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Abstract Amphipathic arginine-rich peptide, A2-17, exhibits moderate perturbation of lipid membranes and the highest cell penetration among its structural isomers. We investigated the direct cell-membrane penetration mechanism of the A2-17 peptide while focusing on structural flexibility. We designed conformationally constrained versions of A2-17, stapled (StpA2-17) and stitched (StchA2-17), whose α-helical conformations were stabilized by chemical crosslinking. Circular dichroism confirmed that StpA2-17 and StchA2-17 had higher α-helix content than A2-17 in aqueous solution. Upon liposome binding, only A2-17 exhibited a coil-to-helix transition. Confocal microscopy revealed that A2-17 had higher cell penetration efficiency than StpA2-17, whereas StchA2-17 remained on the cell membrane without cell penetration. Although the tryptophan fluorescence analysis suggested that A2-17 and its analogs had similar membrane-insertion positions between the interface and hydrophobic core, StchA2-17 exhibited a higher membrane affinity than A2-17 or StpA2-17. Atomic force microscopy demonstrated that A2-17 reduced the mechanical rigidity of liposomes to a greater extent than StpA2-17 and StchA2-17. Finally, electrophysiological analysis showed that A2-17 induced a higher charge influx through transient pores in a planer lipid bilayer than StpA2-17 and StchA2-17. These findings indicate that structural flexibility, which enables diverse conformations of A2-17, leads to a membrane perturbation mode that contributes to cell membrane penetration.

Abstract Purpose There is no consensus concerning restarting anti-tumour necrosis factor (TNF)-α therapy for uveitis after treatment for active tuberculosis (TB). We report a case of Behcet disease (BD) in which treatment with TNF inhibitor was successfully resumed after treatment for miliary TB. Case report A 48-year-old Japanese male was treated for uveitis of unknown aetiology in the left eye at a general ophthalmology clinic. He was referred to Department of Ophthalmology, Tokyo Medical University Hospital because of macula oedema (ME) not responding to prednisolone (PSL) 20 mg. BD was diagnosed based on fluorescein angiographic findings of diffuse retinal vasculitis characteristic of BD, recurrent oral aphthous ulcer, erythema nodosum-like rash in his legs, and HLA-A26 positivity. After a screening test, adalimumab (ADA) was started as steroid-sparing therapy. Eight months after starting ADA, the patient was diagnosed with miliary TB. ADA and PSL were discontinued immediately due to TB. Anti-TB treatment was completed after 6 months based on clinical improvement, although T-SPOT.TB was still positive. Infliximab with isoniazid was started due to relapse of ME, worsened vitreous haze, and worsened visual acuity in his left eye. Subsequently, his ocular symptoms subsided and there was no relapse of TB. Conclusion This case suggests that in patients with BD who have discontinued anti-TNF therapy due to miliary TB, restarting anti-TNF therapy may be a therapeutic option after TB has been treated appropriately with careful monitoring for relapse.

Abstract Risks of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to high low-density lipoprotein cholesterol levels. This study aimed to examine the impact of the severe FH status defined by the International Atherosclerosis Society (IAS). Data of patients with FH (N = 1050, male = 490) who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed up were retrospectively reviewed. The number of major adverse cardiac events (MACEs), including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1000 person-years, was calculated. Hazard ratio was also calculated using Cox proportional model. Overall, 545 (51.9%) patients had severe FH. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. Severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56–10.40, P = 1.2 × 10−5). The event rates per 1000 person-years in the primary prevention group of non-severe FH and severe FH, were 0.0 and 15.6, respectively. The event rates per 1000 person-years in the secondary prevention group of non-severe FH and severe FH, were 2.0 and 32.3, respectively. Patients with severe FH exhibited significantly higher risks in primary and secondary prevention settings. This simple criterion provides useful information for identifying patients with even higher risk who may need further management.

