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Prognosis of breast cancer patients has been improved along with the progress in cancer therapies. However, cancer therapeutics-related cardiac dysfunction (CTRCD) has been an emerging issue. For early detection of CTRCD, we examined whether native T1 mapping and global longitudinal strain (GLS) using cardiac magnetic resonance (CMR) and biomarkers analysis are useful.We prospectively enrolled 83 consecutive chemotherapy-naïve female patients with breast cancer (mean age, 56 ± 13 yrs.) between 2017 and 2020. CTRCD was defined based on echocardiography as left ventricular ejection fraction (LVEF) below 53% at any follow-up period with LVEF10% points decrease from baseline after chemotherapy. To evaluate cardiac function, CMR (at baseline and 6 months), 12‑lead ECG, echocardiography, and biomarkers (at baseline and every 3 months) were evaluated.A total of 164 CMRs were performed in 83 patients. LVEF and GLS were significantly decreased after chemotherapy (LVEF, from 71.2 ± 4.4 to 67.6 ± 5.8%; GLS, from -27.9 ± 3.9 to -24.7 ± 3.5%, respectively, both P 0.01). Native T1 value also significantly elevated after chemotherapy (from 1283 ± 36 to 1308 ± 39 msec, P 0.01). Among the 83 patients, 7 (8.4%) developed CTRCD. Of note, native T1 value before chemotherapy was significantly higher in patients with CTRCD than in those without it (1352 ± 29 vs. 1278 ± 30 msec, P 0.01). The multivariable logistic regression analysis revealed that native T1 value was an independent predictive factor for the development of CTRCD [OR 2.33; 95%CI 1.15-4.75, P = 0.02].These results indicate that CMR is useful to detect chemotherapy-related myocardial damage and predict for the development of CTRCD in breast cancer patients.

The Thermal and Near-Infrared Sensor for Carbon Observation Fourier-Transform Spectrometer-2 (TANSO-FTS-2) onboard the Japanese Greenhouse Gases Observing SATellite-2 (GOSAT-2) observes a wide spectral region of the atmosphere, from the ShortWave-InfraRed (SWIR) to the longwave Thermal InfraRed radiation (TIR) with 0.2 cm−1 spectral sampling, and the corresponding spectral resolution (full width at half maximum, FWHM) of TIR region is less than 0.27 cm−1. TANSO-FTS-2 has operated nominally since February 2019, and the atmospheric radiance spectra it has acquired have been released to the public. This paper describes an updated model for spectral radiance calibration and its validation. The model applies to the version v210210 TIR products of TANSO-FTS-2 and integrates polarization sensitivity correction for the internal optics and the pointing mirror thermal emission. These correction parameters are characterized by an optimization that depends on the difference between the spectral radiance of TANSO-FTS-2 and coincident nadir observation data from the Infrared Atmospheric Sounding Interferometer (IASI) on METOP-B. To validate the updated spectral radiance product against other satellite products, temporally and spatially coincident observation points were considered for the simultaneous nadir overpass (SNO) from February 2019 to March 2021 from the Atmospheric Infrared Sounder (AIRS) on Aqua, IASI on METOP-B, and TANSO-FTS on GOSAT. The agreement of brightness temperatures between TANSO-FTS-2 and AIRS and IASI was better than 0.3 K (1σ) from 180 to 330 K for the 680 cm−1 CO2 spectral range. The brightness temperatures between TANSO-FTS-2 and TANSO-FTS of version v230231, which implemented a new polarization reflectivity of the pointing mirror and was released in June 2021, generally agree from 220 to 320 K. However, there is a discrepancy at lower brightness temperatures, pronounced for CO2 spectral ranges at high latitudes. To characterize the spectral radiance bias for along-track and cross-track angles, a 2-orthogonal simultaneous off-nadir overpass (2O-SONO) is now done for TANSO-FTS-2 and IASI, TANSO-FTS-2 and AIRS, and TANSO-FTS-2 and TANSO-FTS. The 2O-SONO comparison results indicate that the TIR product for TANSO-FTS-2 has a bias that exceeds 0.5 K in the CO2 spectral range for scenes with forward and backward viewing angles greater than 20∘. These multi-satellite sensor and multi-angle comparison results suggest that the calibration of spectral radiance for TANSO-FTS-2 TIR, version v210210, is superior to that of the previous version in its consistency of multi-satellite sensor data. In addition, the paper identifies the remaining challenging issues in current TIR products.

Although cardiac troponin and natriuretic peptide have been shown to decrease after balloon pulmonary angioplasty (BPA) with improved right ventricular afterload in chronic thromboembolic pulmonary hypertension (CTEPH), biomarkers to evaluate the effects of BPA independently of heart failure status remain to be developed.In 39 consecutive CTEPH patients including 31 who underwent BPA, we measured plasma levels of cyclophilin A (CyPA), which we demonstrated is secreted from pulmonary vascular smooth muscle cells in response to mechanical stretch and hypoxia.CyPA levels were elevated in CTEPH patients (12.7, IQR: 7.6-16.0) compared with 8 thromboembolic controls with a history of venous thromboembolism (4.9, IQR: 2.4-11.2) or 18 healthy controls (4.1, IQR: 2.4-6.8) (both p0.05) and were linearly correlated with mean pulmonary arterial pressure (r=0.50, p = 0.0003) and pulmonary vascular resistance (r=0.32, p= 0.026). BPA reduced CyPA levels and tended to lower brain-type natriuretic peptide (BNP) levels (p0.01 and p = 0.07). When comparing the changes in CyPA before and after BPA in the two subgroups with higher (≥35pg/mL) and normal (35pg/mL) BNP at baseline, CyPA decreased both in patients with higher BNP and those with normal BNP (both p0.05). In contrast, BNP decreased only in patients with higher BNP (p0.05). Also, CyPA decreased both in patients with lower (25 kg/mCyPA could be a useful biomarker to evaluate the effects of BPA even in patients with normal BNP or high BMI.

