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Superconducting (SC) tokamak JT-60SA plays an essential role in fusion research and development by supporting and complementing the ITER project, providing directions to the DEMO design activity and fostering next generation scientists and engineers. Since the short circuit incident at the terminal joints of equilibrium field coil #1 during the integrated commissioning (IC) in March 2021, both EU and JA implementing agencies (IAs) have examined how to ensure safe operation of JT-60SA by mitigating the risk of possible discharge occurrence inside the cryostat. Based on the experience of the global Paschen tests, the IAs have established a strategy of risk mitigation measures, which is a combination of (i) reinforcement of insulation, (ii) avoiding unnecessary voltage application to the coil systems and (iii) immediate de-energization of the coils when deteriorated vacuum conditions are detected. Thanks to the considerable efforts of the Integrated Project Team members, the IC restarted in May 2023. After confirmation of the SC state of the coil systems (TF, EF and CS), the coil energization test and the plasma operation phase 1 (OP-1) started. The first plasma was successfully achieved on 23 October 2023 with a limited value of voltage and current applied to the coils. The plasma configuration control was also confirmed with low plasma current and low auxiliary heating power conditions. Based on the IO–F4E–QST collaboration, activities of JT-60SA have been shared with the IO and provided an important lesson for ITER assembly and commissioning, and will provide an outstanding contribution to fusion research at large. After OP-1, maintenance & enhancement phase 1 (M/E-1) starts from January 2024, in which in-vessel components are installed, and heating and diagnostic systems are extensively upgraded to allow a high power heating experiment planned in OP-2. In order to make the best use of JT-60SA, a newly organized JT-60SA experiment team will refine the research plan for the future high heating power operation phase.

Abstract In this paper, we present the first high‐speed video observation of a cloud‐to‐ground lightning flash and its associated downward‐directed Terrestrial Gamma‐ray Flash (TGF). The optical emission of the event was observed by a high‐speed video camera running at 40,000 frames per second in conjunction with the Telescope Array Surface Detector, Lightning Mapping Array, interferometer, electric‐field fast antenna, and the National Lightning Detection Network. The cloud‐to‐ground flash associated with the observed TGF was formed by a fast downward leader followed by a very intense return stroke peak current of −154 kA. The TGF occurred while the downward leader was below cloud base, and even when it was halfway in its propagation to ground. The suite of gamma‐ray and lightning instruments, timing resolution, and source proximity offer us detailed information and therefore a unique look at the TGF phenomena.

Characteristics of the early current quench (CQ) time in mitigated disruptions are studied for a full-current (5.5 MA) scenario in the JT-60SA superconducting tokamak. Self-consistent evolution of the plasma temperature and current density profiles during the early CQ phase before the plasma moves vertically is simulated using the axisymmetric disruption code INDEX for given impurity source profiles. It is shown that the hollow (flat) impurity density profiles peaks (flattens) the current density, and it causes a temporal change in the internal inductance in this phase. However the resultant CQ time is found to be insensitive to the impurity source profile for the same assimilated quantity. The simulation results are interpreted by the L/R model including the temporal change in the internal inductance as well as the effect of a gap between the plasma and the conducting vessel structures and stabilizing plates. This results will improve the accuracy to estimate the amount of impurity assimilated into plasma from the observed CQ rate in the massive gas injection (MGI) experiment planned in JT-60SA. The accessible range in which the CQ time can be scanned as well as the electron densities to suppress runaway electrons is also shown for different injected amounts of neon, argon, and their deuterium mixture under the limitation of the MGI gas amount. Mitigated disruptions in JT-60SA typically lead to the CQ time shorter than the vessel wall time, which is expected to produce relevant contributions to disruption mitigation in ITER and future reactors.

Background and Aims: Cohort studies in Japan indicate that citrus fruit and β-cryptoxanthin–rich Satsuma mandarin are candidate foods for lowering cardiovascular risk; however, there have been few intervention studies of β-cryptoxanthin and Satsuma mandarin supplementation. Methods and Results: A randomized, placebo-controlled, double-blind parallel trial was performed. Apparently healthy men and women were randomly assigned to two groups: one receiving concentrated β-cryptoxanthin–rich Satsuma mandarin juice (β-cryptoxanthin 4 mg per 125 mL/day: active group) and one receiving β-cryptoxanthin–deprived Satsuma mandarin juice (β-cryptoxanthin 0 mg per 125 mL/day: control group) for 12 weeks. The primary outcome was brachial-ankle pulse wave velocity (baPWV), which assesses arterial stiffness. An oxidative stress biomarker and clinical outcomes were also evaluated. Effect of the intervention on the outcome variables was analyzed using generalized linear mixed models. After the trial, a prespecified 8-month follow-up examination was conducted. One hundred eighteen subjects were randomly assigned, and 117 completed the intervention. Serum β-cryptoxanthin concentration was increased among the active group after β-cryptoxanthin–rich Satsuma mandarin juice supplementation. Both supplementations lowered baPWV and oxidative stress biomarker levels; however, there was no additional effect in the active group compared with the control group. At the 8-month examination, the increase in baPWV among the active group was smaller than that among the control group. Conclusion: Satsuma mandarin juice supplementation is potentially beneficial for reducing cardiovascular risk; however, additional β-cryptoxanthin supplementation did not enhance this effect. Further study is needed to evaluate the long-term effect of β-cryptoxanthin supplementation. Registration: UMIN-CTR, UMIN000013579.

Analyses of hourly radiosonde data of temperature, wind, and relative humidity during four days (two with convection and two with no convection) as a part of an intensive observation period in CPEA-2 campaign over Koto Tabang (100.32° E, 0.20° S), Indonesia, are presented. Characteristics of gravity waves in terms of dominant wave frequencies at different heights and their vertical wavelengths are shown in the lower stratosphere during a convective and non-convective period. Gravity waves with periods ~10 h and ~4–5 h were found dominant near tropopause (a region of high stability) on all days of observation. Vertical propagation of gravity waves were seen modified near heights of the three identified strong wind shears (at ~16, 20, and 25 km heights) due to wave-mean flow interaction. Between 17 and 21 km heights, meridional wind fluctuations dominated over zonal wind, whereas from 22 to 30 km heights, wave fluctuations with periods ~3–5 h and ~8–10 h in zonal wind and temperature were highly associated, suggesting zonal orientation of wave propagation. Gravity waves from tropopause region to 30 km heights were analyzed. In general, vertical wavelength of 2–5 km dominated in all the mean-removed (~ weekly mean) wind and temperature hourly profiles. Computed vertical wavelength spectra are similar, in most of the cases, to the source spectra (1–16 km height) except that of zonal wind spectra, which is broad during active convection. Interestingly, during and after convection, gravity waves with short vertical wavelength (~2 km) and short period (~2–3 h) emerged, which were confined in the close vicinity of tropopause, and were not identified on non-convective days, suggesting convection to be the source for them. Some wave features near strong wind shear (at 25 km height) were also observed with short vertical wavelengths in both convective and non-convective days, suggesting wind shear to be the sole cause of generation and seemingly not associated with deep convection below. A drop in the temperature up to ~4–5 K (after removal of diurnal component) was observed at ~16 km height near a strong wind shear (~45–55 m s−1 km−1) during active period of convection.

