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Introduction: Recent studies have reported the efficacy of the cryoballoon (CB)‐guided left atrial roof block line (LARB) creation in patients with persistent atrial fibrillation (AF). However, it can be technically challenging to attach the balloon to the left atrial (LA) roof due to its anatomical variations. We designed a new procedure called the "Raise‐up Technique," which may facilitate the firm adhesion of the CB to the LA roof during freezing. This study aimed to evaluate the efficacy of the Raise‐up technique in LARB creation. Methods and Results: In total, 100 consecutive patients with persistent AF who underwent CB‐LARB creation were enrolled. Fifty‐seven patients underwent LARB creation using the Raise‐up technique (Raise‐up group), and the remaining 43 did not use it (control group). The Raise‐up technique was performed as follows: An Achieve catheter was inserted as deeply as possible into the upper branch of the right superior pulmonary vein to anchor the CB. The balloon was placed below the targeted site on the LA roof and frozen. When the temperature of the CB reached approximately −10°C and the CB was easier to attach to the LA tissue, the CB was raised and pressed against the LA roof immediately by sheath advancement. Then the balloon could be in firm contact with the target site on the roof. If necessary, additional sheath advancement after sufficient freezing (−20°C to −30°C) was allowed the CB to have more firm and broad contact with the target site. LARB creation without touch‐up ablation was achieved in 54 of 57 patients (94.7%) in the Raise‐up group and 33 of 43 patients (76.7%) in the control group (p <.05). The lesion size of the LARB in the Raise‐up group was significantly larger than that in the control group (15.2 cm2 vs. 12.8 cm2, p <.05). Moreover, the width of the LARB lesion in the Raise‐up group was wider than that in the control group (32.0 mm vs. 26.6 mm, p <.05). Conclusion: The Raise‐up technique enabled the creation of seamless and thick LARB lesions with a single stroke. In addition, the CB‐LARB lesions created using the Raise‐up technique tended to be large, resulting in extensive debulking of the LA posterior wall arrhythmia substrates. In CB ablation for persistent AF, the Raise‐up technique can be considered one of the key strategies for LARB creation. [ABSTRACT FROM AUTHOR]

Buckling-restrained braced frames (BRBFs) are attracting interest worldwide by virtue of their extraordinary response reduction performance. The system relies strongly on the energy dissipation of buckling-restrained braces (BRBs). Therefore, the surrounding members (beams, columns, or gusset plates) must sustain the force imposed by a BRB. Notably, beams are not designed primarily to support the axial force. The sections consequently tend to become deep and slender to enhance the flexural strength and stiffness effectively, thereby leading to local buckling, which lessens the reaction force to the BRB. Moreover, the instability is activated by the compressive axial force transferred from the BRB. However, beams in the BRBFs generally become composite beams through an assemblage with a concrete slab by stud shear connectors. The concrete slab shifts the neutral axis of the beam, which imposes more strain on the bottom flange. The BRB axial force and composite effect therefore influence the steel beam buckling behavior. Eventually, the beam might be subjected to instability at a smaller-than-expected deformation. However, the rotation capacity of the composite beam in BRBFs has not been clarified yet. To address this concern, this study established a finite-element analysis (FEA) model referring to a former specimen and an experiment scheme. Additionally, a parametric study of the influential factors was conducted using the experimentally validated FEA model. This study examined a proposed evaluation equation of an apparent axial force issued from the composite effect based on the obtained results. An earlier evaluation index established for bare steel beams was ultimately modified to include the axial force influence. Eventually, the results demonstrated that the structural performance can be assessed appropriately using the existing evaluation equations proposed using a steel frame subassembly. [ABSTRACT FROM AUTHOR]

Recent innovations in composite dowels have led to the realization that robust hybrid systems can provide excellent strength and stiffness. In this contemporary era, puzzle-shaped and modified clothoid-shaped shear connectors are attracting interest, particularly in Europe. Their popularity stems from their outstanding shear capacities and their ease of manufacturing by virtue of having a single cutting line. Moreover, earlier studies based on pushout tests have proven this fact. Composite beams in buildings experience fully reversed cyclic stress between compression and tension during seismic events. When the concrete slab starts to crack under tensile stress, the shear capacity of the composite dowel can deteriorate considerably. Nevertheless, the influence of this cyclically applied stress on mechanical performance remains unclear. This study specifically examined puzzle-shaped shear connectors, with cyclic loading tests conducted using a component model of the composite beam, which can carry the various stress histories to the concrete slab. In all, findings obtained from 14 specimens with several influential factors clarified the cyclic behaviors and stress transfer mechanisms of puzzle-shaped shear connectors. Based on the experimentally obtained results, the applicability of existing evaluation equations was investigated with respect to the ultimate shear strength and shear force–slip displacement relation. Results indicate that those formulas overestimate the mechanical capacities of composite dowels under fully reversed cyclic stress. For that reason, this study has led to an evaluation formulation of mechanical performance that reflects the stress history effects. Ultimately, this study has proven that the proposed equations can assess the ultimate shear strength and shear force–slip displacement accurately while embracing simplicity. [ABSTRACT FROM AUTHOR]

Tubular epithelial cells are routinely exposed to severe changes in osmolarity. Although the autophagic activity of cells is an indispensable process to maintain cellular homeostasis and respond to stressors, the effect of hyperosmotic stress on autophagic activity in tubular epithelial cells remains unknown. The aim of this study was to determine the effect of hyperosmotic stress on autophagy in rat kidney tubular epithelial cells focusing on the role of actin and microtubule cytoskeletons. Normal rat kidney (NRK)-52E cells exposed to mannitol-induced hyperosmotic stress. As a result, NRK-52E cells showed elevated protein levels of the autophagosome marker LC3-II, indicating enhancement of the autophagic flux. Hyperosmotic stress also transiently decreased cell volume and caused the reorganization of actin and microtubule cytoskeletal structures in NRK-52E cells. The inhibition of the actin cytoskeleton reorganization by cytochalasin D impaired the increase in the levels of LC3-II; however, disassembly of the microtubules following treatment with nocodazole did not affect the increase. These results indicate that hyperosmotic stress can induce autophagy mediated by the reorganization of the actin cytoskeleton in tubular epithelial cells. • Hyperosmotic stress enhances autophagic flux in proximal tubular epithelial cells. • Transient cell volume reduction by hyperosmolarity causes actin reorganization. • Inhibition of actin reorganization impairs the hyperosmolarity-induced autophagy. [ABSTRACT FROM AUTHOR]

CH3NH3PbI3 perovskite solar cells using metal phthalocyanines (MPcs) with decaphenylcyclopentasilane (DPPS) are fabricated and characterized. The effect of addition of MPcs on the photovoltaic properties is investigated by changing the central element of the MPc and depositing MPc and DPPS successively on the perovskite layer. When silicon phthalocyanine is used to the cell, the microstructure of the perovskite film improves, which results in improvement of the open‐circuit voltage, fill factor, and photoconversion efficiency. For cells with only MPcs as the hole‐transport layer, the conversion efficiency increases by passivation with the phthalocyanine and crystal growth at room temperature. [ABSTRACT FROM AUTHOR]