The Thermal and Near-Infrared Sensor for Carbon Observation Fourier-Transform Spectrometer-2 (TANSO-FTS-2) onboard the Japanese Greenhouse gases Observing SATellite-2 (GOSAT-2) observes a wide spectral region of the atmosphere, from the ShortWave-InfraRed (SWIR) to longwave Thermal InfraRed radiation (TIR) with 0.2 cm-1 spectral intervals. The TANSO-FTS-2 has operated nominally since Feb 2019, and the atmospheric radiance spectra it has acquired have been released to the public. This paper describes an updated model for spectral radiance calibration and its validation. The model applies to the version 210210 TIR products of the TANSO-FTS-2 and integrates polarization sensitivity correction for the internal optics and the scanner mirror thermal emission. These correction parameters are characterized by an optimization which depends on the difference between the spectral radiance of the TANSO-FTS-2 and coincident nadir observation data from the Infrared Atmospheric Sounding Interferometer (IASI) on METOP-B. To validate the updated spectral radiance product against other satellite products, temporally and spatially coincident observation points were considered for Simultaneous Nadir Overpass (SNO) from February 2019 to March 2021 from the Atmospheric Infrared Sounder (AIRS) on Aqua, IASI on METOP-B, and TANSO-FTS on GOSAT. The agreement of brightness temperatures between the TANSO-FTS-2 and AIRS and IASI was better than 0.3 K (1σ) from 180 K to 330 K for the 680 cm-1 CO2 channel. The brightness temperatures between the TANSO-FTS-2 and TANSO-FTS of version v230231, which implemented a new polarization reflectivity of the pointing mirror and was released in June 2021, generally agree from 220 K to 320 K. However, there is a discrepancy at lower brightness temperatures, pronounced for CO2 channels at high latitudes. To characterize the spectral radiance bias for along-track and cross-track angles, a 2-Orthogonal Simultaneous Off-Nadir Overpass (2O-SONO) is now done for the TANSO-FTS-2 and IASI, the TANSO-FTS-2 and AIRS, and the TANSO-FTS-2 and TANSO-FTS. The 2O-SONO comparison results indicate that the TIR product for the TANSO-FTS-2 has a bias that exceeds 0.5 K in the CO2 channel for scenes with forward and backward viewing angles greater than 20°. These multi-satellite sensor and multi-angle comparison results suggest that the calibration of spectral radiance for the TANSO-FTS-2 TIR, version v210210, is superior to that of the previous version in its consistency of multi-satellite sensor data. In addition, the paper identifies the remaining challenging issues in current TIR products.

Objective: Excessive proliferation and apoptosis resistance are special characteristics of pulmonary artery smooth muscle cells (PASMCs) in pulmonary arterial hypertension (PAH). However, the drugs in clinical use for PAH target vascular dilatation, which do not exert adequate effects in patients with advanced PAH. Here, we report a novel therapeutic effect of emetine, a principal alkaloid extracted from the root of ipecac clinically used as an emetic and antiprotozoal drug. Approach and Results: We performed stepwise screenings for 5562 compounds from original library. First, we performed high-throughput screening with PASMCs from patients with PAH (PAH-PASMCs) and found 80 compounds that effectively inhibited proliferation. Second, we performed the repeatability and counter assay. Finally, we performed a concentration-dependent assay and found that emetine inhibits PAH-PASMC proliferation. Interestingly, emetine significantly reduced protein levels of HIFs (hypoxia-inducible factors; HIF-1α and HIF-2α) and downstream PDK1 (pyruvate dehydrogenase kinase 1). Moreover, emetine significantly reduced the protein levels of RhoA (Ras homolog gene family, member A), Rho-kinases (ROCK1 and ROCK2 [rho-associated coiled-coil containing protein kinases 1 and 2]), and their downstream CyPA (cyclophilin A), and Bsg (basigin) in PAH-PASMCs. Consistently, emetine treatment significantly reduced the secretion of cytokines/chemokines and growth factors from PAH-PASMCs. Interestingly, emetine reduced protein levels of BRD4 (bromodomain-containing protein 4) and downstream survivin, both of which are involved in many cellular functions, such as cell cycle, apoptosis, and inflammation. Finally, emetine treatment ameliorated pulmonary hypertension in 2 experimental rat models, accompanied by reduced inflammatory changes in the lungs and recovered right ventricular functions. Conclusions: Emetine is an old but novel drug for PAH that reduces excessive proliferation of PAH-PASMCs and improves right ventricular functions.

