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Yes-associated protein 1 (YAP1) interacts with numerous transcription factors, including TEA-domain family proteins (TEAD) and p73. YAP1 is negatively regulated by the tumor suppressor Hippo pathway. In human cancers, the deregulation of the Hippo pathway and YAP1 gene amplification lead to the activation of YAP1, which induces epithelial–mesenchymal transition (EMT) and drug resistance. YAP1 inhibitors are expected to be useful in cancer therapy. On the other hand, in certain cancers, YAP1 upregulates p73-dependent gene transcription and behaves as a tumor suppressor. Moreover, as YAP1 regulates self-renewal and differentiation of tissue stem cells and plays an important role in tissue homeostasis, YAP1 activators may contribute to the regenerative medicine. With this in our mind, we screened for YAP1 activators by using human retinal pigment epithelial ARPE-19 cells expressing the TEAD-responsive fluorescence reporter under the coexpression of YAP1. From an extensive chemical compound library (n = 18,606) 47 candidate YAP1 activators were identified. These compounds were characterized to determine whether this assay provides bona fide YAP1 activators. Importantly, one YAP1 activator was effective against the human multiple myeloma IM-9 cells and chronic myeloid leukemia K562 cells.Implications: YAP1 activation limits growth, induces apoptosis, and may be useful at suppressing hematological cancers. Mol Cancer Res; 16(2); 197–211. ©2017 AACR.

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Supported Au nanoparticles modified with basic Lindqvist-type [Nb6O19]8− clusters were fabricated by a simple adsorption method and exhibited efficient reduction activity for p-nitrophenol due to the base and reduction dual functional catalysis.

The eye and brain are composed of elaborately organized tissues, development of which is supported by spatiotemporally precise expression of a number of transcription factors and developmental regulators. Here we report the molecular and genetic characterization of Integrator complex subunit 15 (INTS15). INTS15 was identified in search for the causative gene(s) for an autosomal-dominant eye disease with variable individual manifestation found in a large pedigree. While homozygous INTS15 knockout mice are embryonic lethal, mutant mice lacking a small C-terminal region of INTS15 show ocular malformations similar to the human patients. INTS15 is highly expressed in the eye and brain during embryogenesis and stably interacts with the Integrator complex to support snRNA 3′ end processing. Its knockdown resulted in missplicing of a large number of genes, probably as a secondary consequence, and substantially affected genes associated with eye and brain development. Moreover, studies using human iPS-derived neural progenitor cells showed that INTS15 is critical for axonal outgrowth in retinal ganglion cells. This study suggests a new link between general transcription machinery and a highly specific hereditary disease.

This study is the first to demonstrate that deep ocean water (DOW) has physiological significant effects on squid. After 36 h of rearing squids, those reared with DOW had significantly higher total and free cholesterol levels and lower alanine transaminase activity in hemolymph as compared with those reared with surface water (SSW). SSW rearing also resulted in 6.95% weight loss, while DOW rearing caused only 2.5% weight loss, which might be due to liver metabolism suppression. Furthermore, both monovalent (sodium, chloride, and potassium ions) and divalent (calcium, inorganic phosphorus, and magnesium ions) ions in hemolymph were elevated when reared with DOW compared to those when reared with SSW. A study of genes expressed in the brain revealed that five genes were specifically remarked in DOW rearing. Most altered genes were neuropeptides, including those from vasopressin superfamily. These neuropeptides are involved in cholesterol and/or mineral metabolisms and physiological significant effects on squid. This study is the first report the effects of DOW on cholesterol and mineral metabolism of squid and will contribute to squid aquaculture using DOW.