We evaluated whether modified Model for End-Stage Liver Disease (MELD) scores are useful for predicting the postdischarge prognosis in hospitalized patients with heart failure (HF) who are discharged alive. The MELD-XI and MELD-Na scores were calculated at discharge for a total of 1156 patients in the HIJ-HF II study. We also studied 3 groups on the basis of the left ventricular ejection fraction (LVEF): the HFrEF (LVEF < 40%), HFmrEF (LVEF 40–49%) and HFpEF (LVEF ≥ 50%) groups. The primary outcome was all-cause mortality, and the secondary outcome was rehospitalization due to worsening HF. The median MELD-XI and MELD-Na scores were 12 and 14, respectively. After a median follow-up of 19 months, there were significantly higher rates of all-cause mortality in patients with MELD-XI scores ≥ 12 than in those with MELD-XI scores < 12; there were also higher rates of all-cause mortality in patients with MELD-Na scores ≥ 14 than in those with MELD-Na scores < 14 (both log-rank p < 0.001). The cumulative incidence function based on a competing risks model showed a higher rate of rehospitalization due to worsening HF in patients with MELD-XI scores ≥ 12 than in those with MELD-XI scores < 12 and a higher rate of rehospitalization due to worsening HF in those with MELD-Na scores ≥ 14 than in those with MELD-Na scores < 14 (both Gray's test p < 0.001). The adjusted hazard ratios (HRs) of all-cause mortality for patients with MELD-XI scores ≥ 12 and those with MELD-Na scores ≥ 14 were 2.07 [95% confidence interval (CI) 1.25–3.44] and 2.79 [95% CI 1.63–4.79], respectively, in the HFrEF group; however, the HRs were not significant in the HFmrEF or HFpEF groups. Thus, MELD-XI and MELD-Na scores may be useful for predicting prognosis in hospitalized HF patients who are discharged alive, especially for those in the HFrEF group. [ABSTRACT FROM AUTHOR]

A buckling-restrained braced frame (BRBF) reduces the response of buildings during a strong earthquake, during which the surrounding members such as beams and columns must resist the axial force imposed by the buckling-restrained braces (BRBs). However, the steel beams and columns are subjected to reversed axial force from the horizontal and vertical component of BRB axial force. The steel beams might then buckle under the compressive force or even yield under the subsequent tensile axial force because the beams are not designed primarily to sustain the axial force. Therefore, the rotation capacity becomes inconsistent with the typical loading protocols. Faced with this concern, this study examines a BRBF design with reasonable balance between the steel frame and the BRBs. Pushover analyses and nonlinear response history analyses (NRHAs) are undertaken to quantify the magnitude of the beam axial force. Furthermore, a detailed finite-element analysis (FEA) model is constructed based on results obtained from a previous experiment. The strain distribution and axial force transfer mechanism are identified using an experimentally validated FEA model. Results confirm that BRB axial force is transmitted primarily to the single side of the flange. Furthermore, the parametric study in terms of the beam section, BRB axial force, and loading protocols establishes a database of the structural performance. The results of this research are used to formulate a novel index and equations describing the ultimate strength ratio, rotation capacity, and energy dissipation capacity. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) and heart failure (HF) are the first and most frequent comorbidities associated with mortality risks in early-stage type 2 diabetes mellitus (T2DM). However, efficient screening and risk assessment strategies for identifying T2DM patients at high risk of developing CKD and/or HF (CKD/HF) remains to be established. This study aimed to generate a novel machine learning (ML) model to predict the risk of developing CKD/HF in early-stage T2DM patients. The models were derived from a retrospective cohort of 217,054 T2DM patients without a history of cardiovascular and renal diseases extracted from a Japanese claims database. Among algorithms used for the ML, extreme gradient boosting exhibited the best performance for CKD/HF diagnosis and hospitalization after internal validation and was further validated using another dataset including 16,822 patients. In the external validation, 5-years prediction area under the receiver operating characteristic curves for CKD/HF diagnosis and hospitalization were 0.718 and 0.837, respectively. In Kaplan–Meier curves analysis, patients predicted to be at high risk showed significant increase in CKD/HF diagnosis and hospitalization compared with those at low risk. Thus, the developed model predicted the risk of developing CKD/HF in T2DM patients with reasonable probability in the external validation cohort. Clinical approach identifying T2DM at high risk of developing CKD/HF using ML models may contribute to improved prognosis by promoting early diagnosis and intervention. [ABSTRACT FROM AUTHOR]

Over 200 interstitial lung diseases, from ultra rare to relatively common, are recognised. Most interstitial lung diseases are characterised by inflammation or fibrosis within the interstitial space, the primary consequence of which is impaired gas exchange, resulting in breathlessness, diminished exercise tolerance, and decreased quality of life. Outcomes vary considerably for each of the different interstitial lung diseases. In some conditions, spontaneous reversibility or stabilisation can occur, but unfortunately in many people with interstitial lung disease, especially in those manifesting progressive pulmonary fibrosis, respiratory failure and death are a sad reality. Over the past 3 years, the field of interstitial lung disease has had important advances, with the approval of drugs to treat systemic sclerosis-associated interstitial lung disease, interstitial lung disease-associated pulmonary hypertension, and different forms of progressive pulmonary fibrosis. This Seminar provides an update on epidemiology, pathogenesis, presentation, diagnosis, disease course, and management of the interstitial lung diseases that are most frequently encountered in clinical practice. Furthermore, we describe how developments have led to a shift in the classification and treatment of interstitial lung diseases that exhibit progressive pulmonary fibrosis and summarise the latest practice-changing guidelines. We conclude with an outline of controversies, uncertainties, and future directions. [ABSTRACT FROM AUTHOR]

The epithelial-mesenchymal transition (EMT) is a biological process that occurs in the pathogenesis of kidney diseases in which injured tubular epithelial cells transform into myofibroblasts. We previously showed that mannitol-mediated hyperosmotic stress induces EMT of tubular epithelial cells. Although Ca2+ signaling is essential for the induction of EMT in tubular epithelial cells, the role of specific calcium channels is unknown. In this study, we assessed the transient receptor potential vanilloid 4 (TRPV4)-mediated Ca2+ influx in the hyperosmolarity-induced EMT. The Fluo-4 assay was used to examine the effect of hyperosmotic stress on the intracellular Ca2+ level of normal rat kidney (NRK)-52E cells. Expression of a mesenchymal marker α-smooth muscle actin (α-SMA) and an epithelial marker E-cadherin was also observed by fluorescence microscopy. The hyperosmotic stress caused a transient increase in intracellular Ca2+ concentration as well as a decrease in E-cadherin and an increase in α-SMA expressions in tubular epithelial cells, indicating the induction of EMT. A TRPV4 channel antagonist inhibited hyperosmotic stress-induced Ca2+ influx and the EMT, whereas, a TRPV4 channel agonist increased Ca2+ influx and EMT induction in tubular epithelial cells without the hyperosmotic stress. These findings suggest that Ca2+ influx through TRPV4 channels contributes to the hyperosmotic stress-induced EMT of tubular epithelial cells. • Hyperosmotic stress promotes a transient Ca2+ influx in tubular epithelial cells. • TRPV4 blocker attenuates the hyperosmotic stress-induced Ca2+ influx and EMT. • TRPV4 activation induces EMT of proximal tubular epithelial cells. [ABSTRACT FROM AUTHOR]