Glucosylceramide (GlcCer), a representative sphingolipid in cell membranes of plants and fungi, is known to have certain benefits, such as prevention of intestinal impairment and improved skin moisturizing, when consumed. Recently, incidence rates of intestinal impairments have increased in East Asian countries due to changes of people's diet and life style. Therefore, the occurrence of these impairments needs to be prevented through dietary improvement and supplements containing GlcCer. The in vitro and in vivo effects of GlcCer on colon impairment were explored in our previous studies, with focus on sphingolipid structure. Conversely, plant cell membrane contents such as GlcCer are known to be difficult to extract due to the thick cell wall. Therefore, human and other mammals may not be able to utilize GlcCer when digesting food of plant origin. To confirm this hypothesis, we investigated the effects of polished rice and the extract on intestinal impairment. In addition, we discuss the intestinal function of GlcCer contained in polished rice and the relationship between GlcCer and other lipophilic functional components.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH. Objective: We aimed to discover a novel drug for PAH that inhibits PASMC proliferation. Methods and Results: We screened 5562 compounds from original library using high-throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole–type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1α (hypoxia-inducible factor 1α), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domain-containing protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs. Conclusions: These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.

Congestive heart failure (CHF) is rare during pregnancy. We herein report a 35-year-old woman who developed CHF with severe left ventricular dysfunction at 35 weeks' gestation. She underwent emergency Caesarean section followed by intensive-care treatment for CHF. The diagnosis of Cushing's syndrome (CS) caused by adrenal adenoma was confirmed by endocrinological examinations and histology after adrenalectomy. She was discharged on heart failure medications and glucocorticoid replacement therapy. Both the symptoms and cardiac function had recovered after 12 months of follow-up. This case highlights the importance of considering CS-induced cardiomyopathy as a cause of CHF in pregnant women.

In plants and fungi, sphingolipids, characterized by the presence of a sphingoid base (SB), comprise neutral classes, including ceramide (Cer) and glucosylceramide (GlcCer), and acidic classes, including glycosyl inositol phosphoryl ceramide (GIPC). The major class of plant and fungal sphingolipids is GIPC; however, owing to their complicated extraction and analysis, there is still little information regarding the food characteristics of GIPC compounds. In the present study, we evaluated the content and SB composition of highly polar sphingolipids (HPS) in materials that had been obtained from our previous food processing study for GlcCer and Cer. This assessment was based on the changes that occur in HPS containing GIPC in sake rice (saka-mai) during the rice polishing and sake (rice wine) brewing process. In addition, we report a new investigation into the composition of sphingolipids in koji rice and sake yeast. HPS levels were the highest among the sphingolipid classes in brown rice cultivars and highly polished rice. Sake and sake lees (sake-kasu) were produced using three different starter cultures. In sake lees, Cer levels were the highest among the classes, while HPS was greatly reduced based on the amount of highly polished rice and koji rice, and these HPS were mainly composed of sphinganine (d18:0), which is a minor SB in highly polished rice, koji rice, and sake yeast. In addition, considerable levels of free SBs, mainly comprising d18:0, were detected in sake lees. The levels of HPS and free SBs in sake lees were dependent on the starter culture. These results suggest that HPS was hydrolyzed to Cer and that sake yeast also affected the levels of Cer and free SBs during brewing. One interesting question raised by these results is whether changes in the class and base compositions of sphingolipids during brewing contribute to taste of the final product and other food functions.

To track atmospheric CO 2 changes resulting from the lockdowns, observations collected by the NASA Orbiting Carbon Observatory-2 (OCO-2) satellite and Japan's Greenhouse gases Observing SATellite (GOSAT) in 2020 were compared to results collected in previous years. The OCO-2 results were used to search for changes on regional scales over the globe. Targeted observations from GOSAT were used to track changes in large urban areas, such as Beijing and Tokyo. Both types of observations yielded key insights into the CO 2 changes accompanying the economic disruptions caused by the COVID-19 lockdowns. ESA, NASA and JAXA developed the dashboard jointly to monitor the climate impacts of COVID-19.

Objective:Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated.Approach and Results:First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs.Conclusions:These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA.Graphic Abstract:A graphic abstract is available for this article.

Sphingolipids, including ceramide (Cer) and glucosylceramide (GlcCer), have the characteristic structural units called sphingoid bases, and are constituents of cell and vacuole membranes. Plant sphingolipids bear highly diverse base structures and the base composition differs depending on the plant species. It is thought that the composition of sphingolipid classes and sphingoid bases is related to membrane fractions. However, there is little information about differences in sphingolipids among plant cultivars and the changes occurring in sphingolipids during food processing. This study investigated sphingolipids in sake rice (saka-mai) cultivars grown for sake (rice wine), and the changes in sphingolipids during polishing and brewing. In six brown rice samples, there were no large differences of the base composition among Cer or GlcCer of cultivars, whereas there were differences in their sphingolipid contents. When compared to brown rice, highly polished rice contained lower levels of sphingolipids, especially Cer. For three rice brans from different polishing steps, the Cer content was higher in the outer bran than in the inner bran. Sake and sake lees (sake-kasu) were produced by three different starter cultures (shubo preparations: the mixture of koji rice as an enzyme cocktail containing amylases, sake yeast, and adding rice as a carbohydrate source). The Cer/GlcCer ratio in sake and sake lees depended on the starter culture; Cer and GlcCer in sake lees possessed a fungi-specific base, 9-methyl-trans-4,trans-8- sphingadienine. In addition, sake lees had a higher Cer/GlcCer ratio when compared to highly polished rice as a sake source. These results suggest that the sphingolipid content of brown rice differs depending on the rice cultivar; further, the sphingolipids and the sphingolipid composition in sake and sake lees are affected by fungal sphingolipids and self-digestion during brewing.