We previously reported that the oral administration of melatonin from 4 to 20 months to male mice improved femoral bone strength and bone density during the aging. Additionally, melatonin receptor, MT2, was immunologically detected in both osteoblasts and osteoclasts of the mouse femoral bone. Thus, melatonin can act on both osteoblasts and osteoclasts to maintain bone strength during the aging process. Here, we analyzed plasma calcium (Ca2+), magnesium (Mg2+), and inorganic phosphorus ([PO4]3-) in 20-month-old male mice with or without administration melatonin (15-20 mg/kg/day) in drinking water. We found that plasma Ca2+ and Mg2+ levels in melatonin-treated mice increased significantly as compared with control mice. In [PO4]3-, melatonin administration tended to increase its plasma level, but did not reach statistical significance. The potential association between these divalent ions and metabolism markers of femoral bone was also examined. In the femoral diaphysis, the plasma Ca2+ and Mg2+ concentrations were positively correlated with periosteal and endosteal circumference which were significantly associated with the Strength Strain Index. Therefore, melatonin treatment enlarged femoral diaphysis and enhanced bone strength by increasing mineral depositions. In addition, the plasma melatonin levels were significantly positive correlation with total bone density and critical thickness in the femoral diaphysis. Since we had not observed the primary trabecular bone and osteoclasts in 20-month-old mice previously, it is suggested that plasma Ca2+ and Mg2+ are not elevated due to bone resorption. The increased plasma Ca2+ and Mg2+ by melatonin may originate from the intestinal absorption of these ions since melatonin binds to the vitamin D3 receptor, its activation is known to promote the intestinal absorption of Ca2+.

The high plasma glucose induced in glucose metabolism disorders leads to the non‐enzymatic glucose‐dependent modification (glycation) of type 1 collagen, which is an essential component of bone tissue. The glycation of proteins induces the formation of advanced glycation end‐products, such as carboxymethyl arginine, which is preferentially generated in glycated collagen. However, the effect of advanced glycation end‐product formation on the characteristics of type 1 collagen remains unclear due to the lack of suitable in vitro experimental systems analyzing type 1 collagen. Here, we show that the glycation of type 1 collagen can be analyzed in vitro using a goldfish‐scale bone model. Our study using these scales provides evidence that the advanced glycation end‐product formation in type 1 collagen induced by glyoxal, the carboxymethyl arginine inducer, facilitates the crosslinking of type 1 collagen, decreasing both its strength and flexibility., Here we show that the glycation of type 1 collagen can be analyzed in vitro using a goldfish‐scale bone model. Our study using these scales provides evidence that glycation of type I collagen alpha chains facilitates the crosslinking of type I collagen, decreasing both its strength and flexibility.

Exposure to the space environment induces a number of pathophysiological outcomes in astronauts, including bone demineralization, sleep disorders, circadian clock dysregulation, cardiovascular and metabolic dysfunction, and reduced immune system function. A recent report describing experiments aboard the Space Shuttle mission, STS-132, showed that the level of melatonin, a hormone that provides the biochemical signal of darkness, was decreased during microgravity in an in vitro culture model. Additionally, abnormal lighting conditions in outer space, such as low light intensity in orbital spacecraft and the altered 24-h light-dark cycles, may result in the dysregulation of melatonin rhythms and the misalignment of the circadian clock from sleep and work schedules in astronauts. Studies on Earth have demonstrated that melatonin regulates various physiological functions including bone metabolism. These data suggest that the abnormal regulation of melatonin in outer space may contribute to pathophysiological conditions of astronauts. In addition, experiments with high-linear energy transfer radiation, a ground-based model of space radiation, showed that melatonin may serve as a protectant against space radiation. Gene expression profiling using an in vitro culture model exposed to space flight during the STS-132 mission, showed that space radiation alters the expression of DNA repair and oxidative stress response genes, indicating that melatonin counteracts the expression of these genes responsive to space radiation to promote cell survival. These findings implicate the use of exogenous melatonin and the regulation of endogenous melatonin as countermeasures for the physiological consequences of space flight.