We study short period gravity waves (20–120 min) in the equatorial Mesosphere and Lower Thermosphere (MLT) using a Medium Frequency (MF) radar at Pameungpeuk (7.4° S, 107.4° E), Indonesia. In particular, we study local time and seasonal variation of the gravity wave variance and its relation to tropical convection. The gravity wave variance at 88 km enhances between 20:00 LT and 07:00 LT, with a peak at 02:00–03:00 LT. The enhancement is mainly observed during February–April and September–October and shows inter-annual variability. Convective activity over the same location persists from 16:00–21:00 LT with a peak activity ~18:00 LT and enhances between November–April. Time delay between the peak of convection and that of gravity wave activity ranges 1–15 h, which is consistent with theoretical calculations and previous reports based on reverse ray tracing analysis.

In association with the passage of a Tropical Cyclone (TC) around Japan, the secondary circulation in the region from the outer side to the center was investigated in detail by two separately located L-band wind profilers and the rawinsonde observations from 1 to 2 October 2002, for the first time. As the wind profilers can observe wind fields not only within rainbands but also in between, the mesoscale wind circulation including the vertical wind component in wide areas from the lower layer to the upper layer was investigated. While the TC center approached the profiler stations, several rainbands associated with the TC subsequently passed. Relatively warm, moist inflow with a cyclonic rotation was observed in the lower-troposphere while the TC center approached. The inflow reached the inside of the main rainband where the updraft was observed. Above 5-km height (with temperature below 0°C), outflow and weak downdraft corresponding to falling frozen particles were observed. It is considered that the frozen particles formed precipitating clouds mainly in the outer rainband region. The continuous wind circulation transported water vapor from the lower troposphere to the upper troposphere via the vicinity of TC center. On the other hand, after the passage of the TC center, the developed rainband passed, which was located in the south and southwest quadrant of the TC. It is suggested with the profilers' data that the rainband was intensified mainly by warm and moist outflow below 3-km height.

A special observation campaign (X-BAIU), using various instruments (wind profilers, C-band weather radars, X-band Doppler radars, rawinsondes, etc.), was carried out in Kyushu (western Japan) during the Baiu season, from 1998 to 2002. In the X-BAIU-99 and -02 observations, a line-shaped orographic rainband extending northeastward from the Koshikijima Islands appeared in the low-level strong wind with warm-moist airs. The weather radar observation indicated that the rainband was maintained for 11h. The maximum length and width of the rainband observed in 1999 was ~200km and ~20km, respectively. The rainband observed in 2002 was not so developed compared with the case in 1999. The Froude number averaged from sea level to the top of the Koshikijima Islands (~600m) was large (>1), and the lifting condensation level was below the tops of the Koshikijima Islands. Thus, it is suggested that the clouds organizing the rainband are formed by the triggering of the mountains on the airflow passing over them. The vertical profile of horizontal wind in/around the rainband was investigated in the wind profiler observations. In the downdraft region 60km from the Koshikijima Islands, strong wind and its clockwise rotation with increasing height was observed below 3km altitude. In addition, a strong wind component perpendicular to the rainband was observed when the rainband was well developed. These wind behaviors were related to the evolution of the rainband.

We have developed a method to overcome sequencing problems caused by the presence of homopolymer stretches, such as polyA/T, in cDNA libraries. PolyA tails are shortened by cleaving before cDNA cloning with type IIS restriction enzymes, such as GsuI, placed next to the oligo-dT used to prime the polyA tails of mRNAs. We constructed four rice Cap-Trapper-selected, full-length normalized cDNA libraries, of which the average residual polyA tail was 4 bases or shorter in most of the clones analyzed. Because of the removal of homopolymeric stretches, libraries prepared with this method can be used for direct sequencing and transcriptional sequencing without the slippage observed for libraries prepared with currently available methods, thus improving sequencing accuracy, operations, and throughput.

Typhoon 9707 (Opal) was observed with the VHF-band Middle and Upper atmosphere (MU) radar, an L-band boundary layer radar (BLR), and a vertical-pointing C-band meteorological radar at the Shigaraki MU Observatory in Shiga prefecture, Japan on 20 June 1997. The typhoon center passed about 80 km southeast from the radar site. Mesoscale precipitating clouds developed due to warm-moist airmass transport from the typhoon, and passed over the MU radar site with easterly or southeasterly winds. We primarily present the wind behaviour including the vertical component which a conventional meteorological Doppler radar cannot directly observe, and discuss the relationship between the wind behaviour of the typhoon and the precipitating system. To investigate the dynamic structure of the typhoon, the observed wind was divided into radial and tangential wind components under the assumption that the typhoon had an axi-symmetric structure. Altitude range of outflow ascended from 1–3 km to 2–10 km with increasing distance (within 80–260 km range) from the typhoon center, and in-flow was observed above and below the outflow. Outflow and inflow were associated with updraft and downdraft, respectively. In the tangential wind, the maximum speed of counterclockwise winds was confirmed at 1–2 km altitudes. Based on the vertical velocity and the reflectivity obtained with the MU radar and the C-band meteorological radar, respectively, precipitating clouds, accompanied by the wind behaviour of the typhoon, were classified into stratiform and convective precipitating clouds. In the stratiform precipitating clouds, a vertical shear of radial wind and the maximum speed of counterclockwise wind were observed. There was a strong reflectivity layer called a ‘bright band’ around the 4.2 km altitude. We confirmed strong updrafts and down-drafts below and above it, respectively, and the existence of a relatively dry layer around the bright band level from radiosonde soundings. In the convective precipitating clouds, the regions of strong and weak reflectivities were well associated with those of updraft and downdraft, respectively.Key words. Meteorology and atmospheric dynamics (mesoscale meteorology; precipitation) Radio science (remote sensing)

We have developed the single-strand linker ligation method (SSLLM), which uses DNA ligase to add a dsDNA linker to singlestranded (ss) full-length cDNA. The linkers have random 6-bp (dN6 or dGN5) 3′ overhangs that can ligate to any cDNA sequence, thereby facilitating the production of cDNA libraries with titers exceeding 1 × 106 independent clones. We confirmed that the 5′ ends of cDNA inserts cloned by using SSLLM are full-length and include the 5′ untranslated regions. The great advantage of our method is that the elimination of the GC tail simplifies the sequencing and protein translation of the full-length clones. Further, our method tags ss cDNAs more efficiently than does the traditional RNA ligase reaction.