Abstract The bulk density of grains from a celestial body is a fundamental property related to its composition and structure, contributing to the understanding of its evolutionary history. In this study, we provide the bulk density of 637 grains returned from the C-type near-Earth asteroid 162173 Ryugu. This is the largest number of grains to date for the curation activity, corresponding to 38 wt.% of the total returned samples (approximately 5.4 g). Although several densities of the Ryugu grains were reported, the volume estimation of some samples showed uncertainties. Therefore, we applied a new volume estimation model calibrated by X-ray micro-computed tomography (XCT) to the Ryugu grains to more accurately estimate their bulk density. The obtained average bulk density of 637 Ryugu grains was 1.79 ± 0.31 g/cm3 (1σ variation) for weights of 0.5‒100 mg (sub-mm ‒to 10 mm) irrespective of their 3D shapes characterized by three axial length ratios, considered to be a representative of the returned samples. The bulk density distributions of the grains in Chambers A and C were statistically distinguishable, with mean values of 1.81 ± 0.30 and 1.76 ± 0.33 g/cm3 (1σ variations), respectively. Despite the small difference, bulk density may have differed by sampling site. The obtained average bulk density value of A + C samples was almost the same as that of 16 Ryugu grains estimated based on CT scanned data, and was consistent with the densities of CI chondrites (1.57–1.91 g/cm3). The axial ratios of the grains in Chambers A and C were similar and those of the 724 returned samples and the flying particles ejected during the sampling operations were also similar, suggesting that relatively small Ryugu materials (mm‒cm in size) are similar in shape. The minor difference between the Rygu grains and flying particles could be attributed to events such as scraping during sampling operations and transportation. Graphical Abstract

Abstract Developing a cleanroom and clean chambers (CCs) for Hayabusa2 returned samples has been discussed with the committee for Hayabusa2 sample curation facility since 2015. One major difference from the specifications of the CCs used for Itokawa samples is that a part of samples was decided to be handled and preserved in vacuum to avoid terrestrial nitrogen contamination with organics or unknown materials that might easily react with the samples. Thus, the CCs for Hayabusa2 samples were divided into two CCs for vacuum processes and three CCs for purified nitrogen conditions. The cleanroom was built in summer 2017, while the CCs were installed in the summer of 2018. After the installation of the CCs, instruments for initial descriptions, sample containers, handling tools for powder and particle samples, and jigs to assist handling samples were developed in parallel with functional checks and repeated rehearsals between the fall of 2018 and the fall of 2020. The curatorial works on Hayabusa2-retuned samples were conducted as previously planned. Simultaneously, contaminations and influences of inorganics, organics, microbial, and magnetic constructs have been assessed to evaluate their potential effects on the analysis of the returned samples. Additionally, the tools used to touch samples directly have been demagnetized to avoid sample magnetization during their handling and the tool magnetization was measured before and after their usages. The series of developments and experiences from the curatorial works of Hayabusa2-returned samples represent valuable implications for future sample return missions. Graphical Abstract

Objectives: Antiemetics have been widely recommended for treating opioid-induced nausea and vomiting (OINV). According to a previous study, the use of prophylactic prochlorperazine at the initiation of treatment with oral oxycodone was ineffective in preventing OINV. This study examined whether prochlorperazine injection prevents OINV and induces drowsiness in patients with end-stage cancer (a different patient population from the previous study). Methods: Patients with end-stage cancer who received opioid injections for more than 5 days between April 2017 and March 2020 were classified into two groups: the opioid and prochlorperazine injection group and opioid alone group. Their systemic conditions were evaluated on the basis of the performance status and the palliative performance scale, a prognostic indicator. Results: Of 325 patients who received opioid treatment during the study period, 156 patients met the inclusion criteria. Of these, 103 patients and 53 patients were classified into the opioid and prochlorperazine injection group (prochlorperazine) and opioid alone groups (placebo) , respectively. There was no significant difference in characteristics, age, gender, performance status, or palliative performance scale results between the 2 groups. OINV developed in 4 patients in the opioid and prochlorperazine injection groups and in 1 patient in the opioid alone group. Given that sleep disturbance develops in many patients with end-stage cancer who had a specific condition, it is difficult to conclude regarding the relationship between prochlorperazine injection and drowsiness, although this study examined this relationship. Conclusions: As with the previous study, prophylactic prochlorperazine injection was ineffective in preventing OINV in patients who received opioid injections.

Abstract Approximately one-third of fibrosing interstitial lung diseases exhibit progressive pulmonary fibrosis (PPF), a clinicopathological condition distinct yet resembling idiopathic pulmonary fibrosis (IPF). PPF in ANCA-positive ILD (ANCA-ILD) is poorly documented. To clarify incidence, predictors of PPF in ANCA-ILD, and their prognostic impact, 56 patients with ANCA-ILD were followed for ≥ 1 year (April 2004 to April 2021). PPF was defined per ATS/ERS/JRS/ALAT PPF 2022 guideline. We compared PPF and non-PPF in 38 patients with pulmonary function tests and ≥ 1 year follow up. ANCA-ILD (19 male, 19 female; mean age 72 years) comprised 21 patients with microscopic polyangiitis ILD (MPA-ILD) and 17 with ANCA-positive IP without systemic vasculitis (ANCA-IP). PPF occurred in 15/38 (39.5%) overall, and 27% of patients with MPA-ILD and 53% with ANCA-IP. Patient characteristics did not differ between PPF and non-PPF, however, the survival was significantly worse in patients with PPF than those with non-PPF. On multivariate regression analysis, higher age, higher serum SP-D level, and lower baseline %FVC were associated with PPF. In ANCA-ILD, 39.5% of patients demonstrated PPF, which is associated with increased mortality. Predictors of PPF were older age, higher SP-D, and lower baseline %FVC.

