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Abstract Interannual variations provide insight into the sensitivity of convective processes. Thus, CloudSat and ERA5 are used to explore the relationship among convective cores, outflows and environmental conditions during El Niño‐Southern Oscillation (ENSO) cycles. Results reveal greater upper‐tropospheric stability during El Niño, resulting in a lower level of neutral buoyancy compared to La Niña. However, outflow levels remain relatively consistent across ENSO cycles. This suggests that, despite less favorable conditions for deep convection during El Niño, stronger convective intensity is required to achieve outflow levels comparable to those in La Niña. Indeed, our results suggest that convection observed during El Niño tends to have broader cores and lower entrainment rates, translating to greater intensity compared to La Niña. These findings emphasize the importance of considering both large‐scale and convective‐scale processes, providing an update to the fixed anvil temperature (FAT) and the proportionately higher anvil temperature (PHAT) hypotheses as originally proposed.

Abstract Toward the achievement of reliable global kilometer‐scale (k‐scale) climate simulations, we improve the Nonhydrostatic ICosahedral Atmospheric Model (NICAM) by focusing on moist physical processes. A goal of the model improvement is to establish a configuration that can simulate realistic fields seamlessly from the daily‐scale variability to the climatological statistics. Referring to the two representative configurations of the present NICAM, each of which has been used for climate‐scale and sub‐seasonal‐scale experiments, we try to find the appropriate partitioning of fast/local and slow/global‐scale circulations. In a series of sensitivity experiments at 14‐km horizontal resolution, we test (a) the tuning of terminal velocities of rain, snow, and cloud ice, (b) the implementation of turbulent diffusion by the Leonard term, and (c) enhanced vertical resolution. These tests yield reasonable convection triggering and convection‐induced tropospheric moistening, and result in better performance than in previous NICAM climate simulations. In the mean state, double Intertropical Convergence Zone bias disappears, and the zonal contrast of equatorial precipitation, top‐of‐atmosphere radiation balance, vertical temperature profile, and position/strength of subtropical jet are reproduced dramatically better. Variability such as equatorial waves and the Madden–Julian oscillation (MJO) is spontaneously realized with appropriate spectral power balance, and the Asian summer monsoon, boreal‐summer MJO, and tropical cyclone (TC) activities are more realistically simulated especially around the western Pacific. Meanwhile, biases still exist in the representation of low‐cloud fraction, TC intensity, and precipitation diurnal cycle, suggesting that both higher spatial resolutions and further model development are warranted.

Abstract Clouds are the primary source of uncertainty in the prediction of climate change. To reduce the uncertainty of cloud simulations and overcome this difficulty in prediction, many climate modeling centers are now developing a new type of climate model, the global nonhydrostatic atmospheric model, which reduces the uncertainty arising from a cumulus parameterization by computing clouds explicitly using a cloud microphysics scheme. Among the global nonhydrostatic atmospheric models used in recent intercomparison studies, NICAM aims to project climate change by improving our understanding of cloud changes due to warming and related physical processes. NICAM is the first global nonhydrostatic model and was developed by our research team. This review summarizes the outcomes of a recent major five-year research program in Japan for studying climate using NICAM, as well as providing an overview of current issues regarding the use of global kilometer-scale simulations in high-resolution climate modeling.

Introduction: Artificial dermis is an effective therapeutic method for full-thickness dermal defects. However, the currently available artificial dermis made of porcine or bovine type I collagen has several limitations such as incomplete epithelialization and delayed migration of fibrogenic and angiogenic cells into the graft. We previously developed a composite dermal graft containing a mixture of moon jellyfish collagen and porcine type I collagen, and reported its stimulatory effect on both the re-epithelialization of the epidermis and the migration of fibrogenic and angiogenic cells into the graft. In the present study, we examined whether the same effect was observed by administering jellyfish collagen solution externally onto an artificial dermal graft made of bovine type I collagen. Methods: We used a 6 mm full-thickness wound defect model. Moon jellyfish collagen was prepared as a concentrated 0.5% solution and dripped externally onto a transplanted artificial dermal graft made of bovine type I collagen. Wound repair and long-term dermal tissue remodeling were compared between mice administered jellyfish collagen solution on the bovine collagen graft and those transplanted with a composite dermal graft containing the same amounts of jellyfish and bovine collagens. The stimulatory effect of jellyfish collagen solution was also evaluated using diabetic dB/dB mice. Results: External administration of jellyfish collagen solution onto the bovine collagen graft significantly accelerated wound closure compared to control saline. It also decreased the number of inflammatory cells infiltrating the wound and suppressed absorption of the transplanted graft, as well as reduced subsequent scar formation. Furthermore, external administration of jellyfish collagen solution onto the bovine collagen graft improved the delayed wound healing in diabetic model mice, and this effect was superior to that of the currently used basic fibroblast growth factor. Conclusions: External administration of moon jellyfish collagen solution onto a bovine collagen graft significantly accelerated physiological wound healing and prevented excessive scar formation. It also improved wound closure in diabetic model mice, confirming its therapeutic application for intractable skin ulcers caused by impaired wound healing.