SLC26A4 is a known iodide transporter, and is localized at the apical membrane of thyrocytes. Previously, we reported that SLC26A7 is also involved in iodide transport and that Slc26a7 is a novel causative gene for congenital hypothyroidism. However, its detailed role in vivo remains to be elucidated. We generated mice that were deficient in Slc26a7 and Slc26a4 to delineate differences and associations in their roles in iodide transport. Slc26a7−/− mice showed goitrous congenital hypothyroidism and mild growth failure on a normal diet. Slc26a7−/− mice with a low iodine environment showed marked growth failure. In contrast, Slc26a4−/− mice showed no growth failure and hypothyroidism in the same low iodine environment. Double-deficient mice showed more severe growth failure than Slc26a7−/− mice. RNA-seq analysis revealed that the number of differentially expressed genes (DEGs) in Slc26a7−/− mice was significantly higher than that in Slc26a4−/− mice. These indicate that SLC26A7 is more strongly involved in iodide transport and the maintenance of thyroid function than SLC26A4. [ABSTRACT FROM AUTHOR]

Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is a hallmark of renal tubulointerstitial fibrosis and is associated with chronic renal injury as well as acute renal injury. As one of the incidences and risk factors for acute renal injury, increasing the osmolality in the proximal tubular fluid by administration of intravenous mannitol has been reported, but the detailed mechanisms remain unclear. Hyperosmotic conditions caused by mannitol in the tubular tissue may generate not only osmotic but also mechanical stresses, which are known to be able to induce EMT in epithelial cells, thereby contributing to renal injury. Herein, we investigate the effect of hyperosmolarity on EMT in tubular epithelial cells. Normal rat kidney (NRK)-52E cells were exposed to mannitol-induced hyperosmotic stress. Consequently, the hyperosmotic stress led to a reduced expression of the epithelial marker E-cadherin and an enhanced expression of the mesenchymal marker, α-smooth muscle actin (α-SMA), which indicates an initiation of EMT in NKR-52E cells. The hyperosmotic condition also induced time-dependent disassembly and rearrangements of focal adhesions (FAs) concomitant with changes in actin cytoskeleton. Moreover, prevention of FAs rearrangements by cotreatment with Y-27632, a Rho-associated protein kinase inhibitor, could abolish the effects of hyperosmotic mannitol treatment, thus attenuating the expression of α-SMA to the level in nontreated cells. These results suggest that hyperosmotic stress may induce EMT through FAs rearrangement in proximal tubular epithelial cells. [ABSTRACT FROM AUTHOR]

Normalized maximum likelihood (NML) distribution of probabilistic model gives the optimal code length function in the sense of minimax regret. Despite its optimal property, the calculation of NML distribution is not easy, and existing efficient methods have been focusing on its asymptotic behavior, or on specific models. This paper gives an efficient way to calculate NML by integral on parameter domain, not on data domain, showing that NML distribution is a Bayesian predictive distribution with a complex prior, based on our novel Fourier expansion approach. Our results provide an integrated way to calculate NML for exponential family and also include a non-asymptotic version of previous work on asymptotic behavior for general cases. The applications of our methodology are not limited to but also include normal distribution, Gamma distribution, Weibull distribution, and von Mises distribution. [ABSTRACT FROM AUTHOR]

Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca2+ influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca2+ influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma Cmax) and 1017-fold (AUC plasma) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation. [ABSTRACT FROM AUTHOR]

Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca2+ influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca2+ influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma Cmax) and 1017-fold (AUC plasma) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation. [ABSTRACT FROM AUTHOR]

In general, a steel beam is assembled with a concrete slab using shear connectors. Recently, perfobond-shear connectors have been attracting interest because of their high shear stiffness and strength. Nevertheless, the mechanical behavior and performance of perfobond-shear connectors under a reversed cyclic stress remain unclear. For this study, cyclic loading tests were conducted on the component model of a composite beam possessing different configurations of perfobond-shear connectors, different diameters of transversal reinforcement, and different concrete strengths. The stress transfer mechanisms among components are revealed based on experimentally obtained results. Furthermore, the applicability of earlier evaluation formulas is investigated in terms of the ultimate shear strength and the load–displacement relation. Finally, a novel evaluation equation is proposed for perfobond-shear connectors subjected to fully reversed cyclic stress, reflecting the mechanical interrelation between the dowel plate and the concrete inside of the rib hole. [ABSTRACT FROM AUTHOR]

Quantitative profiles of stable isotopes and trace elements in biogenic carbonates have received considerable attention for the purpose of reconstructing past temperatures. The relationships between temperature and the geochemical parameters of carbonates are often subject to both inter- and intraspecific variations, which critically impair the accuracy of temperature estimation. One of the issues that must be addressed to improve temperature estimation is enhancing our understanding of the influence of the kinetic effect. This effect matters because the purely thermodynamic effect to geochemical profiles cannot be effectively separated from the effect of temperature-driven calcification rate. Cowries (Mollusca, Gastropoda, Cypraeidae) may provide a good model system for quantitatively investigating these two effects, because they undergo a callus-building stage in which aragonitic shell formation exclusively occurs to monotonically increase the thickness outward. We reared a total of 230 juvenile individuals of Monetaria annulus under six constant thermal regimes, ranging from the minimum growing temperature (21 °C) to the maximum tolerated long-term temperature (34 °C). The portions of the shells built in the callus-building stage were analyzed to quantify isotopic and elemental compositions. Shell growth rate positively depended on temperature from 21 °C to 33 °C, but dramatically decreased at 34 °C, presumably because of high temperature stress. Nevertheless, the heat stress did not make any impact on the thermal dependences (and among-individual variabilities within the same temperature) of either δ18O c or Sr/Ca. A linear relationship exists between temperature and the stable oxygen isotope value of the shells (δ18O c) across the entire thermal range (n = 103), whereas the shell Sr/Ca ratio increased exponentially with increasing temperature (n = 227). These results strongly suggest that any chemical processes responsible for quantitative incorporation of 18O and Sr into aragonite crystals were not impacted by heat stress at temperatures up to 34 °C. Within-temperature residual correlations between shell growth rates and δ18O c were weakly positive, which is compatible with a widely accepted hypothesis that carbonic anhydrase suppresses the kinetic effect in molluscs. Likewise, we found no association between shell growth rates and Sr/Ca, which rejected the possibility that faster CaCO 3 precipitation caused the positive relationship between temperature and Sr/Ca. A large proportion of among-individual variability in shell Sr/Ca was caused by unspecified factors other than temperature. This makes it difficult to accurately estimate the past temperature by measuring the Sr/Ca value of a single shell specimen. [ABSTRACT FROM AUTHOR]