GOSAT and GOSAT-2 have simultaneously observed both reflected SWIR solar light and TIR emissions with a single FTS mechanism with the Thermal And Near-infrared Sensor for carbon Observation Fourier...

Background Although chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (APE) share some clinical manifestations, a limited proportion of patients with CTEPH have a history of APE. Moreover, in histopathologic studies, it has been revealed that pulmonary vasculature lesions similar to pulmonary arterial hypertension existed in patients with CTEPH. Thus, it remains unknown whether these 3 disorders also share genetic backgrounds. Methods and Results Whole exome screening was performed with DNA isolated from 51 unrelated patients with CTEPH of Japanese ancestry. The frequency of genetic variants associated with pulmonary arterial hypertension or APE in patients with CTEPH was compared with those in the integrative Japanese Genome Variation Database 3.5KJPN. Whole exome screening analysis showed 17 049 nonsynonymous variants in patients with CTEPH. Although we found 6 nonsynonymous variants that are associated with APE in patients with CTEPH, there was no nonsynonymous variant associated with pulmonary arterial hypertension. Patients with CTEPH with a history of APE had nonsynonymous variants of F5 , which encodes factor V. In contrast, patients with CTEPH without a history of APE had a nonsynonymous variant of THBD , which encodes thrombomodulin. Moreover, thrombin‐activatable fibrinolysis inhibitor, which is one of the pathogenic proteins in CTEPH, was significantly more activated in those who had the variants of THBD compared with those without it. Conclusions These results provide the first evidence that patients with CTEPH have some variants associated with APE, regardless of the presence or absence of a history of APE. Furthermore, the variants might be different between patients with CTEPH with and without a history of APE.

The Japanese Greenhouse gases Observing SATellite-2 (GOSAT-2), in orbit since 29 October 2018, follows up the GOSAT mission, itself in orbit since 23 January 2009. GOSAT-2 monitors carbon dioxide and methane in order to increase our understanding of the global carbon cycle. It simultaneously measures carbon monoxide emitted from fossil fuel combustion and biomass burning, and permits identification of the amount of combustion-related carbon. To do this, the satellite utilizes the Thermal and Near Infrared Sensor for Carbon Observation Fourier-Transform Spectomer-2 (TANSO-FTS-2). This spectrometer detects gas absorption spectra of solar radiation reflected from the Earth’s surface in the shortwave-infrared (SWIR) region as well as the emitted thermal infrared radiation (TIR) from the ground and the atmosphere. TANSO-FTS-2 can measure the oxygen A band (0.76 um), weak and strong CO2 bands (1.6 um and 2.0 um), weak and strong CH4 bands (1.6 um and 2.3 um), a weak CO band (2.3 um), a mid-wave TIR band (5.5–8.4 um) and a long-wave TIR band (8.4–14.3 um) with 0.2 cm−1 spectral resolution. TANSO-FTS-2 is equipped with a solar diffuser target, a monochromatic light source, and a black body for spectral radiance calibration. These calibration sources permit characterization of time-dependent instrument changes in orbit. The onboard-recalibrated instrumental parameters are considered in operational level-1 processing and released as TANSO-FTS-2 level-1 version 102102 products, which were officially released on 25 May 2020. This paper provides an overview of the TANSO-FTS-2 instrument, the level-1 processing, and the first-year on-orbit performance. To validate the spectral radiance calibration during the first year of operation, the spectral radiance of the version 102102 product is compared at temporally coincident and spatially collocated points from February 2019 to March 2020 with TANSO-FTS on GOSAT for SWIR, and with AIRS on AQUA and IASI on METOP-B for TIR. The spectral radiances measured by TANSO-FTS and TANSO-FTS-2 agree within 2 % of the averaged bias and 0.5 % standard deviation for SWIR bands. The agreement of brightness temperature between TANSO-FTS-2 and AIRS, IASI, is better than 0.5 % in the range from 220 K to 320 K. GOSAT-2 not only provides seamless global CO2 and CH4 observation but also observes local emissions and uptake with an additional CO channel, fully customized sampling patterns, higher signal-to-noise ratios, and wider pointing angles than GOSAT.