Pulse length of quasimonoenergetic electrons accelerated by the wakefield generated by 12 TW, 40 fs laser pulses in a gas jet is determined via spectral measurements using a bolometer to detect coherent transition radiation. A quasimonoenergetic electron beam with its mean energy E=21 MeV, dispersion ΔE=4 MeV, total charge q∼30 pC, and the geometrical emittance 0.07π mm mrad is generated with high reproducibility. The averaged duration of only the quasimonoenergetic electron bunches peaked around 20 MeV is 130±30 fs (FWHM), while it is 250±70 fs (FWHM) for electron bunches with quasimonoenergetic distributions peaked around 4 MeV, at a distance of 180 mm far from the gas jet because of relatively large electron energy spread. Pulse elongation of the electron bunch with the quasimonoenergetic distribution after 180 mm path is 60–220 fs (FWHM). Therefore, the initial duration of the electron bunch at the gas-jet rear is expected to be less than 100 fs (FWHM).

Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of "Astrocytoma, IDH-mutant; High Grade" by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors., (© 2024. The Author(s).)

Background and Purpose: Mild cognitive impairment (MCI) is a predictor of future age-related dementia.　We herein investigated associations of MCI with higher-level functional capacities, as well as with subjective difficulty regarding these functions, in community-dwelling older people, to identify a simple method for early MCI detection., Method: We administered a test battery to 118 community-dwelling older people living in an urban area.　The battery consisted of three tests;the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC), the Touch Panel-type Dementia Assessment Scale (TDAS), and the Geriatric Depression Scale-15.　We then excluded participants with possible dementia or depression symptoms, and divided the remainder (n = 67) into an MCI group (n = 16) and a non-MCI group (n = 51), according to TDAS performance., Results: Logistic regression analysis with the MCI and non-MCI groups as dependent variables indicated that TMIG-IC was a significant variable.　Male sex and the perception that preparing meals and filling out pension forms had become more difficult were significantly associated with MCI, each independently increasing the probability of MCI., Conclusions: Subjective difficulty with higher-level functions and impairment in higher-level functional capacity may serve as indices for mass screening for MCI.

Background: The clinical application of human induced pluripotent stem cell-derived cardiomyocytes (CMs) for cardiac repair commenced with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of human induced pluripotent stem cell-derived CMs into the cardiac muscle layer, which has reportedly induced electrical integration, is unclear because of concerns about poor engraftment of CMs and posttransplant arrhythmias. Thus, in this study, we prepared purified human induced pluripotent stem cell-derived cardiac spheroids (hiPSC-CSs) and investigated whether their direct injection could regenerate infarcted nonhuman primate hearts., Methods: We performed 2 separate experiments to explore the appropriate number of human induced pluripotent stem cell-derived CMs. In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks before transplantation and were designated as recipients of hiPSC-CSs containing 2×10 7 CMs or the vehicle. The animals were euthanized 12 weeks after transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6×10 7 CMs)., Results: Recipients of hiPSC-CSs containing 2×10 7 CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle (fractional shortening at 4 weeks after transplantation [mean ± SD]: 26.2±2.1%; 19.3±1.8%; P <0.05), with a low incidence of posttransplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits (fractional shortening at 12 weeks after transplantation: 22.5±1.0%; 16.6±1.1%; P <0.01, left ventricular ejection fraction at 12 weeks after transplantation: 49.0±1.4%; 36.3±2.9%; P <0.01). The incidence of posttransplant arrhythmia slightly increased in recipients of hiPSC-CSs containing 6×10 7 CMs., Conclusions: We demonstrated that direct injection of hiPSC-CSs restores the contractile functions of injured primate hearts with an acceptable risk of posttransplant arrhythmia. Although the mechanism for the functional benefits is not fully elucidated, these findings provide a strong rationale for conducting clinical trials using the equivalent CM products., Competing Interests: S.T. is an advisor to Heartseed Inc. K.F. is the cofounder and CEO of Heartseed Inc. S.T., H. Kanazawa, and K.F. own equity in Heartseed Inc.

Owing to increasing super-aging societies, older adults will be encouraged to continue working. Although demand exists for older adults to continue working in Japanese society, the enabling factors have not been clarified. This study aimed to clarify (1) the life functions that affect the working status among younger-older adults who continue to work and those who do not via the Kihon Checklist (KCL) and (2) examine whether the number of areas of difficulties in daily functions of the KCL affected older adults' employment status. This cross-sectional study involved 5386 older men and women aged 65 years or older in one city in Japan. Employment status and the seven domains of the Kihon Checklist (KCL) were analyzed. The KCL items related to employment status were the physical (odds ratio = 2.46, p < 0.01), socialization (odds ratio = 1.95, p < 0.01), and mood domains (odds ratio = 1.29, p < 0.01). Furthermore, the odds ratio increased to 2.06 when three or more domains were applicable. To remain employed, one must be physically and mentally healthy. Furthermore, since the risk of non-employment increased when one KCL domain was applicable, a broader assessment of life functions is necessary.

Clinical walk tests may not predict the development of frailty in healthy older adults. With advancements in wearable technology, it may be possible to predict the development of frailty using loading asymmetry parameters during clinical walk tests. This prospective cohort study aimed to test the hypothesis that increased limb loading asymmetry predicts frailty risk in community-living older adults. Sixty-three independently ambulant community-living adults aged ≥ 65 years were recruited, and forty-seven subjects completed the ten-month follow-up after baseline. Loading asymmetry index of net and regional (forefoot, midfoot, and rearfoot) plantar forces were collected using force sensing insoles during a 10 m walk test with their maximum speed. Development of frailty was defined if the participant progressed from baseline at least one grading group of frailty at the follow-up period using the Kihon Checklist. Fourteen subjects developed frailty during the follow-up period. Increased risk of frailty was associated with each 1% increase in loading asymmetry of net impulse (Odds ratio 1.153, 95%CI 1.001 to 1.329). Net impulse asymmetry significantly correlated with asymmetry of peak force in midfoot force. These results indicate the feasibility of measuring plantar forces of gait during clinical walking tests and underscore the potential of using load asymmetry as a tool to augment frailty risk assessment in community-dwelling older adults.