Influence of alkali metals such as sodium (Na) and potassium (K) in methyl ammonium lead iodide CH3NH3PbI3 perovskite crystal on electronic structures, spectroscopic properties, and thermodynamic properties was investigated by first-principles calculation. Partial substitution of CH3NH3 with Na or K in the perovskite crystal generated 3s, 3p, 4s, and 4p orbitals of Na or K above conduction band, which promoted the charge transfer from the alkali metals to the conduction band, accelerating the carrier generation and diffusion related to the photovoltaic performances. The molar absorption coefficient and oscillation strength were increased by a slight deviation of the charge distribution near ligand in the coordination structure. The splitting of chemical shift of 127I-NMR in magnetic field was caused by a slight perturbation of the coordination structure with nuclear quadrupole interaction based on electronic field gradient. Decrease of the Gibbs free energy and entropy indicated the thermodynamic stabilization without scattering carrier diffusion as phonon effectiveness. The decrease of the entropy was based on a slight change of stretching vibration mode of Pb–I bond with vending mode of N–H and C–H bonds in the infrared and Raman spectra. The minor addition of 12.5% Na or K into the perovskite crystal will improve the photovoltaic properties, open voltage related to band gap, and short-circuit current density based on the carrier diffusion with phonon effectiveness. [ABSTRACT FROM AUTHOR]

Nonischemic heart failure (HF) is common in Japan. We evaluated the long-term outcome of Japanese patients with nonischemic HF receiving carvedilol based on left ventricular ejection fraction (LVEF) category. We conducted a single-center observation study of 1550 patients with nonischemic HF who were initiated with carvedilol between 2005 and 2015. Of these patients, 38% had an LVEF < 40% (HFrEF, median age 57 years, 28% female) and 62% had an LVEF ≥ 40% (HFpEF, 64 years, 38% female). The primary outcome was all-cause.death The secondary outcomes were cardiac death and sudden cardiac death (SCD). After a median follow-up of 5.5 [interquartile range, 2.9–8.8] years, the median daily maintenance doses of carvedilol in patients with HFrEF and HFpEF were 7.5 [5–12.5] mg and 7.5 [5–10] mg, respectively. The cumulative survival rates of HFrEF patients at 1, 3 and 5 years were 96.1%, 90.2% and 85.5%, respectively, and the cumulative survival rates of HFpEF patients at 1, 3 and 5 years were 97.8%, 94.4% and 90.7%, respectively. The cumulative cardiac death-free rates at 5 years were 94.4% in HFrEF patients and 97.7% in HFpEF patients, and the cumulative SCD-free rates at 5 years were 96.7% in HFrEF patients and 97.9% in HFpEF patients. The adjusted survival rate showed that a higher dose (≥ 7.5 mg daily) was associated with more favourable outcomes than a lower dose (< 7.5 mg daily) in HFrEF patients, but not in HFpEF patients. The adjusted survival rate showed that a lower heart rate (< 75 bpm) was associated with favourable outcomes than a higher heart rate (≥ 75 bpm) in HFrEF patients, but not in HFpEF patients. Long-term survival was good in Japanese patients with nonischemic HF receiving carvedilol. Higher doses and lower heart rates were associated with favourable survival for HFrEF patients, but not in HFpEF patients. [ABSTRACT FROM AUTHOR]

Marine tardigrades in the Antarctic and sub-Antarctic regions are poorly understood. During the 59th Japan Antarctic Research Expedition, a sediment sample was collected from Lützow-Holm Bay, East Antarctica. The sediment sample yielded three species of marine tardigrades belonging to the family Styraconyxidae Kristensen & Renaud-Mornant, 1983: Angursa antarctica Villora-Moreno, 1998, Styraconyx cf. qivitoq Kristensen & Higgins, 1984, and S. takeshii sp. nov. The new species resembles S. nanoqsunguak Kristensen & Higgins, 1984 by the overall morphology, but the new species has thick seminal receptacle ducts that do not terminate in typical, swelled vesicles, in contrast to S. nanoqsunguak's narrow seminal receptacle ducts that terminate in small vesicles. The presence of the undivided mouth papilla and the larger body further differentiates the new species from S. nanoqsunguak. We also report a young adult female with a gonopore, but lacking seminal receptacles in the new species. As well as morphological information, we provided the sequences of the new species' nuclear 28S rRNA and mitochondrial cytochrome c oxidase subunit I fragments. Using the former molecular data, phylogenetic analyses of Styraconyxidae were conducted and polyphyly of Styraconyx was suggested. The biogeography of marine tardigrades in the Antarctic and sub-Antarctic regions are also discussed. [ABSTRACT FROM AUTHOR]

During earthquakes, I-shaped beams (I-beams) in a braced structure are subjected to the flexural moment synchronized with reversed axial forces transmitted from buckling restrained braces. A prior study used the modified width–thickness ratio to evaluate the rotation capacity of I-beams that failed by local buckling under alternating axial force. Generally speaking, I-beams in braced frames are designed with larger sections to resist severe stress conditions. The buckling mode might thereby be switched to web-shear buckling, leading to inaccurate estimation of the rotation capacity when using existing equations. For this study, a classification index of buckling mode is constructed considering axial force and plate interactions. Moreover, a novel index and formulas are proposed for evaluating the rotation capacity of I-beams under alternating axial forces, including buckling-mode transition effects. [ABSTRACT FROM AUTHOR]

Background and objective: Acute exacerbation (AE) is a severe complication of idiopathic pulmonary fibrosis (AE‐IPF). In 2016, an international working group revised its definition and diagnostic criteria; however, few studies have assessed the frequency and prognosis of AE in patients with other fibrotic interstitial lung diseases (FILD). Methods: We used data from 1019 consecutive interstitial lung disease (ILD) patients initially evaluated between January 2008 and July 2015. All subject diagnoses were made by multidisciplinary discussion in December 2018. ILD was categorized as IPF (n = 462) and other FILD which included non‐specific interstitial pneumonia (n = 22), chronic hypersensitivity pneumonitis (n = 29), connective tissue disease‐associated ILD (n = 205) and unclassifiable ILD (n = 209). Using the 2016 definition of AE‐IPF, we identified all subjects with an AE. Results: During the observational period, 193 patients experienced a first AE (AE‐FILD n = 69, AE‐IPF n = 124). The time to first AE was significantly longer in FILD than IPF (log‐rank test, P < 0.001). After adjusting for potentially influential confounders, FILD remained a significant predictor of longer time to first AE compared with IPF (hazard ratio: 0.453; 95% CI: 0.317–0.647, P = 0.006). In a multivariate Cox proportional analysis, baseline disease severity was closely associated with the incidence of AE‐ILD. Even after adjustment for other clinical variables, AE had a negative impact on overall survival. AE‐FILD and AE‐IPF showed similar poor short‐term outcomes. Conclusion: All forms of ILD are at risk of AE and have a similar outcome to AE‐IPF. [ABSTRACT FROM AUTHOR]