Glucosylceramide (GlcCer), a major sphingolipid in plants and fungi, is known to have food functions, such as preventing intestinal impairment and enhancing the moisture content of skin. This study investigated the influence of fermentation on the composition and function of lipophilic components containing GlcCer in plant-based foods; we compared the effects of ethanol extracts from sake rice (SR) and sake lees (SL) on colon impairment in mice. GlcCer and ceramide (Cer) levels in SL were much higher than those in SR, and GlcCer in SL contained 9-methyl-trans-4,trans-8-sphingadienine as a fungi-specific sphingoid base. 1,2-dimethylhydrazine (DMH) treatment markedly increased the formation of aberrant crypt foci (ACF) and the levels of TNF-α and lipid oxidation in mice colons. However, dietary SR or SL significantly suppressed these DMH-induced changes, and SR demonstrated stronger effects than SL. In addition, dietary SR or SL suppressed the expression of apoptotic and anti-apoptotic proteins induced by DMH treatment. This study suggests that SR or SL intake could reduce colon ACF formation via the suppression of inflammation and oxidation-induced cell cycle disturbances. When compared to SR, the weaked effects of SL rich in GlcCer may be the result of the changes in sphingolipid composition (sphingoid base and Cer) and differences in the concentration of other bioactive compounds produced or digested during fermentation.

Background: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms of pulmonary arterial hypertension (PAH). Despite the multiple combination therapy, a considerable number of patients develop severe pulmonary hypertension (PH) because of the lack of diagnostic biomarker and antiproliferative therapies for PASMCs. Methods: Microarray analyses were used to identify a novel therapeutic target for PAH. In vitro experiments, including lung and serum samples from patients with PAH, cultured PAH-PASMCs, and high-throughput screening of 3336 low-molecular-weight compounds, were used for mechanistic study and exploring a novel therapeutic agent. Five genetically modified mouse strains, including PASMC-specific selenoprotein P (SeP) knockout mice and PH model rats, were used to study the role of SeP and therapeutic capacity of the compounds for the development of PH in vivo. Results: Microarray analysis revealed a 32-fold increase in SeP in PAH-PASMCs compared with control PASMCs. SeP is a widely expressed extracellular protein maintaining cellular metabolism. Immunoreactivity of SeP was enhanced in the thickened media of pulmonary arteries in PAH. Serum SeP levels were also elevated in patients with PH compared with controls, and high serum SeP predicted poor outcome. SeP-knockout mice ( SeP –/– ) exposed to chronic hypoxia showed significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling compared with controls. In contrast, systemic SeP-overexpressing mice showed exacerbation of hypoxia-induced PH. Furthermore, PASMC-specific SeP –/– mice showed reduced hypoxia-induced PH compared with controls, whereas neither liver-specific SeP knockout nor liver-specific SeP-overexpressing mice showed significant differences with controls. Altogether, protein levels of SeP in the lungs were associated with the development of PH. Mechanistic experiments demonstrated that SeP promotes PASMC proliferation and resistance to apoptosis through increased oxidative stress and mitochondrial dysfunction, which were associated with activated hypoxia-inducible factor-1α and dysregulated glutathione metabolism. It is important to note that the high-throughput screening of 3336 compounds identified that sanguinarine, a plant alkaloid with antiproliferative effects, reduced SeP expression and proliferation in PASMCs and ameliorated PH in mice and rats. Conclusions: These results indicate that SeP promotes the development of PH, suggesting that it is a novel biomarker and therapeutic target of the disorder.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a debilitating disease associated with progressive vascular remodeling of distal pulmonary arteries leading to elevation of pulmonary artery pressure, right ventricular hypertrophy, and death. Although presenting high levels of DNA damage that normally jeopardize their viability, pulmonary artery smooth muscle cells (PASMCs) from patients with PAH exhibit a cancer-like proproliferative and apoptosis-resistant phenotype accounting for vascular lumen obliteration. In cancer cells, overexpression of the serine/threonine-protein kinase CHK1 (checkpoint kinase 1) is exploited to counteract the excess of DNA damage insults they are exposed to. This study aimed to determine whether PAH-PASMCs have developed an orchestrated response mediated by CHK1 to overcome DNA damage, allowing cell survival and proliferation. APPROACH AND RESULTS: We demonstrated that CHK1 expression is markedly increased in isolated PASMCs and distal PAs from patients with PAH compared with controls, as well as in multiple complementary animal models recapitulating the disease, including monocrotaline rats and the simian immunodeficiency virus–infected macaques. Using a pharmacological and molecular loss of function approach, we showed that CHK1 promotes PAH-PASMCs proliferation and resistance to apoptosis. In addition, we found that inhibition of CHK1 induces downregulation of the DNA repair protein RAD 51 and severe DNA damage. In vivo, we provided evidence that pharmacological inhibition of CHK1 significantly reduces vascular remodeling and improves hemodynamic parameters in 2 experimental rat models of PAH. CONCLUSIONS: Our results show that CHK1 exerts a proproliferative function in PAH-PASMCs by mitigating DNA damage and suggest that CHK1 inhibition may, therefore, represent an attractive therapeutic option for patients with PAH.