Abstract The sample from the near-Earth carbonaceous asteroid (162173) Ryugu is analyzed in the context of carbonaceous meteorites soluble organic matter. The analysis of soluble molecules of samples collected by the Hayabusa2 spacecraft shines light on an extremely high molecular diversity on the C-type asteroid. Sequential solvent extracts of increasing polarity of Ryugu samples are analyzed using mass spectrometry with complementary ionization methods and structural information confirmed by nuclear magnetic resonance spectroscopy. Here we show a continuum in the molecular size and polarity, and no organomagnesium molecules are detected, reflecting a low temperature and water-rich environment on the parent body approving earlier mineralogical and chemical data. High abundance of sulfidic and nitrogen rich compounds as well as high abundance of ammonium ions confirm the water processing. Polycyclic aromatic hydrocarbons are also detected in a structural continuum of carbon saturations and oxidations, implying multiple origins of the observed organic complexity, thus involving generic processes such as earlier carbonization and serpentinization with successive low temperature aqueous alteration.

Abstract Background This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S‐1 in patients with previously treated non‐small cell lung cancer (NSCLC) compared to docetaxel alone. Methods Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S‐1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). Results The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8–15.2) and 12.3 months (95% CI: 9.2–14.5) in arms A and B, respectively. In arms A and B, the median progression‐free survival was 3.5 months (95% CI: 2.7–4.0) and 4.1 months (95% CI: 3.2–4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682–1.419, p = 0.4569) or progression‐free survival (HR: 0.823, 95% CI: 0.528–1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. Conclusions The prematurely terminated study did not show the benefit of two cytotoxic agents over single‐agent therapy for previously treated NSCLC patients.

Abstract Many active volcanoes and various types of seismic activities exist in the southern part of the Northeast Japan subduction zone. One of the geologically most interesting features in this area is the sequential explosive eruptions of a group of volcanoes. The group consists of Mt. Azuma and Mt. Adatara on the volcanic front line, Mt. Bandai west of the volcanic front, and Mt. Numazawa on the back-arc side. A previous petrological study on the eruption products regarded Mt. Numazawa as an anomalous back-arc volcano because its lavas are similar to those of volcanoes on the volcanic front. The reason behind this unique connection was unclear, and hence, this study was intended to understand the deep fluids distribution beneath the area. For this purpose, a 3-D regional electrical resistivity structure was estimated from a series of wide-band magnetotelluric surveys, with 45 observation points deployed from the fore-arc to the back-arc sides. The most important feature of the resistivity structure is a large conductive zone in the central part of the area, spanning from the upper mantle to the lower crust. Interestingly, the lateral elongation of the conductor is oblique to the volcanic front line and consistent with the spatial distribution of the group of volcanoes and the low-frequency earthquake clusters around them. Therefore, the conductor most likely represents a large, elongated magmatic fluid reservoir beneath the volcanoes. Hydrous partial melting might be the cause of the enhanced conductivity. Graphical Abstract

Abstract In the tenuous atmospheric bodies of our solar system, space weathering on the celestial surface is an important process for its chemical and physical evolution and ambient environment on timescales of celestial evolution. Space plasma is a dominant energy and material source for space weathering. Plasma irradiation experiment in the laboratory is an effective method for modeling space weathering driven by space plasma. However, comprehensive modeling of plasma space weathering has not yet been conducted because the capabilities of the earlier facilities were not optimized for realistic space weathering; for example, the incident electron and ion were not irradiated in the same condition. Here, we developed a plasma irradiation system, Plasma Irradiation Emulator for Celestial Environments (PIECE) of the solar system bodies, which reproduces plasma space weathering in tenuous atmospheric bodies by the electron and ion irradiations in the same condition. We successfully developed a system with high electron and ion number fluxes of $$\sim 10^{13} - 10^{16} {\text{ particles cm}}^{{ - {2}}} {\text{s}}^{{ - {1}}}$$ ∼ 10 13 - 10 16 particles cm - 2 s - 1 at any acceleration energy in the range of 1–30 keV, which leads to a fluence of e.g., $$\sim 10^{18} - 10^{21} {\text{ particles cm}}^{{ - {2}}} {\text{s}}^{{ - {1}}}$$ ∼ 10 18 - 10 21 particles cm - 2 s - 1 , with a 1-day irradiation time. This fluence corresponds to a plasma irradiation time of ~ 103–106 years on Europa. Graphical Abstract