The aim of this research is to realize high‐efficiency light‐emitting diodes (LEDs) with a 3D core‐shell GaN nanowire. This article describes the growth of 3D core‐shell GaN nanowires, the formation of indium tin oxide (ITO) around the p‐GaN outer shell of the nanowires, and the characteristics of the fabricated nanowire‐LED (NW‐LED). The structural properties of the n‐GaN core, GaInN/GaN multiquantum shell (MQS), p‐GaN outer shell, and ITO electrode are investigated by scanning electron microscopy and scanning transmission electron microscopy. In addition, the optical and electrical characteristics of the NW‐LEDs are evaluated. The findings show that the grown n‐GaN cores have a uniform height and diameter, the MQS is defect‐free with a uniform film thickness, and p‐GaN outer shells with a uniform thickness are grown on both the m‐ and c‐planes. Consequently, a NW‐LED that emits light from the entire chip area is successfully realized by depositing an ITO electrode that covers the p‐GaN outer shells with a uniform film thickness. [ABSTRACT FROM AUTHOR]

A GaInN/GaN multiquantum shell (MQS) structure grown over GaN nanowires can be utilized as active regions in optoelectronic devices because of its advantages such as high crystalline quality and the absence of internal polarization. To improve the current injection toward the sidewall of the MQS active regions, a tunnel junction (TJ) and n‐GaN‐embedded cap layer are adopted without using an indium‐tin‐oxide film. A light‐emitting diode (LED) composed of n‐GaN nanowires, MQS active regions, TJs, and an n‐GaN‐embedded cap layer is demonstrated for the first time. Without the activation process of Mg acceptors, the MQS LED exhibits a linear increase in the light output with current injection and a high operating voltage. After removing the upper part of the n‐GaN‐embedded cap layer, thermal annealing is confirmed to activate Mg acceptors in p‐GaN and p+‐GaN, and the reduction of the operating voltage is observed, despite the lack of current spreading in the n‐GaN‐embedded cap layer by Mg diffusion. [ABSTRACT FROM AUTHOR]

The effect of chlorogenic acid-enriched green coffee bean extract (cGCE) intake on arterial stiffness was investigated using the cardio-ankle vascular index (CAVI) as a novel surrogate marker for predicting arteriosclerosis. A placebo-controlled double-blind pilot study was conducted with 16 healthy Japanese men. Subjects were divided into two groups and consumed beverages containing either cGCE or placebo daily for 2 weeks. The CAVI, the primary endpoint of the study, was evaluated at the beginning of the study and 2 weeks later. Endothelium-dependent flow-mediated dilation (FMD) and sympathetic nervous activity (SNA), which are thought to be related to the CAVI, were also measured. The CAVI change was significantly greater in the cGCE group than in the placebo group. In addition, FMD increased and SNA decreased in the cGCE group. These findings suggest that 2-week ingestion of cGCE may improve arterial stiffness as assessed by the CAVI. [ABSTRACT FROM AUTHOR]

Ketamine produces a rapid-onset antidepressant effect in patients with treatment-resistant depression (TRD), although it concurrently causes undesirable psychotomimetic side effects. Accumulating evidence suggests that ketamine produces antidepressant effects via activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R), with consequent activation of the mammalian target of rapamycin (mTOR) pathway and up-regulation of brain-derived neurotrophic factor (BDNF). We previously reported that TAK-137, an AMPA-R potentiator with little agonistic effect, had potent procognitive effects with lower risks of bell-shaped dose-response and seizure induction. In this study, we characterized the potential of TAK-137 as a novel antidepressant in rats. In rat primary cortical neurons, TAK-137 increased the phosphorylated form of Akt, extracellular signal-regulated kinase, mTOR, and p70S6 kinase, and dose-dependently increased the expression level of BDNF protein. The antidepressant-like effects of ketamine and TAK-137 were assessed on the day after final administration using the novelty-suppressed feeding test in rats. A single intraperitoneal administration of ketamine shortened the latency to feed. Under these conditions, oral administration of TAK-137 for 3 days shortened the feeding latency. Ketamine induced hyperlocomotion and reduced prepulse inhibition, which may be associated with psychotomimetic effects, while TAK-137 did not. TAK-137 may be a safer and rapid-onset therapeutic drug for the treatment of major depressive disorder, including TRD. • One-day treatment with ketamine shortened the latency to feed in an NSF test. • Three-day treatment with TAK-137 shortened the latency to feed. • Ketamine induced hyperlocomotion and reduced PPI. • TAK-137 did not induce hyperlocomotion or reduce PPI. • Compounds such as TAK-137 may be safer drugs for the treatment of MDD. [ABSTRACT FROM AUTHOR]

Friction between a polymer network of poly(N-isopropylacrylamide) gels and solvent water was investigated. The gel was mechanically constrained in a glass capillary at gelation, and hydrostatic pressure was directly applied to the cross section of the cylinder. The temperature dependence of the flow velocity was extensively measured in the vicinity of the transition temperature for gels with different lengths, l0, at gelation. As the temperature increased, the friction slightly decreased at the transition point and increased rapidly in the collapsed phase. Although the flow velocity depended on l0, the friction in the vicinity of the transition point was well scaled by l0 based on the Hagen-Poiseuille equation for the flux of water flow in a capillary. The results suggested that the assumption that the gel is a bundle of microcapillaries was applicable to the water flow through the hydrogel, which was largely deformed not only by the pressure applied to the solvent but also by the shrinking force caused by the temperature increment. Macroscopic deformation did not affect the friction between the three-dimensional polymer network and water. [ABSTRACT FROM AUTHOR]

The swelling and shrinking kinetics of thin-plate poly(N-isopropylacrylamide) gels with rectangular surfaces under mechanical constraint was investigated. The top and bottom surfaces were chemically clamped on the glass plates, and the gel could swell and shrink only along the thickness direction between two swollen states by the temperature jumps. The time evolution of the thickness was well described by a single exponential except immediately after the temperature change. The characteristic time was found to depend on the lengths of the constrained surfaces and not on the thickness at the time of sample preparation. The swelling and shrinking kinetics of the one-dimensional thickness direction is essentially governed by the relaxation of the polymer network in the two-dimensional direction along the surface. © 2001 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Investigates the shrinkingphase transition of weakly ionized poly(N-isopropylacrylamide) gels prepared in a cylindrical shape with submillimeter diameter. Macroscopic conformation changes obtained on heating processes in two different methods; Macroscopic behavior.

