-molecule drug development remains low. Safety is the second most influential factor of drug attrition in clinical studies; thus, the selection of compounds with fewer toxicity concerns is crucial to increase the success rate of drug discovery. Compounds that promiscuously bind to multiple targets are likely to cause unexpected pharmacological activity that may lead to adverse effects. Therefore, avoiding such compounds during early research stages would contribute to identifying compounds with a higher chance of success in the clinic. To evaluate the interaction profile against a wide variety of targets, we constructed a small-scale promiscuity panel (PP) consisting of eight targets (ROCK1, PDE4D2, GR, PPARγ, 5-HT2B, adenosine A3, M1, and GABAA) that were selected from diverse gene families. The validity of this panel was confirmed by comparison with the promiscuity index evaluated from larger-scale panels. Analysis of data from the PP revealed that both lipophilicity and basicity are likely to increase promiscuity, while the molecular weight does not significantly contribute. Additionally, the promiscuity assessed using our PP correlated with the occurrence of both in vitrocytotoxicity and in vivotoxicity, suggesting that the PP is useful to identify compounds with fewer toxicity concerns. In summary, this small-scale and cost-effective PP can contribute to the identification of safer compounds that would lead to a reduction in drug attrition due to safety issues.

C-reactive protein (CRP) is a powerful biomarker for inflammation, infection and sepsis. However, no reports have investigated canine CRP (c-CRP) concentration changes after orthopaedic procedures. If c-CRP changes were better characterized, it may be possible to identify postoperative complications more quickly. The purpose of this study was to clarify the characteristic changes in serum c-CRP after orthopaedic surgery in dogs. Blood samples were collected from 98 dogs on Day 0 (preoperatively), and then on Days 1, 4, 7, 10 and 13 postoperatively. Day 1 blood sampling was performed 12–24 h postoperatively. We classified the dogs into four groups based on changes in c-CRP pre- to postoperatively. Group 1 dogs showed a peak c-CRP concentration on Day 1, followed by decreases of ≥ 1 mg/dL. Group 2 dogs showed changes in c-CRP concentration by Day 4 that were within ± 1 mg/dL compared with Day 1. Dogs in Group 3 showed a peak c-CRP concentration on Day 4, followed by decreases of ≥ 1 mg/dL. Group 4 dogs showed an initial decrease in c-CRP, then an increase of ≥ 1 mg/dL. Group 1 was the largest group, with 63 dogs. c-CRP on Days 0, 1, 4, 7, 10 and 13 was 0.83 ± 1.03 mg/dL, 8.10 ± 3.15 mg/dL, 3.76 ± 1.94 mg/dL, 1.63 ± 0.92 mg/dL, 0.96 ± 0.70 mg/dL and 0.68 ± 0.51 mg/dL, respectively. Serum c-CRP concentration on Day 1 was significantly higher than at every other timepoint (P < 0.001). In Group 2, surgical site complications were confirmed in 9/15 dogs. In Group 3, surgical site complications were confirmed in 7/14 dogs. In Group 4, two surgical site problems and three surgical site infections were observed, and visceral disease was found in one dog. In Group 1, peak c-CRP was seen on Day 1 postoperatively in 63 dogs (64%), with c-CRP level decreasing by half at each subsequent measurement, which may describe a typical c-CRP change in orthopaedic patients. If deviation from this typical change is observed postoperatively, as in Groups 2–4, this may suggest possible complications.

Cells undergo continual transformations, never retaining their original state. Hematopoietic stem cells (HSCs), at the apex of the hematopoietic hierarchy, are not exempt from this dynamic process. In recent years, the advent of single-cell analysis techniques such as scRNAseq has progressively unveiled the heterogeneity within cell populations previously presumed to be homogeneous. However, these techniques are limited to evaluating the cellular state at a single temporal point based on snapshot analysis, thus failing to account for temporal changes and dynamic behavior of cells. Therefore, the true diversity inherent to the ever-changing HSCs remains uncertain.