Abstract The Kuroshio Extension (KE) flows eastward at the northern boundary of the North Pacific subtropical gyre. By transporting large amounts of seawater with heat, the KE contributes significantly to the formation of sea surface temperature (SST) fields. Recently, poleward shifts of major ocean gyres in the world ocean, including the North Pacific subtropical gyre, have been highlighted based on basin-scale changes in SST and sea surface height (SSH) distributions. However, a detailed investigation of the long-term meridional KE movement has not been presented. Investigation of KE path changes helps provide insights into long-term changes in the physical fields in the western North Pacific. In this study, we identified the KE path from satellite-derived SSH and surface current velocity data using a front identification method and showed that the KE migrated northward by approximately 210 km during 1993–2021. We further explored the cause of the northward KE shift based on atmospheric reanalysis data and numerical experiments using a high-resolution ocean general circulation model. It was revealed that the northward KE shift is mostly caused by the trend of wind stress curl in the North Pacific during 1993–2021.

Abstract Returned samples from Cb-type asteroid (162173) Ryugu exhibit very dark spectra in visible and near-infrared ranges, generally consistent with the Hayabusa2 observations. A critical difference is that a structural water absorption of hydrous silicates is around twice as deep in the returned samples compared with those of Ryugu’s surface, suggesting Ryugu surface is more dehydrated. Here we use laboratory experiments data to indicate the spectral differences between returned samples and asteroid surface are best explained if Ryugu surface has (1) higher porosity, (2) larger particle size, and (3) more space-weathered condition, with the last being the most effective. On Ryugu, space weathering by micrometeoroid bombardments promoting dehydration seem to be more effective than that by solar-wind implantation. Extremely homogeneous spectra of the Ryugu’s global surface is in contrast with the heterogeneous S-type asteroid (25143) Itokawa’s spectra, which suggests space weathering has proceeded more rapidly on Cb-type asteroids than S-type asteroids.

Abstract Samples from the carbonaceous asteroid (162173) Ryugu provide information on the chemical evolution of organic molecules in the early solar system. Here we show the element partitioning of the major component ions by sequential extractions of salts, carbonates, and phyllosilicate-bearing fractions to reveal primordial brine composition of the primitive asteroid. Sodium is the dominant electrolyte of the salt fraction extract. Anions and NH4 + are more abundant in the salt fraction than in the carbonate and phyllosilicate fractions, with molar concentrations in the order SO4 2− > Cl− > S2O3 2− > NO3 − > NH4 +. The salt fraction extracts contain anionic soluble sulfur-bearing species such as S n -polythionic acids (n

Abstract Background This phase II trial was designed to evaluate the efficacy and safety of S‐1 combined with weekly irinotecan as a second‐ or third‐line treatment for patients with advanced or recurrent squamous cell lung cancer. Methods Patients with a body surface area 1.50 m2 received oral S‐1 on days 1–14 at 80, 100, and 120 mg/day, respectively, and irinotecan on days 1 and 8 at 70 mg/m2 every 3 weeks. The primary endpoint was the overall response rate, and the secondary endpoints were progression‐free survival, overall survival, and the incidence and severity of adverse effects. Results Between September 2011 and December 2014, 30 patients were enrolled in this study. The overall response rate was 6.7% (95% confidence interval [CI]: 0.8%–22.1%), and the disease control rate was 73.3%. The median progression‐free survival was 3.0 months (95% CI: 2.5–3.4 months), and the median overall survival was 10.5 months (95% CI: 5.6–13.7 months). Grade 3/4 treatment‐related adverse events were reported in ≥10% of the patients, including leukopenia (21%), neutropenia (21%), anemia (17%), anorexia (10%), and hypokalemia (10%). Conclusions Although the treatment‐related adverse events were manageable, the combination of weekly irinotecan and S‐1 did not have the expected effect.