Mao et al. report highly sensitive quantification of carbon monoxide with a simple colorimetric assay, exploiting a synthetic supramolecular compound, hemoCD1. It can reveal distribution of CO in organs including the brain and can also serve as a CO scavenger for residual CO accumulated in organs. Finally, the authors showed circulating hemoglobin plays a protective role in CO intoxication.

Abstract Previous projections of the frequency of tropical cyclone genesis due to global warming, even in terms of sign of the change, depends on the chosen model simulation. Here, we systematically examine projected changes in tropical cyclones using six global atmospheric models with medium-to-high horizontal resolutions included in the sixth phase of the Coupled Model Intercomparison Project/High-Resolution Model Intercomparison Project. Changes in the frequency of tropical cyclone genesis could be broken down into the contributions from (i) the tropical cyclone seed, a depression having a closed contour of sea level pressure with a warm core and (ii) the survival rate, the ratio of the frequency of tropical cyclone genesis to that of tropical cyclone seeds. The multi-model ensemble mean indicates that tropical cyclone genesis frequencies are significantly decreased during the period 1990–2049, which is attributable to changes in tropical cyclone seeds. Analysis of the individual models shows that although most models project a more or less decreasing trend in tropical cyclone genesis frequencies and seeds, the survival rate also contributes to the result in some models. The present study indicates the usefulness of decomposition into the frequency of the tropical cyclone seeds and the survival rate to understand the cause of uncertainty in projected frequencies of tropical cyclone genesis.

Abstract This is the first paper that analyzes data from atmosphere model intercomparison project‐type climate simulations using a cloud‐system‐resolving global nonhydrostatic model without cumulus parameterization focussing particulaly on the relationship between clouds and circulation, and their changes due to global warming. The decrease in fractional coverage of low clouds is key to evaluating cloud radiative effects, because changes in shortwave cloud radiative effects overwhelm those of longwave cloud radiative effects. Thus, improved evaluation of low clouds is important, even in high‐resolution climate simulations. An analysis of heat redistribution by explicitly computed clouds revealed that column‐integrated heating rate due to phase changes correlates highly with vertical velocity at the altitude corresponding to 500 hPa and is closely linked to column water vapor, similar to the present climate result. Using data from year 1 to year 5, the effective climate sensitivity was evaluated to be 3.6−3.7°C. Possible convective aggregation is also examined using an index of modified subsidence fraction and characteristic changes in the number of cold pools. Despite previous idealized‐planet simulations showing more aggregated tropical convection under warmer conditions, here we show a decrease in the subsidence fraction and an increase in the number of smaller cold pools, suggesting that it is possible to realize less convective organization with warming under real atmospheric conditions.

Fulminant myocarditis causes impaired cardiac function, leading to poor prognosis and heart failure. Cell sheet engineering is an effective therapeutic option for improving cardiac function. Naïve blood mononuclear cells (MNCs) have been previously shown to enhance the quality and quantity of cellular fractions (QQMNCs) with anti-inflammatory and vasculogenic potential using the one culture system. Herein, we investigated whether autologous cell sheet transplant with QQMNCs improves cardiac function in a rat model with experimental autoimmune myocarditis (EAM). Fibroblast sheets (F-sheet), prepared from EAM rats, were co-cultured with or without QQMNCs (QQ+F sheet) on temperature-responsive dishes. QQ+F sheet induced higher expression of anti-inflammatory and vasculogenic genes (Vegf-b, Hgf, Il-10, and Mrc1/Cd206) than the F sheet. EAM rats were transplanted with either QQ+F sheet or F-sheet, and the left ventricular (LV) hemodynamic analysis was performed using cardiac catheterization. Among the three groups (QQ+F sheet, F-sheet, operation control), the QQ+F sheet transplant group showed alleviation of end-diastolic pressure–volume relationship on a volume load to the same level as that in the healthy group. Histological analysis revealed that QQ+F sheet transplantation promoted revascularization and mitigated fibrosis by limiting LV remodeling. Therefore, autologous QQMNC-modified F-sheets may be a beneficial therapeutic option for EAM.