Introduction: Avulsion fractures of the calcaneal tuberosity with significant displacement can cause soft tissue complications in the heel. However, a treatment strategy for calcaneal tuberosity fractures with poor heel-skin condition is yet to be established. Here, we report a case involving avulsion fracture of the calcaneal tuberosity presenting with superficial skin necrosis that was treated with a plate lacking the anterior component and screws inserted percutaneously., Presentation of Case: A 74-year-old woman presented with progressive right heel pain following an injury to her heel sustained approximately six weeks previously. She had experienced difficulty walking due to heel pain and superficial necrosis was observed on the posterior surface of the heel. Radiography and computed tomography revealed an avulsion fracture of the calcaneal tuberosity with superior displacement. Open reduction was performed using a lateral L-shaped incision. After inserting two cancellous screws percutaneously into the calcaneal tuberosity, we fixed a plate lacking the anterior component to the lateral surface of the calcaneus. The superficial necrosis healed gradually post-operatively. Bone union was confirmed using radiography six months post-operatively., Discussion: We developed a novel surgical procedure to treat avulsion fractures of the calcaneal tuberosity with poor skin condition. The combination of a plate lacking the anterior component and the percutaneous insertion of canulated cancellous screws can reduce the risk of post-operative soft tissue complications while maintaining fixation of the fractured fragment., Conclusion: Our findings provide a novel surgical method for the treatment of avulsion fractures of the calcaneal tuberosity with soft tissue complications., Competing Interests: Conflict of interest statement None of the authors have any conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The COVID-19 outbreak might have had several effects on older adults; however, much of the previous research only included self-report, cross-sectional, and online-survey data in the early stage of the pandemic. We conducted a face-to-face survey before and after the COVID-19 pandemic and investigated the influence of the pandemic on several functions to distinguish between changes due to aging and changes due to the pandemic using a linear mixed model., Methods: A total of 8 longitudinal surveys were conducted from 2016 to 2022. Physical function was assessed by weight, body mass index, body fat percentage, skeletal muscle mass index, calf circumference, grip strength, knee extension strength, the 5-times chair stand test, the timed up & go test and 5-m walking test. Functional capacity was measured using the Tokyo Metropolitan Institute of Gerontology index of competence, cognitive function was measured using the Trail Making Test - A, and mental health was measured using the Geriatric Depression Scale., Results: Of a total of 73 participants, 51 (69.9%) were female. The mean age at first participation was 71.82 years (SD = 4.64). The results of the linear mixed model showed that lower-limb muscle strength and body fat percentage and cognitive function changed significantly before and after the pandemic, while grip strength, functional capacity, and mental health did not., Conclusions: The changes in these functions between before and after the pandemic might be attributed to the diminished opportunities for the independent older individuals to go out and engage in activities. Although functional capacity did not change, lower-limb muscle strength is important for functional independence. This decline might influence the functional capacity of these individuals in the future., (© 2024. The Author(s).)

Arf GTPase-activating proteins (ArfGAPs) mediate the hydrolysis of GTP bound to ADP-ribosylation factors. ArfGAPs are critical for cargo sorting in the Golgi-to-ER traffic. However, the role of ArfGAPs in sorting into intralumenal vesicles (ILVs) in multivesicular bodies (MVBs) in post-Golgi traffic remains unclear. Exosomes are extracellular vesicles (EVs) of endosomal origin. CD63 is an EV marker. CD63 is enriched ILVs in MVBs of cells. However, the secretion of CD63 positive EVs has not been consistent with the data on CD63 localization in MVBs, and how CD63-containing EVs are formed is yet to be understood. To elucidate the mechanism of CD63 transport to ILVs, we focused on CD63 localization in MVBs and searched for the ArfGAPs involved in CD63 localization. We observed that ADAP1 and ARAP1 depletion inhibited CD63 localization to enlarged endosomes after Rab5Q79L overexpression. We tested epidermal growth factor (EGF) and CD9 localization in MVBs. We observed that ADAP1 and ARAP1 depletion inhibited CD9 localization in enlarged endosomes but not EGF. Our results indicate ADAP1 and ARAP1, regulate incorporation of CD63 and CD9, but not EGF, in overlapped and different MVBs. Our work will contribute to distinguish heterogenous ILVs and exosomes by ArfGAPs., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene. Central nervous system tumors, such as choroid plexus tumors, medulloblastomas, and diffuse gliomas, are frequently found in patients with LFS. Although molecular profiles of diffuse gliomas that develop in pediatric patients with LFS have been elucidated, those in adults are limited. Recently, diffuse gliomas have been divided into pediatric- and adult-type gliomas, based on their distinct molecular profiles. In the present study, we investigated the molecular profiles of high-grade gliomas in three adults with LFS. These tumors revealed characteristic histopathological findings of high-grade glioma or glioblastoma and harbored wild-type IDH1/2 according to whole exome sequencing (WES). However, these tumors did not exhibit the key molecular alterations of glioblastoma, IDH-wildtype such as TERT promoter mutation, EGFR amplification, or chromosome 7 gain and 10 loss. Although WES revealed no other characteristic gene mutations or copy number alterations in high-grade gliomas, such as those in histone H3 genes, PDGFRA amplification was found in all three cases together with uniparental disomy of chromosome 17p, where the TP53 gene is located. DNA methylation analyses revealed that all tumors exhibited DNA methylation profiles similar to those of pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3-/IDH-wt), RTK1 subtype. These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS., (© 2024. The Author(s).)

Background: In recent years, it has become clear that participation in social activities by the older adult suppresses their need for long-term care. Likewise, social participation can promote long-term care prevention among frail older adults who are at a higher risk of needing long-term care. However, their social participation rate is low, and the factors causing these low rates of participation are unclear. Therefore, this study identifies the factors affecting social participation of frail older adults., Methods: After excluding those certified as requiring long-term care, 28,636 older adults within the target region were selected to receive questionnaires. The questionnaires were distributed and collected via mail. A total of 22,048 respondents (77.0%), including 9,325 men and 10,150 women, were included; 2,655 frail older adults were identified for analysis. Questionnaire items inquired about social participation, basic attributes, need for long-term care, mobility, subjective health, direct and indirect contact with relatives living separately and direct and indirect contact with friends and neighbors. For the statistical analysis, this study employed a binomial logistic regression analysis with social participation as the objective variable., Results: The rate of social participation among frail older adults was 13.7%. Items related to social participation included sex, economic status, mobility, subjective health, direct contact with friends, and indirect contact with friends., Conclusions: Interactions with friends and neighbors and physical functionality are correlated with levels of social participation among frail older adults, suggesting that social participation can be promoted by maintaining friendships, forming new ones, and maintaining and improving physical functionality., (© 2024. The Author(s).)

Explored through EEG/MEG, auditory stimuli function as a suitable research probe to reveal various neural activities, including event-related potentials, brain oscillations and functional connectivity. Accumulating evidence in this field stems from studies investigating neuroplasticity induced by long-term auditory training, specifically cross-sectional studies comparing musicians and non-musicians as well as longitudinal studies with musicians. In contrast, studies that address the neural effects of short-term interventions whose duration lasts from minutes to hours are only beginning to be featured. Over the past decade, an increasing body of evidence has shown that short-term auditory interventions evoke rapid changes in neural activities, and oscillatory fluctuations can be observed even in the prestimulus period. In this scoping review, we divided the extracted neurophysiological studies into three groups to discuss neural activities with short-term auditory interventions: the pre-stimulus period, during stimulation, and a comparison of before and after stimulation. We show that oscillatory activities vary depending on the context of the stimuli and are greatly affected by the interplay of bottom-up and top-down modulational mechanisms, including attention. We conclude that the observed rapid changes in neural activitiesin the auditory cortex and the higher-order cognitive part of the brain are causally attributed to short-term auditory interventions.