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted: 2021-09-20, 資料番号: PA2210075000

The number of research articles from Japan has been dramatically decreasing during the 21st century.1 Although the number of Nobel Prize laureates from Japan in the natural science field (physiology, medicine, physics, and chemistry) ranks second in the world after United States during this century with 16 winners, these prizes are mostly based on the research performed during the 20th century. According to the database of Web of Science, the number of articles from Japan published in the American Heart Association journals ( Circulation , Circulation Research , and Arteriosclerosis, Thrombosis, and Vascular Biology ) was 164 (10.0% of all articles) in 2000, which markedly decreased to only 45 (5.5%) in 2016 (Figure 1A). In contrast, the number of articles from other top 10 countries has been almost unchanged in the same period except for China; the number of articles from China has dramatically increased by 570% (Figure 1A). Regarding the number of publications in Circulation Research , Japan has already dropped from the top countries; Japan was the second in 2000 (11.1%) and 11th in 2016 (only 2.8%; Figure 1B). Similarly, the number of articles from Japan published in the top basic scientific journals ( Nature , Cell , and Science ) was 172 in 2000, which decreased to 151 in 2016 (7.6%; Figure 2A). Again, in other top countries, the number of articles in these top journals has been increased, especially with the marked increase from China (Figure 2A). All these data clearly demonstrate the devastating situation in Japan in the field of basic research as compared with other top countries in the world. Figure 1. Shrinking scientific activity in cardiovascular medicine in Japan. A , Trends in the number ( left ) and percentage ( right ) of articles published in the American Heart Association journals ( Circulation , Circulation Research , or Arteriosclerosis , Thrombosis , …

We report novel high-bandwidth InP-based Mach–Zehnder modulator and in-phase/quadrature (IQ) modulators that we realized by combining an n-i-p-n heterostructure and a capacitively loaded traveling wave electrode. The extremely low electrical and optical loss structure enhances the 3-dB electro-optic bandwidth of over 67 GHz without degrading other properties such as driving voltage and optical loss. The modulator also exhibits a static extinction ratio of over 24 dB with a V π of less than 1.5 V for the entire C-band. Furthermore, we demonstrate the first 120-Gbaud rate IQ modulation without optical pre equalization, and 100-Gb/s non-return-to-zero on-off keying modulation with a dynamic extinction ratio of over 10 dB.

Emissions of atmospheric methane (CH4), which greatly contributes to radiative forcing, have larger uncertainties than those for carbon dioxide (CO2). The Thermal And Near-infrared Sensor for carbon Observation Fourier-Transform Spectrometer (TANSO-FTS) onboard the Greenhouse gases Observing SATellite (GOSAT) launched in 2009 has demonstrated global grid observations of the total column density of CO2 and CH4 from space, and thus reduced uncertainty in the global flux estimation. In this paper, we present a case study on local CH4 emission detection from a single-point source using an available series of GOSAT data. By modifying the grid observation pattern, the pointing mechanism of TANSO-FTS targets a natural gas leak point at Aliso Canyon in Southern California, where the clear-sky frequency is high. To enhance local emission estimates, we retrieved CO2 and CH4 partial column-averaged dry-air mole fractions of the lower troposphere (XCO2 (LT) and XCH4 (LT)) by simultaneous use of both sunlight reflected from Earth’s surface and thermal emissions from the atmosphere. The time-series data of Aliso Canyon showed a large enhancement that decreased with time after its initial blowout, compared with reference point data and filtered with wind direction simulated by the Weather Research and Forecasting (WRF) model.

The authors used 65-nm CMOS technology to develop a linear four-channel driver IC with low temperature dependence and ultra-low power dissipation for 64-Gbaud coherent optical transmitters. The driver showed more than a 48-GHz 3-dB electrical bandwidth and less than 1-W power consumption in four-channel operation. By employing a circuit that suppresses the temperature dependence, they achieved 3-dB electrical bandwidth variation of 3.0 GHz and the gain variation of 1.5 dB under the −5 to 75°C and ±5% supply voltage variation conditions. The CMOS driver has all the necessary functions for a high-bandwidth coherent driver modulator such as a gain control, peaking control, peak detection and temperature monitoring, all of which functions can be controlled by a serial peripheral interface. A fabricated sub-assembly consisting of the CMOS driver and an InP modulator showed a 48-GHz 3-dB electro-optic bandwidth.

In almost Japanese megacities, various CO2 and CH4 emission source like industrial activity (power plant, landfills, gas factory, water processing plants), and agricultural activity (rice cultivati...

Objective: Despite the recent progress in upfront combination therapy for pulmonary arterial hypertension (PAH), useful biomarkers for the disorder still remain to be developed. SeP (Selenoprotein P) is a glycoprotein secreted from various kinds of cells including pulmonary artery smooth muscle cells to maintain cellular metabolism. We have recently demonstrated that SeP production from pulmonary artery smooth muscle cells is upregulated and plays crucial roles in the pathogenesis of PAH. However, it remains to be elucidated whether serum SeP levels could be a useful biomarker for PAH. Approach and Results: We measured serum SeP levels and evaluated their prognostic impacts in 65 consecutive patients with PAH and 20 controls during follow-up (mean, 1520 days; interquartile range, 1393–1804 days). Serum SeP levels were measured using a newly developed sol particle homogeneous immunoassay. The patients with PAH showed significantly higher serum SeP levels compared with controls. Higher SeP levels (cutoff point, 3.47 mg/L) were associated with the outcome (composite end point of all-cause death and lung transplantation) in patients with PAH (hazard ratio, 4.85 [1.42–16.6]; P R =0.78, 0.76, and −0.71 respectively, all P Conclusions: Serum SeP is a novel biomarker for diagnosis and assessment of treatment efficacy and long-term prognosis in patients with PAH.