Abstract In estimates of climate sensitivity obtained from global models, the need to represent clouds introduces a great deal of uncertainty. To address this issue, approaches using a high-resolution global non-hydrostatic model are promising: the model captures cloud structure by explicitly simulating meso-scale convective systems, and the results compare reasonably well with satellite observations. We review the outcomes of a 5-year project aimed at reducing the uncertainty in climate models due to cloud processes using a global non-hydrostatic model. In our project, which was conducted as a subgroup of the Program for Risk Information on Climate Change, or SOUSEI, we use the non-hydrostatic icosahedral atmospheric model (NICAM) to study cloud processes related to climate change. NICAM performs numerical simulations with much higher resolution (about 7 km or 14 km mesh) than conventional global climate models (GCMs) using cloud microphysics schemes without a cumulus parameterization scheme, which causes uncertainties in climate projection. The subgroup had three research targets: analyzing cloud changes in global warming simulations with NICAM with the time-slice approach, sensitivity of the results to the cloud microphysics scheme employed, and evaluating circulation changes due to global warming. The research project also implemented a double-moment bulk cloud microphysics scheme and evaluated its results using satellite observation, as well as comparing it with a bin cloud microphysics scheme. The future projection simulations show in general increase in high cloud coverage, contrary to results with other GCMs. Changes in cloud horizontal-size distribution size and structures of tropical/extratropical cyclones can be discussed with high resolution simulations. At the conclusion of our review, we also describe the future prospects of research for global warming using NICAM in the program that followed SOUSEI, known as TOUGOU.

Abstract Satellite observation and general circulation model (GCM) studies suggest that precipitating ice makes nonnegligible contributions to the radiation balance of the Earth. However, in most GCMs, precipitating ice is diagnosed and its radiative effects are not taken into account. Here we examine the longwave radiative impact of precipitating ice using a global nonhydrostatic atmospheric model with a double‐moment cloud microphysics scheme. An off‐line radiation model is employed to determine cloud radiative effects according to the amount and altitude of each type of ice hydrometeor. Results show that the snow radiative effect reaches 2 W m−2 in the tropics, which is about half the value estimated by previous studies. This effect is strongly dependent on the vertical separation of ice categories and is partially generated by differences in terminal velocities, which are not represented in GCMs with diagnostic precipitating ice. Results from sensitivity experiments that artificially change the categories and altitudes of precipitating ice show that the simulated longwave heating profile and longwave radiation field are sensitive to the treatment of precipitating ice in models. This study emphasizes the importance of incorporating appropriate treatments for the radiative effects of precipitating ice in cloud and radiation schemes in GCMs in order to capture the cloud radiative effects of upper level clouds.

Abstract This article reviews the major outcomes of a 5-year (2011–2016) project using the K computer to perform global numerical atmospheric simulations based on the non-hydrostatic icosahedral atmospheric model (NICAM). The K computer was made available to the public in September 2012 and was used as a primary resource for Japan’s Strategic Programs for Innovative Research (SPIRE), an initiative to investigate five strategic research areas; the NICAM project fell under the research area of climate and weather simulation sciences. Combining NICAM with high-performance computing has created new opportunities in three areas of research: (1) higher resolution global simulations that produce more realistic representations of convective systems, (2) multi-member ensemble simulations that are able to perform extended-range forecasts 10–30 days in advance, and (3) multi-decadal simulations for climatology and variability. Before the K computer era, NICAM was used to demonstrate realistic simulations of intra-seasonal oscillations including the Madden-Julian oscillation (MJO), merely as a case study approach. Thanks to the big leap in computational performance of the K computer, we could greatly increase the number of cases of MJO events for numerical simulations, in addition to integrating time and horizontal resolution. We conclude that the high-resolution global non-hydrostatic model, as used in this five-year project, improves the ability to forecast intra-seasonal oscillations and associated tropical cyclogenesis compared with that of the relatively coarser operational models currently in use. The impacts of the sub-kilometer resolution simulation and the multi-decadal simulations using NICAM are also reviewed.