Aim: To examine spatial-temporal gait parameters associated with comprehensive frailty status in community-dwelling, independent older people., Methods: This cross-sectional study included 225 older people (≥65 years) living independently in the community. The Kihon Checklist was used to assess comprehensive frailty status, and participants were classified as robust, pre-frailty, or frailty. A sheet-type plantar pressure sensor was used to evaluate the following gait parameters, which were extracted at the usual and fast pace: gait speed, cadence, stride time, step length-to-height ratio (step length/height), step width, stance duration, double-support time, and variability of each gait parameter. Ordinal logistic regression analysis adjusted for confounding factors was performed to determine the association between gait parameters and frailty status. In addition, the ability to discriminate frailty status was evaluated by receiver operating characteristic (ROC) curve analysis for gait parameters that were significantly associated with frailty status., Results: Frailty status was pre-frailty in 79 (35.1%) and frailty in 30 (13.3%) participants. Ordinal logistic regression analysis showed a significant association of step length/height (%) at both usual and fast pace with frailty status, even after adjustment for confounding factors (usual pace: odds ratio [OR] = 0.93 [95% confidence interval, CI: 0.86-0.99]; fast pace: OR = 0.93 [95% CI: 0.87-0.99]). ROC curve analysis identified step length/height at fast pace in women as the best discriminator between frailty and non-frailty (area under the curve 0.69, cut-off value 43.4%, sensitivity 50%, specificity 82%)., Conclusions: Step length appears to be a useful gait parameter for discriminating frailty status in community-dwelling, independent older people. Geriatr Gerontol Int 2024; 24: 18-24., (© 2023 Japan Geriatrics Society.)

Background: Previous studies have reported that clinical walk tests could not detect differences between fallers and non-fallers in older adults. With advancements in wearable technology, it may be possible to assess differences in loading parameters in clinical settings using portable data collection methods., Research Question: The purpose of this study was to determine if wearable sensors (loadsol®) are reliable for assessing asymmetry of contact time, peak force, loading rate (LR), and impulse in older adults and determine if the insole can detect differences in these parameters between fallers and non-fallers during walking., Methods: Fifty-five older adults (74.1 ± 6.1 years) walked at their maximum speed on a flat floor. Force data were collected from insoles (100 Hz) during a 10-m walk test. To assess reliability, an intraclass correlation coefficient [ICC(2,k)] was generated for each asymmetry variable. To determine differences between fallers and non-fallers, analysis of covariance (ANCOVA; covariate: body mass index) was completed for each variable., Results: The ICC of peak force asymmetry (PFA) was 0.942, but other ICCs were less than 0.75. The ANCOVA results indicate that the loadsol® can detect differences in PFA between fallers and non-fallers. The PFA was significantly greater in fallers than in non-fallers., Significance: The ability to collect force data while walking using loadsol® has the potential to broaden the research questions investigated, explore clinical applications, and increase generalizability., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest associated with this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Exon-skipping therapy is a promising treatment strategy for Duchenne muscular dystrophy (DMD), which is caused by loss-of-function mutations in the DMD gene encoding dystrophin, leading to progressive cardiomyopathy. In-frame deletion of exons 3-9 (Δ3-9), manifesting a very mild clinical phenotype, is a potential targeted reading frame for exon-skipping by targeting actin-binding domain 1 (ABD1); however, the efficacy of this approach for DMD cardiomyopathy remains uncertain. In this study, we compared three isogenic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing Δ3-9, frameshifting Δ3-7, or intact DMD. RNA sequencing revealed a resemblance in the expression patterns of mechano-transduction-related genes between Δ3-9 and wild-type samples. Furthermore, we observed similar electrophysiological properties between Δ3-9 and wild-type hiPSC-CMs; Δ3-7 hiPSC-CMs showed electrophysiological alterations with accelerated CaMKII activation. Consistently, Δ3-9 hiPSC-CMs expressed substantial internally truncated dystrophin protein, resulting in maintaining F-actin binding and desmin retention. Antisense oligonucleotides targeting exon 8 efficiently induced skipping exons 8-9 to restore functional dystrophin and electrophysiological parameters in Δ3-7 hiPSC-CMs, bringing the cell characteristics closer to those of Δ3-9 hiPSC-CMs. Collectively, exon-skipping targeting ABD1 to convert the reading frame to Δ3-9 may become a promising therapy for DMD cardiomyopathy., Competing Interests: K.F. is a co-founder and CEO of Heartseed Inc. S.T. is an advisor for Heartseed, Inc. S.T. and K.F. have owned equity in Heartseed, Inc., (© 2023 The Authors.)

Aims: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection., Methods and Results: C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL M, ANS-VAL H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signalling pathway compared with the ANS-VAL M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL M while preserving the superior cardioprotective effect of ARNI., Conclusion: PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to treat heart diseases; however, the optimal maturity of hiPSC-CMs for effective regenerative medicine remains unclear. We aimed to investigate the benefits of long-term cultured mature hiPSC-CMs in injured rat hearts., Methods: Cardiomyocytes were differentiated from hiPSCs via monolayer culturing, and the cells were harvested on day 28 or 56 (D28-CMs or D56-CMs, respectively) after differentiation. We transplanted D28-CMs or D56-CMs into the hearts of rat myocardial infarction models and examined cell retention and engraftment via in vivo bioluminescence imaging and histological analysis. We performed transcriptomic sequencing analysis to elucidate the genetic profiles before and after hiPSC-CM transplantation., Results: Upregulated expression of mature sarcomere genes in vitro was observed in D56-CMs compared with D28-CMs. In vivo bioluminescence imaging studies revealed increased bioluminescence intensity of D56-CMs at 8 and 12 weeks post-transplantation. Histological and immunohistochemical analyses showed that D56-CMs promoted engraftment and maturation in the graft area at 12 weeks post-transplantation. Notably, D56-CMs consistently promoted microvessel formation in the graft area from 1 to 12 weeks post-transplantation. Transcriptomic sequencing analysis revealed that compared with the engrafted D28-CMs, the engrafted D56-CMs enriched genes related to blood vessel regulation at 12 weeks post-transplantation. As shown by transcriptomic and western blot analyses, the expression of a small heat shock protein, alpha-B crystallin (CRYAB), was significantly upregulated in D56-CMs compared with D28-CMs. Endothelial cell migration was inhibited by small interfering RNA-mediated knockdown of CRYAB when co-cultured with D56-CMs in vitro. Furthermore, CRYAB overexpression enhanced angiogenesis in the D28-CM grafts at 4 weeks post-transplantation., Conclusions: Long-term cultured mature hiPSC-CMs promoted engraftment, maturation and angiogenesis post-transplantation in infarcted rat hearts. CRYAB, which was highly expressed in D56-CMs, was identified as an angiogenic factor from mature hiPSC-CMs. This study revealed the benefits of long-term culture, which may enhance the therapeutic potential of hiPSC-CMs., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Sharing health data for research purposes across international jurisdictions has been a challenge due to privacy concerns. Two privacy enhancing technologies that can enable such sharing are synthetic data generation (SDG) and federated analysis, but their relative strengths and weaknesses have not been evaluated thus far. In this study we compared SDG with federated analysis to enable such international comparative studies. The objective of the analysis was to assess country-level differences in the role of sex on cardiovascular health (CVH) using a pooled dataset of Canadian and Austrian individuals. The Canadian data was synthesized and sent to the Austrian team for analysis. The utility of the pooled (synthetic Canadian + real Austrian) dataset was evaluated by comparing the regression results from the two approaches. The privacy of the Canadian synthetic data was assessed using a membership disclosure test which showed an F1 score of 0.001, indicating low privacy risk. The outcome variable of interest was CVH, calculated through a modified CANHEART index. The main and interaction effect parameter estimates of the federated and pooled analyses were consistent and directionally the same. It took approximately one month to set up the synthetic data generation platform and generate the synthetic data, whereas it took over 1.5 years to set up the federated analysis system. Synthetic data generation can be an efficient and effective tool for enabling multi-jurisdictional studies while addressing privacy concerns., (© 2023. The Author(s).)