The circadian clock is a highly conserved 24 h biological oscillation mechanism and is affected by environmental stimuli such as light, food and temperature. Disruption of the circadian clock results in disorders of diverse biological processes, including the sleep-wake cycle and metabolism. Although we previously identified several components of the circadian clock in zebrafish, our understanding of the relationship between light-inducible clock genes and metabolism remains incomplete. To investigate how light-inducible clock genes regulate metabolism, we performed transcriptomic and metabolomic analyses of the light-inducible clock genes zPer2, zCry1a, and zCry2a in zebrafish. Transcriptomic analysis of zPer2/zCry1a double knockout (DKO) and zPer2/zCry1a/zCry2a triple knockout (TKO) mutants showed that their gene expression profiles differed from that of wild type (WT) zebrafish. In particular, mRNA levels of zKeap1a, which encodes an oxidative stress sensor, were increased in DKO and TKO mutants. Metabolomic analysis showed genotype-dependent alteration of metabolomic profiles. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) showed the alteration of cysteine/methionine metabolism and glutathione metabolism. Specifically, cysteine and glutathione were decreased but methionine sulfoxide was increased in TKO zebrafish. These results indicate that the light-inducible genes zPer2, zCry1a, and zCry2a are involved in regulating the oxidative status of zebrafish.

Gold (Au) clusters with well-defined geometrical structures have attracted substantial attention due to their unique optical and catalytic properties, which are drastically changed by the ligands, ...

The structure-activity relationship of silica-supported Pt catalysts in aerobic oxidation of 50 ppm ethylene was studied at 0 degrees C with a fixed-bed flow reactor and in situ characterization techniques using Fourier-transform infrared (FTIR) spectroscopy. The activity of all Pt catalysts examined here decreased by water molecules formed during stoichiometric oxidation of ethylene and became stable steadily. A mesoporous silica-supported Pt catalyst improved its steady-state activity after calcination of the support in air at 800 degrees C, whereas no such effect was observed for a nonporous silica support. CO-pulse titration, H2O adsorption measurements, Si-29 MAS NMR, and in situ FTIR along with catalytic activity studies revealed that the activity of the mesoporous silica-supported Pt catalyst is higher than that of nonporous silica-supported ones, despite showing similar hydrophobicity and low Pt dispersion. In situ characterization using CO as a molecular probe indicates that a part of the Pt surface inside hydrophobic mesopores is not involved in the hydrogenbonding network among physisorbed water molecules and surface SiOH groups even after full hydration of the catalyst surface, and bare Pt sites are expected to work more effectively for ethylene oxidation. Such a "hydrophobic Pt surface" can only be formed on a hydrophobic mesoporous silica support, which is probably because of Pt nanoparticles surrounded by a hydrophobic siloxane network entirely. A unique environment derived from the condensed siloxane network and restricted mesopores contributes largely to the high activity of Pt nanoparticles for low-temperature oxidation of trace ethylene.

Propylene production via propane dehydrogenation (PDH) requires high reaction temperatures to obtain sufficient propylene yields, which results to prominent catalyst deactivation due to coke formation. Developing highly stable catalysts for PDH without deactivation even at high temperatures is of great interest and benefit for industry. Here, we report that single-atom Pt included in thermally stable intermetallic PtGa works as an ultrastable and selective catalyst for PDH at high temperatures. Intermetallic PtGa displays three-hold-Pt ensembles and single Pt atoms isolated by catalytically inert Ga at the surface, the former of which can be selectively blocked and disabled by Pb deposition. The PtGa-Pb/SiO2 catalyst exhibits 30% conversion with 99.6% propylene selectivity at 600 °C for 96 h without lowering the performance. The single-atom Pt well catalyzes the first and second C–H activation, while effectively inhibits the third one, which minimizes the side reactions to coke and drastically improves the selectivity and stability., Propylene production via propane dehydrogenation demands a highly stable catalyst that works without deactivation even at high temperatures. Here, the authors show that single-atom Pt included in thermally stable intermetallic PtGa works as an active and selective catalyst for propane dehydrogenation even at 600 °C for 96 h without deactivation.

Efficient conversion of crystalline cellulose to useful chemicals is a grand challenge in biorefining. In this work, we report that amorphization and semi-dry conversion of crystalline cellulose to...