Abstract A stratocumulus‐to‐cumulus transition as observed in a cold air outbreak over the North Atlantic Ocean is compared in global climate and numerical weather prediction models and a large‐eddy simulation model as part of the Working Group on Numerical Experimentation “Grey Zone” project. The focus of the project is to investigate to what degree current convection and boundary layer parameterizations behave in a scale‐adaptive manner in situations where the model resolution approaches the scale of convection. Global model simulations were performed at a wide range of resolutions, with convective parameterizations turned on and off. The models successfully simulate the transition between the observed boundary layer structures, from a well‐mixed stratocumulus to a deeper, partly decoupled cumulus boundary layer. There are indications that surface fluxes are generally underestimated. The amount of both cloud liquid water and cloud ice, and likely precipitation, are under‐predicted, suggesting deficiencies in the strength of vertical mixing in shear‐dominated boundary layers. But also regulation by precipitation and mixed‐phase cloud microphysical processes play an important role in the case. With convection parameterizations switched on, the profiles of atmospheric liquid water and cloud ice are essentially resolution‐insensitive. This, however, does not imply that convection parameterizations are scale‐aware. Even at the highest resolutions considered here, simulations with convective parameterizations do not converge toward the results of convection‐off experiments. Convection and boundary layer parameterizations strongly interact, suggesting the need for a unified treatment of convective and turbulent mixing when addressing scale‐adaptivity.

BackgroundConsidering the impaired function of regenerative cells in myocardial infarction (MI) patients with comorbidities and associated risk factors, cell therapy to enhance the regenerative microenvironment was designed using regeneration-associated cells (RACs), including endothelial progenitor cells (EPCs) and anti-inflammatory cells.MethodsRACs were prepared by quality and quantity control culture of blood mononuclear cells (QQMNCs). Peripheral blood mononuclear cells (PBMNCs) were isolated from Lewis rats and conditioned for 5 days using a medium containing stem cell factors, thrombopoietin, Flt-3 ligand, vascular endothelial growth factor, and interleukin-6 to generate QQMNCs.ResultsA 5.3-fold increase in the definitive colony-forming EPCs and vasculogenic EPCs was observed, in comparison to naïve PBMNCs. QQMNCs were enriched with EPCs (28.9-fold, PConclusionQQMNCs conferred potent angiogenic and anti-inflammatory properties to the regenerative microenvironment, enhancing myocardiogenesis and functional recovery of rat MI hearts.

Oxidative stress contributes to myocardial ischemia-reperfusion injury, which causes cardiomyocyte death and precipitate life-threatening heart failure. Propofol has been proposed to protect cells or tissues against oxidative stress. However, the mechanisms underlying its beneficial effects are not fully elucidated. In the present study, we employed an in vitro oxidative injury model, in which rat cardiac H9c2 cells were treated with H2O2, and investigated roles of propofol against oxidative stress. Propofol treatment reduced H2O2-induced apoptotic cell death. While H2O2 induced expression of the antioxidant enzyme HO-1, propofol further increased HO-1 mRNA and protein levels. Propofol also promoted nuclear localization of Nrf2 in the presence of H2O2. Knockdown of Nrf2 using siRNA suppressed propofol-inducible Nrf2 and expression of Nrf2-downstream antioxidant enzyme. Knockdown of Nrf2 suppressed the propofol-induced cytoprotection. In addition, Nrf2 overexpression induced nuclear localization of Nrf2 and HO-1 expression. These results suggest that propofol exerts antioxidative effects by inducing nuclear localization of Nrf2 and expression of its downstream enzyme in cardiac cells. Finally, we examined the effect of propofol on cardiomyocytes using myocardial ischemia-reperfusion injury models. The expression level of Nrf2 protein was increased at 15 min after reperfusion in the ischemia-reperfusion and propofol group compared with ischemia-reperfusion group in penumbra region. These results suggest that propofol protects cells or tissues from oxidative stress via Nrf2/HO-1 cascade.

Aerobic glycolysis, the main pathway of energy production in tumors (Warburg effect) allows detection of tumors by positron emission tomography (PET) using 18F-fluoro-2-deoxy-D-glucose (18F-FDG). Since ionizing radiation (IR) is reported to switch aerobic glycolysis to mitochondrial oxidative phosphorylation, radiotherapeutic efficacy was monitored by the activity of mitochondrial complex I (MC-I), using a new PET probe 18F-BCPP-EF, 18F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoro-ethoxy)-ethoxy] -pyridine-3-ylmethoxy}-2H-pyridazin-3-one, compared with 18F-FDG uptake and the apoptosis index.Tumor uptake of 18F-BCPP-EF or 18F-FDG was examined in C3H/HeN mice inoculated with murine squamous cell carcinoma SCCVII at various time points after a single dose of x-ray irradiation at 0, 6, 15, or 30 Gy. Apoptosis incidence was determined by TUNEL staining in excised tumor tissue.Tumor growth suppression was dose-dependent; tumor grew 10-fold (0 Gy), 5-fold (6 Gy), 2-fold (15 Gy), and reduced to half in its volume (30 Gy) 14 days after treatment. 18F-BCPP-EF uptake was significantly increased as early as 3 days after 15 Gy or 30 Gy, when tumor size and apoptosis index showed no difference among radiation doses. In contrast, 18F-FDG uptake was initially increased dose-dependently, remained elevated up to 7 days, and eventually decreased 10 days after 30 Gy and also 14 days after 15 Gy when tumor size was already reduced. Apoptosis index was increased after irradiation but failed to correlate with tumor response.Tumor uptake of 18F-BCPP-EF was increased dose-dependently early after effective doses of IR when 18F-FDG uptake as well as apoptosis incidence were not indicative of tumor response. The results suggest that 18F-BCPP-EF is a promising "positive" MC-I imaging PET probe for early detection of efficacy of tumor radiotherapy.