Pluripotent stem cell (PSC)-derived cardiomyocytes are a promising source of cells in myocardial regeneration therapy for end-stage heart failure. Because most previous reports have focussed on xenotransplantation models using immunocompromised animals, studies on immune rejection in allogeneic transplantation models are needed for preclinical and clinical applications. Human leukocyte antigen (HLA) plays an important role in allogeneic transplantation, and cell bank projects are currently underway worldwide to stock induced pluripotent stem cells (iPSCs) generated from healthy individuals with homozygous HLA haplotypes. However, it is difficult to stock iPSCs that match the entire population in these cell banks; thus, several groups have produced hypoimmunogenic PSCs by knocking out HLA. These HLA-knockout PSCs were able to avoid rejection by T cells but still suffered rejection by natural killer (NK) cells caused by 'missing self-recognition'. Recent studies have attempted to generate hypoimmunogenic PSCs with gene editing to inhibit NK cell activation. Regenerative medicine using autologous iPSCs can be an ideal transplantation therapy, but, currently, there are major hurdles to its practical application. Hopefully, further research will resolve these issues. This review provides an overview of the current understanding and progress in this field., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Transmembrane protein 72 (TMEM72) is involved in normal kidney development and tumorigenesis in renal cell carcinoma. However, the function of TMEM72 has not been experimentally examined; therefore, the role of TMEM72 is incompletely understood. In this study, we initially demonstrated that TMEM72 has four transmembrane domains (TMDs) and a long C-terminal tail. Immunofluorescence analysis showed that TMEM72 is localized on the plasma membrane but not on the outer mitochondrial membrane. Experiments performed with a series of TMEM72 deletion mutants and an evaluation of the unfolded protein response indicated that these TMDs are needed for proper protein folding or assembly. In contrast, domain-specific replacement analysis indicated the essential role of the C-terminal region of TMEM72 in protein transport. Spatial colocalization and immunoprecipitation assays showed that the proximal C-terminal region is responsible for anterograde protein transport. An amino acid sequence analysis and an immunocytochemical evaluation revealed that KRKKRKAAPEVLA, which corresponds to amino acid positions 132-144 in TMEM72, participates in efficient cellular transport. The motifs 132KRKKRK137 and 139APEVLA144 are associated with COPII and are considered to cooperate with membrane trafficking. Because efficient membrane trafficking is crucial for cells to maintain normal function, our data may contribute to elucidating the pathogenesis of membrane trafficking-associated diseases, particularly renal carcinoma and chronic kidney disease., (© 2022 Federation of European Biochemical Societies.)

Aim/background: To aim of this study is to develop an artificial intelligence (AI) that aids in the thought process by providing retinal clinicians with clinically meaningful or abnormal findings rather than just a final diagnosis, i.e., a "wayfinding AI.", Methods: Spectral domain optical coherence tomography B-scan images were classified into 189 normal and 111 diseased eyes. These were automatically segmented using a deep-learning based boundary-layer detection model. During segmentation, the AI model calculates the probability of the boundary surface of the layer for each A-scan. If this probability distribution is not biased toward a single point, layer detection is defined as ambiguous. This ambiguity was calculated using entropy, and a value referred to as the ambiguity index was calculated for each OCT image. The ability of the ambiguity index to classify normal and diseased images and the presence or absence of abnormalities in each layer of the retina were evaluated based on the area under the curve (AUC). A heatmap, i.e., an ambiguity-map, of each layer, that changes the color according to the ambiguity index value, was also created., Results: The ambiguity index of the overall retina of the normal and disease-affected images (mean ± SD) were 1.76 ± 0.10 and 2.06 ± 0.22, respectively, with a significant difference (p < 0.05). The AUC used to distinguish normal and disease-affected images using the ambiguity index was 0.93, and was 0.588 for the internal limiting membrane boundary, 0.902 for the nerve fiber layer/ganglion cell layer boundary, 0.920 for the inner plexiform layer/inner nuclear layer boundary, 0.882 for the outer plexiform layer/outer nuclear layer boundary, 0.926 for the ellipsoid zone line, and 0.866 for the retinal pigment epithelium/Bruch's membrane boundary. Three representative cases reveal the usefulness of an ambiguity map., Conclusions: The present AI algorithm can pinpoint abnormal retinal lesions in OCT images, and its localization is known at a glance when using an ambiguity map. This will help diagnose the processes of clinicians as a wayfinding tool., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: the employees of NIDEK CO., LTD. (Shiba, Yoshiki Kumagai, Naoto Honda) This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Shiihara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This study aimed to evaluate the efficacy and safety of combination therapy with bevacizumab (Bev), irinotecan (CPT-11), and temozolomide (TMZ) in children with central nervous system (CNS) embryonal tumor relapse., Methods: The authors retrospectively examined 13 consecutive pediatric patients with relapsed or refractory CNS embryonal tumors who received combination therapy comprising Bev, CPT-11, and TMZ. Specifically, 9 patients had medulloblastoma, 3 had atypical teratoid/rhabdoid tumor (AT/RT), and 1 had CNS embryonal tumor with rhabdoid features. Of the 9 medulloblastoma cases, 2 were categorized in the Sonic hedgehog subgroup and 6 in molecular subgroup 3 for medulloblastoma., Results: The complete and partial objective response rates were 66.6% in patients with medulloblastoma and 75.0% in patients with AT/RT or CNS embryonal tumors with rhabdoid features. Furthermore, the 12- and 24-month progression-free survival rates were 69.2% and 51.9% for all patients with recurrent or refractory CNS embryonal tumors, respectively. In contrast, the 12- and 24-month overall survival rates were 67.1% and 58.7%, respectively, for all patients with relapsed or refractory CNS embryonal tumors. The authors observed grade 3 neutropenia, thrombocytopenia, proteinuria, hypertension, diarrhea, and constipation in 23.1%, 7.7%, 23.1%, 7.7%, 7.7%, and 7.7% of patients, respectively. Furthermore, grade 4 neutropenia was observed in 7.1% of patients. Nonhematological adverse effects, such as nausea and constipation, were mild and controlled with standard antiemetics., Conclusions: This study demonstrated favorable survival outcomes in patients with relapsed or refractory pediatric CNS embryonal tumors and thus helped to investigate the efficacy of combination therapy comprising Bev, CPT-11, and TMZ. Moreover, combination chemotherapy had high objective response rates, and all adverse events were tolerable. To date, data supporting the efficacy and safety of this regimen in the relapsed or refractory AT/RT population are limited. These findings suggest the potential efficacy and safety of combination chemotherapy in patients with relapsed or refractory pediatric CNS embryonal tumors.