Electronic structures of alkali metals (Li, Na, K or Rb)-incorporated formamidinium lead halide perovskite compounds were investigated by first-principles calculation. The conduction band were supplied with electrons from energy levels at 2 s , 3 s , 4 s and 5 s orbital of alkali metal to energy levels at 6 p orbital of Pb atom in the perovskite crystal. Deviation of charge distribution in the perovskite crystal promoted the photo-induced charge generation, electron correlation and electron-lattice interaction as phonon effectiveness. The chemical shifts of 127I-NMR in the perovskite crystal were originated in a slight perturbation of the coordination structure with nuclear quadruple interaction based on the electric field gradient. The slight incorporation of alkali metal near the ligand structure decreased the enthalpy with the Gibbs free-energy by contribution of the entropy due to the P I stretching vibration. Unlabelled Image • Electrons were supplied from alkali metal to conduction band in perovskite crystal. • Deviation of charge promoted photo-induced charge generation. • Chemical shifts of I-NMR were based on nuclear quadruple interaction. • Incorporation of alkali metal decreased Gibbs free-energy and enthalpy. • Entropy was based on Pb-I stretching vibration in IR and Raman spectra. [ABSTRACT FROM AUTHOR]

Transition metal doped cesium lead halide (CsPbI3) perovskite compounds were studied for application in photovoltaic solar cells. Electronic structures, chemical shifts of 207Pb and 127I-NMR, vibration modes in infrared and Raman spectra of transition metals (Mn2+, Fe2+ or Cu2+)-doped CsPbI3 perovskite compounds were studied by the first-principles calculation using density functional theory. The CsPb(Fe)I3 perovskite crystals had a slight perturbation of crystal field in the coordination structure. The electron density distribution was delocalized on the 5p orbital of I atom, the 3d orbital of Fe atom and the 6p orbital of Pb atom. The first excited process was based on ligand metal charge transfer from the 5p orbital on I atom to the 3d orbital of Fe atom. The chemical shifts of 127I-NMR were associated with the electron correlation of electron-nuclear spin interaction and nuclear quadrupole interactions based on electron field graduate. The asymmetric vibrations of Pb–I bonds stretching mode related to electron conductivity with scattering of the carrier diffusion as phonon effectiveness. The slight perturbation of the coordination structure in the CsPb(Fe)I3 perovskite crystal will improve the photovoltaic and optical properties. [ABSTRACT FROM AUTHOR]

This paper presents two high-voltage direct-current circuit breakers that have the capability of interrupting a short-circuit current within several milliseconds. They consist of a current-limit inductor, a current-control inductor, one or two mechanical switches, and a multilevel converter with phase-shifted-carrier pulsewidth modulation. The two breakers can commutate an almost zero current from the main branch to the auxiliary branch. This paper proposes an original breaker with low-voltage and high-voltage mechanical switches connected in series, followed by a simplified breaker with a single high-voltage mechanical switch. Finally, this paper includes experimental verification by two slightly different downscaled breakers rated at 300 Vdc and 150 Adc, as well as confirmation of an actual original breaker by circuit simulation using the “PSCAD/EMTDC” software package. [ABSTRACT FROM AUTHOR]

Stability of the output obtained from a pressure sensor using a quartz oscillator for outdoor measurement was improved by the normalization of pressure and temperature changes. Maximum fluctuation ratio, which is the index of the fluctuation, was reduced sufficiently to a practical level by the present pressure- and temperature- normalization. This level corresponds to the degree of the level which shows 0.33% of the output, which is in agreement with the application for hydrogen sensing. [ABSTRACT FROM AUTHOR]

Species constituting the family Echiniscidae are highly derived, armoured and inhabit terrestrial habitats, in contrast to other heterotardigrades that are predominantly marine. The genus Echiniscus C.A.S. Schultze, 1840, nominal for the family Echiniscidae, is currently the most speciose tardigrade genus. However, the great morphological variability, in comparison with other heterotardigrade genera, suggests the polyphyletic character of the genus. Here, we analyse new specimens of Echiniscus pseudelegans Séméria, 1994 collected in Japan and conclude that the species as well as two other related taxa, E. elegans Richters, 1907 and E. latifasciatus Dudichev and Biserov, 2000, represent a new genus, Stellariscus , gen. nov. The new genus is characterised by a mixture of peculiar morphological apomorphies: black eyes, star-like dorsal plate sculpturing, no trunk appendages (only cephalic cirri present), two types of ventral plates, and striking sexual dimorphism in both qualitative and quantitative traits. Morphological phylogeny of the family Echiniscidae suggests a close affinity between Stellariscus , Hypechiniscus Thulin, 1928 and Pseudechiniscus Thulin, 1911. The polyphyletic status of both Echiniscus and Testechiniscus Kristensen, 1987 is also inferred. The taxonomic significance of ventral armature in echiniscid phylogeny and taxonomy is discussed. Many tardigrades can be easily found in garden mosses, but the members of the family Echiniscidae are quite rare, thus poorly known. This paper presents morphological clues for an artificial character of the largest echiniscid genus Echiniscus , by erecting new genus restricted to Asia. Therefore, by demonstrating the value of cuticular pattern in the systematics, further changes can be made to elucidate echiniscid classification. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background and objective: The St George’s Respiratory Questionnaire (SGRQ) is a self‐administered questionnaire used to assess health‐related quality of life (HRQoL) in various chronic respiratory diseases. Few studies have assessed the performance of the SGRQ in patients with connective tissue disease‐associated interstitial lung disease (CTD‐ILD). We aimed to examine the SGRQ’s performance characteristics and generate data to support its reliability and validity in patients with CTD‐ILD. Methods: We used data from 193 CTD‐ILD patients evaluated at Tosei General Hospital from May 2007 to July 2016 to assess the cross‐sectional and longitudinal validity of the SGRQ. Results: The mean age of the patients was 64.2 years and 122 (63.2%) were women. There were no significant differences in SGRQ scores between any of the CTD groups. Internal consistency (Cronbach’s α = 0.905) and repeatability (intraclass correlation coefficient (ICC) = 0.873) for the SGRQ total score were excellent. At baseline, SGRQ total score was significantly associated with clinically meaningful measures of physiological function, exercise capacity and dyspnoea. Change in SGRQ total score over 6 months was also associated with change in other measures. Cox proportional hazards models showed that higher baseline SGRQ total score was a significant predictor of mortality. The estimated minimal clinically important difference of SGRQ total score was 4–13 points. Conclusion: These data support the validity and reliability of SGRQ as a sensitive measure for capturing HRQoL in patients with CTD‐ILD. [ABSTRACT FROM AUTHOR]