Acute aortic dissection is the most common life-threatening vascular disease, with sudden onset of severe pain and a high fatality rate. Clarifying the detailed mechanism for aortic dissection is of great significance for establishing effective pharmacotherapy for this high mortality disease. In the present study, we evaluated the influence of biomechanical stretch, which mimics an acute rise in blood pressure using an experimental apparatus of stretching loads in vitro, on rat aortic smooth muscle cell (RASMC) death. Then, we examined the effects of azelnidipine and mitogen-activated protein kinase inhibitors on mechanical stretch-induced RASMC death. The major findings of the present study are as follows: (1) cyclic mechanical stretch on RASMC caused cell death in a time-dependent manner up to 4 h; (2) cyclic mechanical stretch on RASMC induced c-Jun N-terminal kinase (JNK) and p38 activation with peaks at 10 min; (3) azelnidipine inhibited RASMC death in a concentration-dependent manner as well as inhibited JNK and p38 activation by mechanical stretch; and (4) SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) protected against stretch-induced RASMC death; (5) Antioxidants, diphenylene iodonium and tempol failed to inhibit stretch-induced RASMC death. On the basis of the above findings, we propose a possible mechanism where an acute rise in blood pressure increases biomechanical stress on the arterial walls, which induces RASMC death, and thus, may lead to aortic dissection. Azelnidipine may be used as a pharmacotherapeutic agent for prevention of aortic dissection independent of its blood pressure lowering effect.

Toward the achievement of reliable global kilometer‐scale (k‐scale) climate simulations, we improve the Nonhydrostatic ICosahedral Atmospheric Model (NICAM) by focusing on moist physical processes. A goal of the model improvement is to establish a configuration that can simulate realistic fields seamlessly from the daily‐scale variability to the climatological statistics. Referring to the two representative configurations of the present NICAM, each of which has been used for climate‐scale and sub‐seasonal‐scale experiments, we try to find the appropriate partitioning of fast/local and slow/global‐scale circulations. In a series of sensitivity experiments at 14‐km horizontal resolution, we test (a) the tuning of terminal velocities of rain, snow, and cloud ice, (b) the implementation of turbulent diffusion by the Leonard term, and (c) enhanced vertical resolution. These tests yield reasonable convection triggering and convection‐induced tropospheric moistening, and result in better performance than in previous NICAM climate simulations. In the mean state, double Intertropical Convergence Zone bias disappears, and the zonal contrast of equatorial precipitation, top‐of‐atmosphere radiation balance, vertical temperature profile, and position/strength of subtropical jet are reproduced dramatically better. Variability such as equatorial waves and the Madden–Julian oscillation (MJO) is spontaneously realized with appropriate spectral power balance, and the Asian summer monsoon, boreal‐summer MJO, and tropical cyclone (TC) activities are more realistically simulated especially around the western Pacific. Meanwhile, biases still exist in the representation of low‐cloud fraction, TC intensity, and precipitation diurnal cycle, suggesting that both higher spatial resolutions and further model development are warranted. Plain Language Summary: In the near future, increasing computational power will make it possible to perform a global kilometer‐scale "cloud‐resolving" model (GCRM) simulation on the climate time scale, which is expected to reduce the uncertainty of cloud‐related processes in the climate system. In this sense, it is important to make GCRMs more reliable tools in the evaluation and prediction of the variabilities over a wide range of spatio‐temporal scales. With this perspective, we improve a Japanese GCRM, the Nonhydrostatic Atmospheric Icosahedral Model (NICAM), to achieve the realistic representation of both weather phenomena and climatological features in long‐term simulations. We revise the NICAM by the reconsideration of cloud microphysics properties, the implementation of diffusion processes around strong convection cores, and increased vertical layers. These revisions lead to the substantial improvements in the climatological mean precipitation distributions, radiative energy balance at the top of the atmosphere, westerly jets in the mid‐latitude, and temperature fields. We also find that weather phenomena such as the Asian summer monsoon and tropical cyclone (TC) genesis are simulated more realistically. We expect that, in addition to the above model improvements, kilometer‐scale horizontal resolutions can resolve a part of remaining issues of the representation of TC intensity and precipitation diurnal cycle. Key Points: We improve a global nonhydrostatic atmospheric model focusing on resolution‐independent errors that can exist even in k‐scale climate runsKey improvements are retuning of cloud microphysics properties, consideration of grid‐scale turbulent mixing, and increased vertical layersBiases in mean rainfall, radiation balance, and circulation as well as weather (monsoon, Madden–Julian oscillation, equatorial wave, tropical cyclone) are reduced [ABSTRACT FROM AUTHOR]