Introduction: Early detection and intervention are important to prevent dementia. Gait parameters have been recognized as a potentially easy screening tool for mild cognitive impairment (MCI); however, differences in gait parameters between cognitive healthy individuals (CHI) and MCI are small. Daily life gait change may be used to detect cognitive decline earlier. In the present study, we aimed to clarify the relationship between cognitive decline and daily life gait., Methods: We performed 5-Cog function tests and daily life and laboratory-based gait assessments on 155 community-dwelling elderly people (75.5 ± 5.4 years old). Daily life gait was measured for 6 days using an iPod-touch with an accelerometer. Laboratory-based 10-m gait (fast pace) was measured using an electronic portable walkway., Results: The subjects consisted of 98 CHI (63.2%) and 57 cognitive decline individuals (CDI; 36.8%). Daily life maximum gait velocity in the CDI group (113.7 [97.0-128.5] cm/s) was significantly slower than that in the CHI group (121.2 [105.8-134.3] cm/s) ( p = 0.032). In the laboratory-based gait, the stride length variability in the CDI group (2.6 [1.8-4.1]) was significantly higher than that in the CHI group (1.8 [1.2-2.7]) ( p < 0.001). The maximum gait velocity in daily life gait was weakly but significantly correlated with stride length variability in laboratory-based gait ( ρ = -0.260, p = 0.001)., Conclusion: We found an association between cognitive decline and slower daily life gait velocity among community-dwelling elderly people., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic RNA sensor that plays an important role in innate immune responses to viral RNAs. Double-stranded RNA (dsRNA)-dependent protein kinase (PKR) is a eukaryotic initiation factor 2α (eIF2α) kinase that is initially involved in the responses of the translational machinery to dsRNA. PKR is also thought to play an essential role in antiviral innate immunity. However, the coordinated mechanisms of RIG-I and PKR that induce the expression of type I interferons (IFNs), essential cytokines involved in antiviral defense, are not completely understood. In this study, we show that PKR negatively participates in the RIG-I-mediated induction of IFN-β expression. Stress granule (SG) formation is crucial to sequester mRNA to prevent aberrant protein synthesis by various stresses. SG formation in response to dsRNA was triggered by a PKR-mediated antiviral stress response. However, IFN-β mRNA was not sequestered in the SGs of dsRNA-treated cells. dsRNA-induced translational silencing was thought to be PKR dependent. However, our results indicated that some proteins, including IFN-β, were clearly translated despite PKR-mediated translational silencing. This study suggests that RIG-I responds mainly to IFN-β expression in cells to which non-self dsRNA is introduced. In addition, PKR negatively regulates IFN-β protein expression induced by RIG-I signaling. This may explain the essential role of PKR in fine-tuning the expression of IFN-β in RIG-I-mediated antiviral immune responses., (© 2023 Federation of American Societies for Experimental Biology.)

In the sexual reproduction of flowering plants, two independent fertilization events occur almost simultaneously: two identical sperm cells fuse with either the egg cell or the central cell, resulting in embryo and endosperm development to produce a seed. GCS1/HAP2 is a sperm cell membrane protein essential for plasma membrane fusion with both female gametes. Other sperm membrane proteins, DMP8 and DMP9, are more important for egg cell fertilization than that of the central cell, suggesting its regulatory mechanism in GCS1/HAP2-driving gamete membrane fusion. To assess the GCS1/HAP2 regulatory cascade in the double fertilization system of flowering plants, we produced Arabidopsis transgenic lines expressing different GCS1/HAP2 variants and evaluated the fertilization in vivo. The fertilization pattern observed in GCS1 &#95;RNAi transgenic plants implied that sperm cells over the amount of GCS1/HAP2 required for fusion on their surface could facilitate membrane fusion with both female gametes. The cytological analysis of the dmp8dmp9 sperm cell arrested alone in an embryo sac supported GCS1/HAP2 distribution on the sperm surface. Furthermore, the fertilization failures with both female gametes were caused by GCS1/HAP2 secretion from the egg cell. These results provided a possible scenario of GCS1/HAP2 regulation, showing a potential scheme for capturing additional GCS1/HAP2-interacting proteins.

Appetite loss, a common but serious issue in older patients, is an independent risk factor for sarcopenia, which is associated with high mortality. However, few studies have explored the phenomenon of appetite loss after discharge from the intensive care unit (ICU). Therefore, we aimed to describe the prevalence of appetite loss and relationship between appetite loss and depression in patients living at home 12 months after intensive care. This study involved secondary analysis of data obtained from a published ambidirectional study examining post-intensive care syndrome 12 months after discharge (SMAP-HoPe study) conducted in 12 ICUs in Japan. We included patients aged > 65 years. The Short Nutritional Assessment Questionnaire and Hospital Anxiety Depression Scale were used for the analysis. Descriptive statistics and a multilevel generalized linear model were used to clarify the relationship between appetite loss and depression. Data from 468 patients were analyzed. The prevalence of appetite loss was 25.4% (95% confidence interval [CI], 21.5-29.4). High severity of depression was associated with a high probability of appetite loss (odds ratio, 1.2; 95%CI, 1.14-1.28; p = 0.00). Poor appetite is common 12 months after intensive care and is associated with the severity of depression., (© 2023. The Author(s).)

Induced pluripotent stem cell (iPSC)-based disease model is a useful tool that can represent the pathophysiology of patient organs that are inaccessible due to invasiveness. Here, we present a method to induce differentiation of Duchenne muscular dystrophy (DMD) patient-derived iPSCs into cardiomyocytes and restore dystrophin expression by exon skipping using antisense nucleic acids. This involves a 20-day multi-step culture process for differentiation to cardiomyocytes, followed by exon-skipping experiments. Additionally, RT-PCR, western blotting, and immunocytochemistry are used to confirm the restoration of dystrophin expression., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Advances in stem cell biology have facilitated cardiac regeneration, and many animal studies and several initial clinical trials have been conducted using human pluripotent stem cell-derived cardiomyocytes (PSC-CMs). Most preclinical and clinical studies have typically transplanted PSC-CMs via the following two distinct approaches: direct intramyocardial injection or epicardial delivery of engineered heart tissue. Both approaches present common disadvantages, including a mandatory thoracotomy and poor engraftment. Furthermore, a standard transplantation approach has yet to be established. In this study, we tested the feasibility of performing intracoronary administration of PSC-CMs based on a commonly used method of transplanting somatic stem cells. Six male cynomolgus monkeys underwent intracoronary administration of dispersed human PSC-CMs or PSC-CM aggregates, which are called cardiac spheroids, with multiple cell dosages. The recipient animals were sacrificed at 4 weeks post-transplantation for histological analysis. Intracoronary administration of dispersed human PSC-CMs in the cynomolgus monkeys did not lead to coronary embolism or graft survival. Although the transplanted cardiac spheroids became partially engrafted, they also induced scar formation due to cardiac ischemic injury. Cardiac engraftment and scar formation were reasonably consistent with the spheroid size or cell dosage. These findings indicate that intracoronary transplantation of PSC-CMs is an inefficient therapeutic approach., (Copyright © 2022. Published by Elsevier Ltd.)