The intestine has fundamental functions for the maintenance of homeostasis, including food digestion and nutrient/water absorption. Although the lumen of the intestine is always exposed to pathogens, intestinal epithelial cells form monolayer sheets that act as an epithelial barrier to prevent the invasion of pathogens. Thus, disruption of the intestinal epithelial barrier causes inflammatory bowel diseases. To investigate the details of these intractable intestinal diseases, it is necessary to analyze the characteristics of intestinal epithelial cells in vitro. However, it is difficult to maintain and propagate intestinal epithelial cells in culture. Recently, intestinal organoid culture systems have been established, in which differentiated intestinal epithelial lineage cells can be continuously produced from intestinal stem cells and form epithelial organoids with crypt‐like structures in long‐term culture. Moreover, intestinal epithelial organoids can be generated not only from intestinal tissue‐derived cells, embryonic stem cells, and induced pluripotent stem cells, but also by inducing direct conversion of nonintestinal somatic cells into intestinal epithelial cells. These intestinal organoids can be used in basic studies for understanding the mechanisms underlying intestinal development and diseases and will be applied in future transplantation therapy and drug discovery to treat intestinal diseases. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Acute exacerbation (AE) is a severe complication of idiopathic pulmonary fibrosis (IPF), which shares some common pathological features with acute respiratory distress syndrome (ARDS). The new definition of ARDS requires positive end‐expiratory pressure (PEEP) to assess gas exchange and has better predictive validity for short‐term mortality compared with the previous definition. Objectives: The aim of this study was to evaluate the prognostic utility of oxygenation with PEEP in AE‐IPF. Methods: We performed a retrospective cohort study using the data of AE‐IPF patients between 2007 and 2015. At the time of diagnosis, PaO2/FiO2 was evaluated before and 30 minutes after PEEP. We evaluated the prognostic utility of PaO2/FiO2 with PEEP after including other candidate prognostic factors. Considering the definition of ARDS, patients with AE‐IPF were classified into a severe group (PaO2/FiO2 ≤ 300 with PEEP) and a non‐severe group (PaO2/FiO2 > 300 with PEEP). Results: We identified 62 consecutive patients with AE‐IPF. All patients were treated with mechanical ventilation on the first day. The median PaO2/FiO2 before and 30 minutes after PEEP was significantly increased (237.5‐425.5, P < .001). In multivariate Cox proportional analysis, Krebs von den Lungen‐6 (KL‐6) (HR 1.239; 95%CI 1.050‐1.461; P = .011), D‐dimer (HR 1.039; 95%CI 1.015‐1.064; P = .001), % neutrophils in bronchoalveolar lavage fluid (HR 1.015; 95%CI 1.003‐1.027; P = .017), and being in the severe group (HR 3.233; 95%CI 1.503‐6.957; P = .003) had significant impacts on survival up to 90 days. Conclusion: Evaluation of oxygenation with PEEP may provide useful information for predicting short‐term mortality in patients with AE‐IPF. [ABSTRACT FROM AUTHOR]

The chemical states of Ni species were systematically investigated using an in situ XAFS technique for a series of SiO 2 -supported Ni catalysts with different Ni particle sizes. The Ni particles were refined by varying the Ni loading in the range between 0.10 and 5 wt% and by adding citric acid into the precursor solution. An in situ observation cell for fluorescence-yield XAFS measurements was developed for the dilute Ni catalysts. The chemical state of the supported Ni species converted between Ni(0) and NiO, and no other stable species were formed during the temperature-programmed oxidation and reduction processes. Refinement of the Ni particles resulted in decreasing the oxidation temperature and increasing the reduction temperature. These shifts were explained by the affinity of NiO to SiO 2 , and more effective stabilization was thus anticipated for flattened small NiO particles with an increased contact area. In addition, the inhomogeneous distribution of small Ni particles observed for dilute catalysts was explained in terms of the precursor solution volume when nuclei of the precursor compound precipitated on SiO 2 during the drying process. [ABSTRACT FROM AUTHOR]

The color of Undaria pinnatifida after boiling is an important factor determining its marketable value. Our previous study showed that decreased nutrients and elevated irradiance resulted in increases of lightness and yellowness (i.e., discoloration) of this alga. However, little is known about the optimal levels of nutrients and irradiance required to decrease these color values and the combined effects of these factors and boiling. We conducted two culture experiments to test the effects of nutrients (non-enriched and 1.25, 5, and 25% PESI enriched treatments), irradiance (0, 10, 30, and 180 µmol m s), and boiling on lightness L*, redness a*, and yellowness b* of this alga. L* and b* did not differ between non-enriched and 1.25-5% PESI treatments, but were lower in the 25% PESI treatment. L* and b* were lowest at 0-10 µmol m s, although negative growth occurred at 0 µmol m s. Decreased irradiance had a positive or little effect on a* before boiling, but had a negative effect after boiling. These results suggest that around 25% PESI and 10 µmol m s were the optimal levels to decrease the three color values of this species after boiling. [ABSTRACT FROM AUTHOR]

SUMMARY This paper presents a new hybrid dc circuit breaker producing no conducting power loss under normal operating conditions and having the capability to interrupt a large amount of short-circuiting current within several milliseconds. It consists of two reactors for current limiting and current control, two mechanical contactors, and a multilevel converter based on the cascade connection of multiple full-bridge dc/dc converter cells. It is characterized by achieving current commutation from the main mechanical contactor to the multilevel converter with fast current control. This results in eliminating auxiliary power semiconductor switches that produce a nonnegligible conducting power loss under normal operating conditions. This paper discusses both principles of operation and control method of the new hybrid dc circuit breaker. Experimental verification is performed by a downscaled system rated at 300 V and 150 A, along with verification by computer simulation. [ABSTRACT FROM AUTHOR]

A new species of free-living marine nematode, Oncholaimus langhovdensis sp. nov., is described from the intertidal zone of Langhovde (near Syowa Station), Dronning Maud Land, East Antarctica. It closely resembles 11 congeners in the conico-cylindrical tail shape present in males and amphid and excretory pore positions, short spicules, and Demanian system structure present in females. However, it mainly differs from these congeners in body size, de Man's ratios, tail length and shape, and Demanian system structure present in females. Oncholaimus langhovdensis sp. nov. also resembles four congeners known only by females, but it can be distinguished from them based on the tail length and uvette position. In addition to O. langhovdensis sp. nov., two undescribed species (Tripyloididae gen. sp. and Axonolaimidae gen. sp.) and four unidentified species (Sphaerolaimus sp., Oncholaimidae gen. sp., Comesomatidae gen. sp., and Chromadorida fam. gen. sp.) were found from the same locality. [ABSTRACT FROM AUTHOR]