S-Nitrosoglutathione reductase (GSNOR) is a key regulator of protein S-nitrosylation, the covalent modification of cysteine residues by nitric oxide that can affect activities of many proteins. We recently discovered that excessive S-nitrosylation from GSNOR deficiency in mice under inflammation inactivates the key DNA repair protein O(6) -alkylguanine-DNA alkyltransferase and promotes both spontaneous and carcinogen-induced hepatocellular carcinoma. To explore further the mechanism of tumorigenesis due to GSNOR deficiency, we compared the protein expression profiles in the livers of wild-type and GSNOR-deficient (GSNOR(-/-) ) mice that were challenged with lipopolysaccharide to induce inflammation and expression of inducible nitric oxide synthase (iNOS). Two-dimensional difference gel electrophoresis analysis identified 38 protein spots of significantly increased intensity and 31 protein spots of significantly decreased intensity in the GSNOR(-/-) mice compared to those in the wild-type mice. We subsequently identified 19 upregulated and 19 downregulated proteins in GSNOR(-/-) mice using mass spectrometry. Immunoblot analysis confirmed in GSNOR(-/-) mice a large increase in the expression of the pro-inflammatory mediator S100A9, a protein previously implicated in human liver carcinogenesis. We also found a decrease in the expression of multiple members of the protein disulfide-isomerase (PDI) family and an alteration in the expression pattern of the endoplasmic reticulum (ER) chaperones in GSNOR(-/-) mice. Furthermore, altered expression of these proteins from GSNOR deficiency was prevented in mice lacking both GSNOR and iNOS. In addition, we detected S-nitrosylation of two members of the PDI protein family. These results suggest that S-nitrosylation resulting from GSNOR deficiency may promote carcinogenesis under inflammatory conditions in part through the disruption of inflammatory and ER stress responses.

Abstract Peritoneal inflammation and fibrosis remain major challenges to the long-term maintenance of peritoneal dialysis. Pemafibrate, a selective peroxisome proliferator-activated receptor α (PPARα) modulator, has been implicated in the management of fibrosis-related disorders. We investigated whether pemafibrate ameliorates peritoneal inflammation and fibrosis and explored the underlying mechanisms in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO mice). MGO mice exhibited peritoneal fibrosis with increased expression of mesenchymal markers, transforming growth factor-β1 (TGF-β1), and substantial deposition of extracellular matrix (ECM) proteins. Additionally, MGO mice exhibited peritoneal inflammation as indicated by elevated tumor necrosis factor-α expression and macrophage infiltration in peritoneal tissue. These effects were mitigated by pemafibrate treatment, which also restored peritoneal membrane function. Furthermore, pemafibrate promoted anti-inflammatory macrophage polarization in both mice and THP-1 cells. In human peritoneal mesothelial cells (HPMCs), pemafibrate effectively inhibited interferon-γ-induced production of TGF-β1 and ECM while suppressing the proinflammatory cytokines nuclear factor-κB (NF-κB) and activator protein 1. The NF-κB inhibitory effect of pemafibrate involved stabilization of the NF-κB inhibitory protein IkBα. Notably, pemafibrate hindered activation of the NLR family pyrin domain containing 3/caspase-1 axis in interferon-γ-stimulated THP-1 cells. These findings suggest that pemafibrate ameliorates peritoneal inflammation and fibrosis, making it a promising candidate for peritoneal fibrosis therapy.