Abstract The JAXA Astromaterials Science Research Group developed a web-based database system for the Hayabusa2-returned samples from C-type asteroid Ryugu. The Ryugu Sample Database System database (RS-DBS) is designed as an online catalog for users of wide scientific communities to choose their preferred samples and propose the sample loan through the JAXA Ryugu Sample Announcement of Opportunity. Ryugu samples can be sorted and given identification numbers as individual particles larger than 1 mm and aggregate samples consisting of less than 1 mm particle through the Phase1 curation (i.e., the initial description). The RS-DBS lists all samples with analytical data such as a microscopy image, size, mass, spectroscopic data, and shape model obtained by the initial description at the JAXA curation facility. The list also includes research results conducted by previous projects (i.e., the Hayabusa2 initial analysis team and Phase2 curation teams). The RS-DBS, built with open-source technologies, archives the data securely and long-term on the Data Archives and Transmission System (DARTS) at ISAS/JAXA. Graphical Abstract

Ectopic pituitary neuroendocrine tumors (PitNETs) are uncommon conditions that develop outside of the sella turcica. The sphenoid sinus is the most common site for ectopic PitNET, followed by the suprasellar region, clivus, and cavernous sinus. PitNETs, regardless of whether inside or outside sella, may display avid 18F-fluorodeoxyglucose (FDG) uptake and masquerade as malignant tumors. Herein, we report a case of ectopic PitNET arising in the sphenoid sinus, which was found as an FDG-avid mass during cancer screening. On magnetic resonance imaging, the tumor showed heterogeneous and intermediate signal intensity areas on T1- and T2-weighted images with cystic components, which was consistent with PitNET. The localization and the presence of empty sella were suggestive of ectopic PitNET, and the diagnosis of ectopic PitNET (prolactinoma) was confirmed by endoscopic biopsy. Ectopic PitNET should be considered in a mass similar in nature to an orthogonal PitNET in areas near the sella turcica especially in patients with empty sella.

Perinatal cohort studies with a prospective longitudinal design are critical for determining the effects of early-life exposures on offspring’s health outcomes. The Sri Lanka Mother and Newborn Growth cohort study aims to investigate the impact of maternal nutritional and psychosocial factors on newborns’ birth weight in the Sri Lankan context. This paper presents the methodology of participant recruitment, follow-ups, an overview of measurements, and planned data analyses. This study included a nationally representative sample of Sri Lankan pregnant women recruited in their first trimester of pregnancy. Follow-up assessments were conducted once during the second and third trimesters of pregnancy and after the baby’s birth, prospectively tracking the women’s dietary intake, mental health, hemoglobin concentrations, and gestational weight gain data. Once the participants delivered their babies, the data on gestational age, sex of the newborn, birth weight, length and occipitofrontal circumference at birth, and mode of delivery were collected. Between August 2022 and August 2023, we recruited 2000 first-trimester pregnant women to the cohort and continued to follow up with them until the baby’s birth. The response rates were 90.4%, 81.4%, and 75.2% in the first, second, and third follow-ups. We plan to analyze the data in July 2024. We expect this study to provide valuable insights into various early-life exposures affecting neonatal birth weight. The study’s findings will serve as a valuable information resource for a broader scientific community, enabling the development of effective policies to prevent low-birth-weight deliveries in low-resource settings.

The problem of antimicrobial resistance (AMR) is not limited to the medical field but is also becoming prevalent on a global scale in the environmental field. Environmental water pollution caused by the discharge of wastewater into aquatic environments has caused concern in the context of the sustainable development of modern society. However, there have been few studies focused on the treatment of hospital wastewater, and the potential consequences of this remain unknown. This study evaluated the efficacy of the inactivation of antimicrobial-resistant bacteria (AMRB) and antimicrobial resistance genes (AMRGs) in model wastewater treatment plant (WWTP) wastewater and hospital effluent based on direct ultraviolet (UV) light irradiation provided by a conventional mercury lamp with a peak wavelength of 254 nm and an ultraviolet light-emitting diode (UV-LED) with a peak emission of 280 nm under test conditions in which the irradiance of both was adjusted to the same intensity. The overall results indicated that both UV- and UV-LED-mediated disinfection effectively inactivated the AMRB in both wastewater types (>99.9% after 1–3 min of UV and 3 min of UV-LED treatment). Additionally, AMRGs were also removed (0.2–1.4 log10 for UV 254 nm and 0.1–1.3 log10 for UV 280 nm), and notably, there was no statistically significant decrease (p < 0.05) in the AMRGs between the UV and UV-LED treatments. The results of this study highlight the importance of utilizing a local inactivation treatment directly for wastewater generated by a hospital prior to its flow into a WWTP as sewage. Although additional disinfection treatment at the WWTP is likely necessary to remove the entire quantity of AMRB and AMRGs, the present study contributes to a significant reduction in the loads of WWTP and urgent prevention of the spread of infectious diseases, thus alleviating the potential threat to the environment and human health risks associated with AMR problems.