The number of foreign workers in Japan has been increasing in recent years. In Shimane Prefecture, people from non-English speaking countries account for most of the foreign resident population. Language barriers pose numerous challenges for this population. Their problems communicating in the medical context, in particular, contribute to their avoidance of hospitals. In addition to translation machines and English, "Easy Japanese" has been found to help Japanese healthcare workers communicate with foreign patients. "Easy Japanese" refers to easy-to-understand Japanese that involves rephrasing words and sentences. The use of Easy Japanese should be promoted among medical professionals in Japan as it is considered a communication skill that can be improved through practice. A voluntary study group was formed among medical students. During the first session, students were presented with background information, explaining why the need for Easy Japanese is increasing. In the second session, they practiced paraphrasing words. Finally, in the third session, they conducted simulated medical communication and practiced Easy Japanese with foreign residents to determine whether they were able to convey their intentions. Participants were recruited via social networking service, with five participants in the first session, five in the second, and eight in the third. Through this project, it became clear that for participants, the usual way of speaking Japanese came first in practice and that it was difficult for them to produce easy-to-understand phrases at the spur of the moment without practice. Additionally, medical students reported that the expressions they acquired through several practice sessions were helpful when talking with international students on campus. The final session involved a student-led Easy Japanese study group. Based on the students' comments, we found that this study group was useful for them. Accordingly, Easy Japanese education should be continued and expanded to more students in the medical field and to the local community, including foreign residents, to measure its effectiveness., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Oi et al.)

Objective: After revascularization surgery in pediatric patients with moyamoya disease (MMD), resting and avoiding crying is important. However, this inaction is often difficult because of pain or anxiety. Dexmedetomidine (DEX), which has sedative and analgesic properties, may be useful in reducing those uncomfortable conditions; however, its common side effects include bradycardia and hypotension, which have a risk of decreasing the cerebral blood flow. The aim of this study was to investigate the efficacy and safety of using DEX for pediatric patients with MMD in the acute period after revascularization surgery., Methods: This retrospective study included pediatric patients with MMD who underwent revascularization surgery. Based on whether DEX was used for light sedation during postoperative days (PODs) 0-1 after extubation, the patients were divided into DEX or control groups. For neurological outcomes, the incidence of symptomatic cerebral infarction and transient neurological events (TNEs) during PODs 0-1 and the entire hospitalization were investigated. In addition, the Richmond Agitation-Sedation Scale (RASS) was used to assess the effect of DEX, and bradycardia and hypotension were evaluated as side effects., Results: A total of 84 surgical procedures were included in this study (27 in the DEX group and 57 in the control group). During PODs 0-1, symptomatic infarction was not observed in either group. The incidence of TNEs was almost the same in both groups: 2 (7.4%) of the 27 procedures in the DEX group and 4 (7.0%) of the 57 procedures in the control group (p > 0.99). Moreover, the incidences of symptomatic infarction and TNEs during the entire hospitalization did not differ significantly (symptomatic infarction, p > 0.99; TNEs, p = 0.20). Regarding the DEX effect, the median RASS scores during PODs 0-1 were -1.0 (drowsy) in the DEX group and +1.0 (restless) in the control group, showing a significant difference (p < 0.01). Regarding side effects, bradycardia was observed only in 3 (11.1%) of the 27 procedures in the DEX group (p = 0.03), and hypotension was not observed in any of the cases., Conclusions: In pediatric patients with MMD who are extubated after revascularization surgery, DEX produced appropriate light sedation and analgesia. The risk for symptomatic infarction is almost the same in cases in which DEX is used and those in which it is not; however, neurosurgeons should be cautious of bradycardia and TNEs as potential side effects.

Previous studies have shown a relationship between physical and social aspects of the neighborhood environment (e.g., built environment, safety) and physical function in older adults. However, these associations are unclear in older Asian adults because longitudinal studies are lacking. This study examined the effects of neighborhood physical and social environment on longitudinal changes in physical function among Japanese older adults. We analyzed 299 Japanese community-dwelling adults aged ≥65 years. Neighborhood environment was assessed using the International Physical Activity Questionnaire Environment Module. Physical function was assessed using handgrip strength, knee extension muscle strength, 5-m walking time, and a timed up-and-go test (TUG) in baseline and follow-up surveys. Changes in physical function over one year were calculated and classified into decline or maintenance groups based on minimal detectable changes. Multiple logistic regression analysis showed that even after adjusting for confounding factors, good access to recreational facilities affected the maintenance of 5-m walking time (odds ratio [OR] = 2.31, 95% confidence interval [CI]: 1.02-5.21) and good crime safety affected the maintenance of TUG (OR = 1.87, 95%CI: 1.06-3.33). Therefore, it is important to assess both physical and social environmental neighborhood resources in predicting decline in physical function among Japanese older adults.

Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function., Competing Interests: The authors declare that they have no conflicts of interest., (© 2022 The Authors.)

Background: Social isolation and decline of physical function, such as muscle strength and physical performance, are known to be associated with deterioration of functional capacity. However, the relationship between social isolation and physical function has not been sufficiently clarified by a longitudinal observational study., Aims: The aim of this study was to examine whether social isolation is associated with a future decline in physical function in older people., Methods: The participants were 166 community-dwelling older people (aged ≥ 65 years). Social isolation and physical function were assessed using the 6-item Lubben Social Network Scale and handgrip strength, knee extensor strength, usual walking time, and the Timed Up and Go (TUG) test in both the baseline and follow-up surveys. To define the presence or absence of physical function decline over time, we used the minimal detectable change. The associations between social isolation and physical function were analyzed using logistic regression analysis adjusted for confounding factors. Further, to examine the possibility of drop-out bias, inverse probability weighting (IPW) was performed., Results: The results of the logistic regression analysis adjusted for confounding factors showed social isolation at baseline was significantly associated with future TUG decline (OR 2.88, 95% CI 1.15-7.22). Social isolation was not associated with a decline in other physical functions. Similar results were found in an analysis using IPW., Conclusions: Social isolation was an independent risk factor for future TUG decline in community-dwelling older people. Our results indicated that assessment of social isolation may be necessary to assess the risk of physical performance decline., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)