Abstract Background In the context of cardiovascular surgery, the foremost concern lies in delayed functional recovery, as typified by the acquisition of independent walking after surgery, among older patients with decline in skeletal muscle mass and quality. Computed tomography (CT), which is typically employed for the preoperative assessment of pathological conditions in patients undergoing cardiovascular surgery, is also suitable for screening for potential decline in skeletal muscle mass and quality. The aim of this study was to examine the predictive capabilities of CT‐derived parameters such as muscle mass and muscle quality for the delayed acquisition of independent walking in the postoperative period. Methods This retrospective study enrolled consecutive Japanese patients who underwent elective cardiovascular surgery between May 2020 and January 2023. In total, 139 patients were included in the analyses. Based on the preoperative CT image, the psoas muscle volume index (PMVI) and psoas muscle attenuation (PMA) were calculated. Information on patient characteristics, including preoperative physical fitness such as handgrip strength/body mass index (GS/BMI), short physical performance battery (SPPB), and 6‐min walking distance (6MWD), were obtained from the medical records. We defined delayed acquisition of independent walking after surgery as the inability to walk 100 m within 4 days after surgery. Results The median age of the patients was 72 (interquartile: 64–78) years, and 74.8% (104/139) were men; 47.5% corresponded to the delayed group. The areas under the curves of SPPB, GS/BMI, 6MWD, PMVI, and PMA against delayed acquisition of independent walking after surgery were 0.68 [95% confidence interval (CI): 0.59 to 0.77], 0.72 (95% CI: 0.63 to 0.80), 0.73 (95% CI: 0.65 to 0.82), 0.69 (95% CI: 0.60 to 0.78), and 0.78 (95% CI: 0.70 to 0.85), respectively. In the multivariate logistic regression analysis, low PMA was significantly associated with delayed acquisition of independent walking even after adjustment for patient characteristics including physical fitness [model 1: SPPB (OR, 1.14; 95% CI: 1.03–1.25), model 2: GS/BMI (OR, 1.13; 95% CI: 1.03–1.25), and model 3: 6MWD (OR, 1.14; 95% CI: 1.03–1.25)], but PMVI was not. Conclusions Our study revealed a strong association between PMA, a marker of CT‐derived muscle quality, and the postoperative delay in achieving independent walking in patients who underwent cardiovascular surgery. The technique to obtain information on muscle quality during the time period before surgery may be an option for timely therapeutic intervention in patients who may have delayed acquisition of independent walking after surgery.

Purpose: Non-obstructive azoospermia (NOA) represents the persistent absence of sperm in ejaculate without obstruction, stemming from diverse disease processes. This survey explores global practices in NOA diagnosis, comparing them with guidelines and offering expert recommendations. Materials and Methods:Materials and Methods: A 56-item questionnaire survey on NOA diagnosis and management was conducted globally from July to September 2022. This paper focuses on part 1, evaluating NOA diagnosis. Data from 367 participants across 49 coun-tries were analyzed descriptively, with a Delphi process used for expert recommendations. Results:Results: Of 336 eligible responses, most participants were experienced attending physicians (70.93%). To diagnose azoosper-mia definitively, 81.7% requested two semen samples. Commonly ordered hormone tests included serum follicle-stimulating hormone (FSH) (97.0%), total testosterone (92.9%), and luteinizing hormone (86.9%). Genetic testing was requested by 66.6%, with karyotype analysis (86.2%) and Y chromosome microdeletions (88.3%) prevalent. Diagnostic testicular biopsy, distinguishing obstructive azoospermia (OA) from NOA, was not performed by 45.1%, while 34.6% did it selectively. Differ-entiation relied on physical examination (76.1%), serum hormone profiles (69.6%), and semen tests (68.1%). Expectations of finding sperm surgically were higher in men with normal FSH, larger testes, and a history of sperm in ejaculate. Conclusions:Conclusions: This expert survey, encompassing 367 participants from 49 countries, unveils congruence with recommended guidelines in NOA diagnosis. However, noteworthy disparities in practices suggest a need for evidence-based, international consensus guidelines to standardize NOA evaluation, addressing existing gaps in professional recommendations.

Abstract Hepatic glucose metabolism serves dual purposes: maintaining glucose homeostasis and converting glucose into energy sources; however, the underlying mechanisms are unclear. We quantitatively measured liver metabolites, gene expression, and phosphorylated insulin signaling molecules in mice orally administered varying doses of glucose, and constructed a transomic network. Rapid phosphorylation of insulin signaling molecules in response to glucose intake was observed, in contrast to the more gradual changes in gene expression. Glycolytic and gluconeogenic metabolites and expression of genes involved in glucose metabolism including glucose-6-phosphate, G6pc, and Pck1, demonstrated high glucose dose sensitivity. Whereas, glucokinase expression and glycogen accumulation showed low glucose dose sensitivity. During the early phase after glucose intake, metabolic flux was geared towards glucose homeostasis regardless of the glucose dose but shifted towards energy conversion during the late phase at higher glucose doses. Our research provides a comprehensive view of time- and dose-dependent selective glucose metabolism.