Background Circulating proteins are exposed to vascular endothelial layer and influence their functions. Among them, adipsin is a member of the trypsin family of peptidases and is mainly secreted from adipocytes, monocytes, and macrophages, catalyzing the rate‐limiting step of the alternative complement pathway. However, its pathophysiological role in cardiovascular disease remains to be elucidated. Here, we examined whether serum adipsin levels have a prognostic impact in patients with coronary artery disease. Methods and Results In 370 consecutive patients undergoing diagnostic coronary angiography, we performed a cytokine array analysis for screening serum levels of 50 cytokines/chemokines and growth factors. Among them, classification and regression analysis identified adipsin as the best biomarker for prediction of their long‐term prognosis (median 71 months; interquartile range, 55–81 months). Kaplan–Meier curve showed that higher adipsin levels (≥400 ng/ mL ) were significantly associated with all‐cause death (hazard ratio [HR], 4.2; 95% CI, 1.7–10.6 [ P HR , 2.4; 95% CI, 1.7–3.5 [ P HR, 3.2; 95% CI, 1.7–5.9 [ P HR, 1.5, 95% CI, 1.1–1.9 [ P mL ) and high‐sensitivity C‐reactive protein (≥1 mg/L) was more significantly associated with all‐cause death ( HR, 21.0; 95% CI, 2.9–154.1 [ P Conclusions These results indicate that adipsin is a novel biomarker that predicts all‐cause death and rehospitalization in patients with coronary artery disease, demonstrating the novel aspects of the alternative complementary system in the pathogenesis of coronary artery disease.

Background Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of mitochondrial metabolism to a hyperproliferative state. However, at present, since all the drugs in clinical use target pulmonary vascular dilatation, they may not be so effective for patients with advanced PAH. Purposes We aimed to discover a novel drug for PAH that inhibits PASMC proliferation. Methods In the first screening, we examined 5,562 compounds from our original library using high-throughput screening system to discover a compound that inhibits proliferation of PASMCs from PAH patients (PAH-PASMCs). In the second screening, we performed concentration-dependent assays and counter assays with PAH-PASMCs and PASMCs from healthy donors. We also performed apoptosis assays and mechanistic analysis for inflammation, reactive oxygen species (ROS), and mitochondrial function. Results We found that celastramycin, a benzoyl pyrrole-type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with minimal effects on PASMCs from healthy donors. Moreover, celastramycin inhibited proliferation with minimal increase in apoptosis and low rate of cell death. Then, we synthesized 25 analogues of celastramycin, and finally selected the lead compound that significantly inhibited proliferation of PAH-PASMCs and reduced cytosolic ROS levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of hypoxia-inducible factor-1α, which was abnormally activated in PAH-PASMCs and impaired aerobic metabolism, and nuclear factor-κB, which induces pro-inflammatory signals, in PAH-PASMCs compared with vehicle controls, leading to reduced secretion of inflammatory cytokines. Importantly, celastramycin treatment reduced the ROS levels in PAH-PASMCs with increased protein levels of NF-E2-related factor 2 (Nrf2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. We also discovered that celastramycin-mediated effects on these transcriptional modulators could be regulated by zinc finger C3H1 domain-containing protein, which is a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in three experimental animal models of PH in mice and rats, accompanied by reduced inflammatory changes in the lungs. Conclusions These results indicate that celastramycin ameliorates pulmonary hypertension through inhibition of excessive proliferation of PAH-PASMCs, for which its anti-inflammatory and beneficial effects on mitochondrial energy metabolism may be involved. Thus, celastramycin could be a novel drug for PAH as it exerts anti-proliferative effects on PAH-PASMCs.

Background Despite the recent progress in upfront combination therapy for pulmonary arterial hypertension (PAH), a useful biomarker for the disorder still remains to be developed. Selenoprotein P (SeP) is a glycoprotein secreted mainly from hepatocytes but also from other various kinds of cells, including pulmonary artery smooth muscle cells (PASMCs), to maintain selenium homeostasis and cellular energy metabolism. We have recently demonstrated that SeP expression in PASMCs is markedly up-regulated in PAH patients and plays crucial roles in the pathogenesis of the disorder. In this study, we thus examined whether serum levels of SeP could be a useful biomarker for the disorder. Methods In the experimental study, we performed gene expression microarray and in silico analyses to identify a novel therapeutic target for PAH. We also used the lung, serum, and cultured PAMSCs derived from patients with PAH for mechanistic experiments. In the clinical study, we enrolled a total of 65 consecutive patients with PAH who underwent right heart catheterization for hemodynamic assessment. We measured serum SeP levels and evaluated their prognostic impacts during follow-up (mean 1,520 days, IQR: 1,393–1,804 days). Serum SeP level was measured using a newly developed sol particle homogeneous immunoassay. As controls, we collected serum samples from 20 controls without any known cardiac disorders evaluated by hematological examination, echocardiography, and coronary angiography. In PAH patients, we examined the relationship between baseline SeP levels and composite endpoint of all-cause death and lung transplantation. The correlation between the absolute changes in SeP and those in hemodynamic parameters during follow-up were also examined. Results In the experimental study, SeP promoted PASMC proliferation through increased oxidative stress and mitochondrial metabolic dysfunction, which were associated with activated HIF-1α and dysregulated glutathione metabolism. In the clinical study, PAH patients showed significantly higher levels of serum SeP compared with controls (3.07±0.57 vs. 2.43±0.25 mg/L, P Figure 1 Conclusions These results indicate that SeP is a novel therapeutic target of PAH and that serum SeP levels are a novel biomarker for diagnosis and assessment of treatment efficacy and long-term prognosis in PAH patients. Acknowledgement/Funding Grants-in-aid for Scientific Research from the Japan Agency for Medical Research and Development, Tokyo, Japan (16ek0109176h0001, 17ek0109227h0001).

Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH.We aimed to discover a novel drug for PAH that inhibits PASMC proliferation.We screened 5562 compounds from original library using high-throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole-type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1α (hypoxia-inducible factor 1α), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domain-containing protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs.These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.

Glucosylceramide (GlcCer), a major sphingolipid in plants and fungi, is known to have food functions such as preventing intestinal impairment and enhancing the moisture content of skin. However, there is little information about functions of GlcCer in food sources as most of the studies on GlcCer functions are done using purified GlcCer. This study was performed to investigate the effects of GlcCer contained in food on intestinal impairment; polished rice flour (RF) and this ethanol extract (RE) were used as sources of GlcCer, and these were evaluated by studying the formation of aberrant crypt foci (ACF) in 1,2-dimethylhydrazine (DMH)-treated mice, which is a model of colon cancer. Mice were fed with either a control diet, a RF diet where RF replaces cornstarch (150 g/kg), or a plus RE diet (0.5 g/kg; RE was extracted from the same amount of RF present in the RF diet). The amount of GlcCer was similar in both the RF and RE diets (3.0 and 2.7 mg/kg, respectively). DMH treatment induced the formation of ACF and the production of inflammation-related cytokines. Both dietary RF and RE suppressed ACF formation and RE, in particular, showed a significant suppressive effect. Dietary RE inhibited the production of almost all of the inflammation-related cytokines studied, while RF suppressed only a few of these cytokines. The present study suggests that the lipophilic fraction including GlcCer, present in polished rice has protective effects against intestinal impairment, but it requires extraction since digestion alone is not enough to elicit its complete protective action.

Objective— Basigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinases and promotes inflammation. However, the role of Bsg in the pathogenesis of cardiac hypertrophy and failure remains to be elucidated. We examined the role of Bsg in cardiac hypertrophy and failure in mice and humans. Approach and Results— We performed transverse aortic constriction in Bsg +/– and in wild-type mice. Bsg +/– mice showed significantly less heart and lung weight and cardiac interstitial fibrosis compared with littermate controls after transverse aortic constriction. Both matrix metalloproteinase activities and oxidative stress in loaded left ventricle were significantly less in Bsg +/– mice compared with controls. Echocardiography showed that Bsg +/– mice showed less hypertrophy, less left ventricular dilatation, and preserved left ventricular fractional shortening compared with littermate controls after transverse aortic constriction. Consistently, Bsg +/– mice showed a significantly improved long-term survival after transverse aortic constriction compared with Bsg +/+ mice, regardless of the source of bone marrow ( Bsg +/+ or Bsg +/– ). Conversely, cardiac-specific Bsg-overexpressing mice showed significantly poor survival compared with littermate controls. Next, we isolated cardiac fibroblasts and examined their responses to angiotensin II or mechanical stretch. Both stimuli significantly increased Bsg expression, cytokines/chemokines secretion, and extracellular signal–regulated kinase/Akt/JNK activities in Bsg +/+ cardiac fibroblasts, all of which were significantly less in Bsg +/– cardiac fibroblasts. Consistently, extracellular and intracellular Bsg significantly promoted cardiac fibroblast proliferation. Finally, serum levels of Bsg were significantly elevated in patients with heart failure and predicted poor prognosis. Conclusions— These results indicate the crucial roles of intracellular and extracellular Bsg in the pathogenesis of cardiac hypertrophy, fibrosis, and failure in mice and humans.

A compact (200 μm) spot-size converter (SSC) with a vertically tapered core layer is developed, which is fabricated with a simple wafer process using the micro-loading effect. It is confirmed that the vertical spot size of the SSC exceeded 2 μm, which was double that of the original waveguide. As a result, an InP waveguide integrated with the SSCs exhibited a coupling loss of

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are fatal diseases; however, their pathogenesis still remains to be elucidated. We have recently screened novel pathogenic molecules and have performed drug discovery targeting those molecules. Pulmonary artery smooth muscle cells (PASMCs) in patients with PAH (PAH-PASMCs) have high proliferative properties like cancer cells, which leads to thickening and narrowing of distal pulmonary arteries. Thus, we conducted a comprehensive analysis of PAH-PASMCs and lung tissues to search for novel pathogenic proteins. We validated the pathogenic role of the selected proteins by using tissue-specific knockout mice. To confirm its clinical significance, we used patient-derived blood samples to evaluate the potential as a biomarker for diagnosis and prognosis. Finally, we conducted a high throughput screening and found inhibitors for the pathogenic proteins.

We developed ultra-low power ( 44 GHz) coherent modulator modules with a CMOS driver IC and an InP modulator. Dual polarization 64-Gbaud 16-QAM modulation was successfully demonstrated.