The treatment outcomes of multiple myeloma (MM) have drastically improved with the use of novel agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies. However, ultimately, the disease relapses and results in a fatal outcome. Even in cases of relapse, treatment outcomes have improved with the use of novel agents. However, in situations where novel agents have been exhausted or when the disease rapidly progresses, bortezomib (Velcade), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD-PACE) is frequently utilized, with reported effectiveness. However, its outcomes in the era of monoclonal antibodies remain unclear. Therefore, this retrospective cohort study assessed the clinical outcomes of 60 patients with RRMM (median four prior treatment lines) administered VTD-PACE at the Japanese Red Cross Medical Center between June 2016 and April 2023. The characteristics of the 60 patients are shown in Table 1. The VTD-PACE regimen consisted of 1 mg/m 2of bortezomib on days 1, 4, 8, and 11 administered subcutaneously; 200 mg of thalidomide administered orally on days 1-4; 40 mg of dexamethasone administered orally on days 1-4; and a 4-day continuous intravenous infusion of 10 mg/m 2cisplatin, 40 mg/m 2cyclophosphamide, 40 mg/m 2etoposide, and 10 mg/m 2doxorubicin. The cisplatin dose was adjusted based on renal function, as determined by the treating physician. The responses were evaluated according to the International Myeloma Working Group response criteria. High-risk cytogenetic abnormalities (HRCA) included del (17p), t(4;14), and t(14;16). Double-class refractory disease was defined as refractoriness to PIs and IMiDs, whereas triple-class refractory disease was defined as refractoriness to PIs, IMIDs, and anti-CD38 monoclonal antibodies. Penta-drug refractory disease was defined as refractoriness to bortezomib, carfilzomib, lenalidomide, pomalidomide, and anti-CD38 antibodies. The median follow-up period was 11.1 months (range, 0.5-72.0 months), during which they received a median of two cycles of VTD-PACE. The overall response (ORR), stringent complete response, complete response, and very good partial response rates were 66.7% (40 patients), 13.3% (8 patients), 5% (3 patients), and 20% (12 patients), respectively. The results of univariate analysis for factors associated with response rate are shown in Table 2. The ORRs in patients with ≥4 and ≤3 prior lines were 53.1% and 82.1%, respectively ( P= 0.027). Extramedullary disease (EMD), refractoriness to anti-CD38 antibody, HRCA, and triple-class/penta-drug refractory disease did not significantly reduce the ORR. The median overall survival (OS) was 17 months with a median progression-free survival (PFS) of 9.8 months. The median PFS in patients with and without receiving hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell therapy (CART) following VTD-PACE were 9.8 and 5.1 months, respectively ( P= 0.023). The median OS in patients with and without renal dysfunction were 10.7 months and 21.5 months, respectively ( P= 0.0091). A trend for longer OS was observed in patients with HSCT or CART following VTD-PACE (P = 0.18). Therefore, VTD-PACE is useful as a bridging therapy for HSCT or CART, as a response is expected regardless of organ damage, disease risk, or history of anti-CD38 antibody use. However, the response rate decreased in late lines; therefore, its use in early lines is recommended.

Amine-functionalized materials have been widely investigated as promising candidates for CO2capture. However, they are prone to degradation in the presence of O2, resulting in loss in the CO2capture ability as well as a decrease in the sorbent lifetime. In this study, we evaluated the effect of different oxidation inhibitors on degradation of polyamines, including tetraethylenepentamine- and polyethylenimine-impregnated mesoporous silica. Sulfur-containing compounds and traditional antioxidants were selected as additives. Oxidative degradation tests of the amine solid sorbents were performed in a packed-bed reactor equipped with a temperature controller. The results showed that traditional antioxidants, such as butylated hydroxytoluene, N,N′-diphenyl-1,4-phenylenediamine, N,N′-di-2-butyl-1,4-phenylenediamine, 2,2′-thiodiethylene bis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], and pentaerythritol tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], catalyzed oxidative degradation. In contrast, sulfur-containing additives, which owe their effectiveness to free-radical scavenging and peroxide decomposition actions, decreased the oxidation rate. Amine solid sorbents containing such additives had 1.5–2 times higher CO2adsorption capacity retention values than the nonadditive sorbents under accelerated oxidation conditions. Furthermore, the long-term stability of the amine solid sorbents over 15 months storage was demonstrated. These sulfur-containing additives also delayed sorbent degradation.

The stability of silica impregnated with commercial tetraethylenepentamine (TEPA) under accelerated oxidizing conditions was evaluated, and the changes in the composition of sorbents during oxidative degradation were first reported. The oxidative stability of sorbents depended on the TEPA loading, oxidation duration, temperature, and O2concentration. The marked loss of the CO2adsorption capacity of the sorbents in O2-containing environments was mainly caused by changes in the functional groups of TEPA and the sorbent composition, as supported by thermogravimetric, elemental, infrared spectroscopic, and gas chromatography analyses. The results suggested that the hydroxyl groups of silica help to protect TEPA from oxidation. The pore and surface characteristics of sorbent have a significant influence on the O2diffusion, regulating the oxidation rate. Among isolated components in commercial TEPA, 1,4,7,10,13-pentaazatridecane, 4-(2-aminoethyl)-N-(2-aminoethyl)-N′-[2-[(2-aminoethyl)amino]ethyl]-1,2-ethanediamine, and 1-[2-[[2-[(2-aminoethyl)amino]ethyl]amino]ethyl]piperazine were revealed to be sensitive to O2, whereas 1-(2-aminoethyl)-4-[[(2-aminoethyl)amino]ethyl]piperazine displayed strong O2resistance.

Supplemental Digital Content is available in the text.

Prolonging the circulation time (CT) of microparticles (MPs) in the blood is key for a successful microparticle-based medicinal approach to serve as drug delivery systems (DDSs). Previously, we reported that MPs that mimic the shape of red blood cells (RBCs) avoid accumulation in the spleen and lungs. We now describe the effectiveness of mimicking not only the shape of RBCs but also their surface structure for the prolongation of CT. RBC-shaped MPs (RBC-MPs) were electrosprayed with cellulose and covered with a native RBC membrane (RBCM) collected from mouse blood. Seven hours after intravenous injection, approximately twice as many RBCM-covered RBC-MPs (RBC-MPs@RBCM) were present in the blood of mice compared to unmodified RBC-MPs. Twenty-four hours postinjection, the concentration of RBC-MPs@RBCM in the blood was 4 times higher. These findings suggest that an RBCM covering the MPs contributed to significant CT prolongation, which may positively impact their applications as DDSs.