Inductive interactions mediated by the TGF-β and FGF–MAPK pathways are essential for specification of the germ layers and embryonic body axes during early vertebrate embryogenesis. TGF-β and FGF ligands signal through receptor Ser/Thr and Tyr kinases, respectively, and these signaling pathways cross-talk to regulate transcription and cell behavior. The allotetraploid Xenopus laevis and its ancestral diploid Xenopus tropicalis are versatile model organisms with which to study the inductive interactions and mechanisms of these signal transduction pathways. Here we have analyzed the draft genome of X. laevis with respect to the genomic organization and differential expression of genes in the TGF-β and FGF pathways. Genomic structure and gene expression analyses of pathway components in X. laevis revealed that genetic modulations, including deletions resulting in singletons and differential expression of homeologs, have occurred frequently among extracellular regulatory factors of the TGF-β pathway after allotetraploidization. Moreover, differential gene expression was found for factors regulating various cellular responses including co-receptors, decoy receptors, and intracellular negative regulators in both the TGF-β and FGF–MAPK pathways. We summarize the patterns of genetic alterations in the allotetraploid frog X. laevis and discuss the importance of these changes with regard to developmental processes. [ABSTRACT FROM AUTHOR]

Extracellular factors belonging to the TGF-β family play pivotal roles in the formation and patterning of germ layers during early Xenopus embryogenesis. Here, we show that the vg1 and nodal3 genes of Xenopus laevis are present in gene clusters on chromosomes XLA1L and XLA3L, respectively, and that both gene clusters have been completely lost from the syntenic S chromosome regions. The presence of gene clusters and chromosome-specific gene loss were confirmed by cDNA FISH analyses. Sequence and expression analyses revealed that paralogous genes in the vg1 and nodal3 clusters on the L chromosomes were also altered compared to their Xenopus tropicalis orthologs. X. laevis vg1 and nodal3 paralogs have potentially become pseudogenes or sub-functionalized genes and are expressed at different levels. As X. tropicalis has a single vg1 gene on chromosome XTR1, the ancestral vg1 gene in X. laevis appears to have been expanded on XLA1L. Of note, two reported vg1 genes, vg1(S20) and vg1(P20) , reside in the cluster on XLA1L. The nodal3 gene cluster is also present on X. tropicalis chromosome XTR3, but phylogenetic analysis indicates that nodal3 genes in X. laevis and X. tropicalis were independently expanded and/or evolved in concert within each cluster by gene conversion. These findings provide insights into the function and molecular evolution of TGF-β family genes in response to allotetraploidization. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective Drug-induced lung injury ( DLI) can result from a vast number of agents, and sometimes presents findings similar to those of acute respiratory distress syndrome ( ARDS). Previous studies have reported that circulating levels of soluble thrombomodulin ( TM) reflect endothelial injuries, which play key roles in the development of ARDS. We hypothesized that endothelial injuries are an important aspect of pathogenesis in severe DLI. The primary aim of this study was to examine the associations between soluble TM and disease severity in DLI patients. Methods Of the 2580 patients who underwent a bronchoalveolar lavage ( BAL) procedure at Tosei General Hospital between May 2007 and February 2015, we retrospectively analysed the data of 68 DLI patients. Soluble TM in plasma and BAL fluid ( BALF), and other biomarkers were included in our analysis. Results At the time of diagnosis, 39 patients (57%) had respiratory failure (partial pressure of oxygen/inspiratory oxygen fraction ratio, PaO2 / FiO2 ratio < 300). There was a significant negative linear correlation between the PaO2 / FiO2 ratio and soluble TM in BALF (r = −0.448, P < 0.001). In a stepwise multiple regression analysis, soluble TM in BALF and surfactant protein D ( SP-D) were the only independent determinants of the PaO2 / FiO2 ratio. Additionally, in a multivariate logistic regression model, soluble TM in BALF (adjusted OR ( aOR): 7.48, 95% CI: 1.60-34.98) and SP-D ( aOR: 5.31, 95% CI: 1.40-20.15) was an independent predictor of respiratory failure ( PaO2 / FiO2 ratio < 300). Conclusion Soluble TM in BALF is an independent predictor of severe DLI. These findings underscore the importance of pulmonary endothelial injuries in the pathogenesis of severe DLI. [ABSTRACT FROM AUTHOR]

SUMMARY Both global and local environmental changes threaten coral reef ecosystems. To evaluate the effects of high seawater temperature and phosphate enrichment on reef-building crustose coralline algae, fragments of Porolithon onkodes were cultured for 1 month under laboratory conditions. The calcification rate of the coralline algae was not affected at 30° C, but it decreased to the negatives at 32° C in comparison to the control treatment of 27° C, indicating that the temperature threshold for maintaining positive production of calcium carbonate lies between 30 and 32° C. Phosphate enrichment of 1-2 μmol L−1 did not affect the calcification rate. The net oxygen production rate was enhanced by phosphate enrichment, suggesting that the photosynthetic rate was limited by the availability of phosphate. It was concluded that moderate phosphate enrichment does not directly deteriorate algal calcification but instead ameliorates the negative effects of high seawater temperature on algal photosynthesis. [ABSTRACT FROM AUTHOR]

Ketamine exerts rapid and long-lasting antidepressant effects in patients with treatment-resistant depression. However, its clinical use is limited by its undesirable psychotomimetic side effects. Accumulating evidence from preclinical studies has shown that the antidepressant effects of ketamine are dependent on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) activation, which triggers activation of the mechanistic target of rapamycin pathway and brain-derived neurotrophic factor release. Thus, AMPA-R has emerged as a promising new target for novel antidepressants with a rapid onset of action. However, almost all known AMPA-R potentiators carry the risk of a narrow bell-shaped dose-response curve and a poor safety margin against seizures. Our data suggest that agonistic activity is not only related to the risks of bell-shaped dose-response curves and seizures but also to the reduced synaptic transmission and procognitive effects of AMPA-R potentiators. In this review, we describe our original screening approach that led to the discovery of an investigational AMPA-R potentiator with low agonistic activity, TAK-653. We further review the in vitro and in vivo profiles of TAK-653, including its procognitive and antidepressant-like effects, as well as its safety profile, in comparison with known AMPA-R potentiators with agonistic activity and AMPA, an AMPA-R agonist. The low agnostic activity of TAK-653 may overcome limitations of known AMPA-R potentiators. This article is part of the Special Issue on 'Ketamine and its Metabolites'. • AMPA-R activation is involved in the antidepressant activity of ketamine. • Minimal agonism is key to enhancing synaptic transmission and procognitive effects. • TAK-653 with low agonistic effects was discovered by an original screening approach. • TAK-653 has a wide safety window with procognitive effect at broad range of dosages. • TAK-653 stimulated BDNF-mTOR signaling and showed antidepressant-like effects. [ABSTRACT FROM AUTHOR]