Background: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is reported to be a secondary cause of chronic intestinal pseudo-obstruction (CIPO). Although few case reports have described CIPO in MELAS, effective treatment for CIPO has not been established. Here, we present a case report of amelioration of CIPO symptoms using acotiamide in a patient with MELAS. Case Presentation: A 51-year-old Japanese female with a mitochondrial disorder with m.3243A>G mutation and a history of anorexia for two years presented to our hospital with a left temporal headache and acute paraphasia. A stroke-like episode of MELAS was suspected, and combined therapy with arginine, edaravone, and levetiracetam was initiated. Although her symptoms improved, she presented with nausea and vomiting and abdominal distension six days following admission. Abdominal contrast-enhanced computed tomography revealed dilatation from the stomach to the intestine, particularly marked the stomach, with neither obstruction nor impaired blood flow in the intestine. CIPO exacerbation with MELAS was suspected, and the patient’s symptoms gradually improved with acotiamide. Conclusion: Patients with MELAS could possibly experience stroke-like episodes during CIPO. Since acetylcholine possibly plays an important role in the pathophysiology of CIPO and acotiamide possesses prokinetic activity by inhibiting acetylcholinesterase, acotiamide could possibly improve CIPO symptoms.

Abstract Purpose Postoperative venous thromboembolism (VTE) risk is pronounced after abdominal cancer surgery. Enoxaparin shows promise in preventing VTE in gastrointestinal, gynecological, and urological cancers, but its application after surgery for hepatobiliary‐pancreatic malignancy has been under‐evaluated due to bleeding concerns. We confirmed the safety of enoxaparin administration in patients undergoing curative hepatobiliary‐pancreatic surgery for malignancies in a prospective, multi‐center, phase I study. Methods The study was conducted from April 2015 to May 2021 across eight specialized centers. Patients (n = 262) were randomized to enoxaparin prophylaxis given postoperatively for 8 days (n = 131) or control (n = 131). The primary endpoint was the efficacy in reducing VTE. Secondary endpoints examined safety. Results The full analysis set included 259 patients (131 control, 129 enoxaparin). The per‐protocol population included 233 patients (117 control, 116 enoxaparin). Most cases were hepatic malignancies (111 control, 111 enoxaparin). The median administration duration of enoxaparin was 7 days, with 92% receiving 4000 units/day. Despite a reduction in the relative risk (RR) of VTE due to postoperative enoxaparin administration, the results were not significant (control: four cases, 3.4% vs. treatment: two cases, 1.7%; RR 0.50, 95% CI 0.09–2.70; p = 0.6834). No significant difference was found in the incidence of bleeding events (control: five cases, 4.3% vs. treatment: five cases, 4.3%, RR 1.00, 95% CI 0.53–1.89; p = 1.0000). Conclusions The perioperative administration of enoxaparin in hepatobiliary‐pancreatic malignancies is feasible and safe. However, further case accumulation and investigation are necessary to assess its potential in reducing the occurrence of VTE.

Introduction: TP53 is a strong tumor suppressor gene; its deactivation contributes to carcinogenesis and influences clinical outcomes. However, the prognostic influence of p53 deactivation on early relapse in patients with surgically resected non–small cell lung cancer remains unclear. Materials and methods: A cohort of 170 patients with primary stage I through III lung adenocarcinoma (LADC) and lung squamous cell carcinoma who underwent complete resection at Tokyo Medical and Dental University was screened for TP53 mutations using panel testing, and association studies between TP53 mutations and clinical data, including histology and postoperative recurrence, were performed. The association between TP53 mutations and postoperative recurrence was validated using data from 604 patients with MSK-IMPACT from The Cancer Genome Atlas. Additional immunohistochemistry for p53 was performed on some subsets of the Tokyo Medical and Dental University population. Results: Mutations in TP53 were recurrently observed (35.9%; 61 out of 170) in the Tokyo Medical and Dental University cohort. In the histology-stratified analysis, patients with LADC histology showed TP53 mutations that were associated with poor relapse-free survival (log-rank test; P = .020), whereas patients with lung squamous cell carcinoma histology showed TP53 mutations that were not (P = .99). The poor prognosis of TP53 mutation-positive LADCs was validated in The Cancer Genome Atlas-LADC cohort (log-rank test; P = .0065). Additional immunohistochemistry for p53 in patients with LADC histology in the Tokyo Medical and Dental University cohort showed a significant correlation between TP53 mutations and abnormal IHC pattern of p53 (Cramer's correlation coefficient V = 0.67). Conclusions: TP53 mutation is a potential marker for worse prognosis in surgically resected LADC; immunohistochemistry for p53 could be a surrogate method to identify patients with LADC with a worse prognosis.