Alongside TiO2, Magneli-phase titanium suboxide having the composition of TinO2n-1 is a kind of attractive functional materials composed of titanium. However, there still remain problems to be overcome in the synthesis of titanium suboxide; the existing synthesis methods require high temperature typically over 1000 degrees C and/or postsynthesis purification. This study presents a novel approach to synthesis of titanium suboxide nanoparticles through solid-phase reaction of TiO2 with TiH2. Crystal phases of titanium suboxide were easily controlled by changing TiO2/TiH2 molar ratios in a TiO2-TiH2 mixed precursor, and a series of titanium suboxide nanoparticles including Ti2O3, Ti3O5, Ti4O7, and Ti8O15 were successfully obtained. The reaction of TiO2 with TiH2 proceeded at a relatively low temperature due to the high reactivity of TiH2, giving titanium suboxide nanoparticles without any postsynthesis purification. Ti2O3 nanoparticles and TiO2 were applied as solid acid catalysts for reaction of furfural with 2-propanol. Ti2O3 showed a high catalytic activity and high selectivity for acetalization of furfural, while TiO2 showed only poor activity for transfer hydrogenation of furfural. The difference in catalytic properties is discussed in terms of the acid properties of Ti2O3 and TiO2.

To study the toxicity of 3-hydroxybenzo[c]phenanthrene (3-OHBcP), a metabolite of benzo[c]phenanthrene (BcP), first we compared it with its parent compound, BcP, using an in ovo-nanoinjection method in Japanese medaka. Second, we examined the influence of 3-OHBcP on bone metabolism using goldfish. Third, the detailed mechanism of 3-OHBcP on bone metabolism was investigated using zebrafish and goldfish. The LC

We evaluated the influences of the priming process (washing with saline), saline circulation conditions, and saline incubation on the in vitro elution of substances from three types of polysulfone (PSu) membrane dialyzers sterilized using gamma irradiation [NV-15X (Toray Industries, Inc.)], autoclaving [RENAK-PS1.6 (Kawasumi Laboratories, Inc.)], or in-line steam [FX-140J (Fresenius Medical Care)] methods as well as a non-PSu cellulose triacetate (CTA) membrane dialyzer [FB-150U(NIPRO)]. The effect of priming was evaluated by circulating 1000 mL of saline through the dialyzers at a rate of 100 mL/min and measuring the elution level of the substances by determining their ultraviolet (UV) absorption at 220 nm using spectrophotometry. All the tested dialyzers showed that the elution of the substances decreased as per the order of sample collection. Primed dialyzers were used in the subsequent experiments. Circulating saline through the primed membrane dialyzers at a flow rate of 100 mL/min caused time-dependent elution of substances from all the tested dialyzers; increasing the flow rate to 200 mL/min did not have a significant effect on the time-dependence or elution amount at each time point (0–8 h). The elution was also evaluated after incubating the membrane dialyzers with saline for 24 h. A co-submitted article (Sato et al., 2021) detailed the preparation of the identical experimental circuits, as well as the influences of saline washing, saline circulation conditions, and saline incubation on the elution of the hydrophilic agent polyvinylpyrrolidone (PVP) from each dialyzer using the Muller method, which can enable specific detection of PVP (Muller, 1968). The relative elution levels of PVP among the dialyzers and the experimental conditions were different from those of substances determined using UV (220 nm) absorption. Our data might be used for further development of experiments for identifying non-PVP substances eluted from dialyzers by providing information regarding the conditions of the elutions and types of dialyzers from which they are eluted.

The phase separation between a liquid amine and the solid carbamic acid exhibited >99% CO2 removal efficiency under a large-scale gas stream of 400 ppm CO2. Isophorone diamine [IPDA; 3-(aminomethyl)-3,5,5-trimethylcyclohexylamine] reacted with CO2 in the CO2/IPDA molar ratio of ≥ 1 even in H2O as a solvent. The captured CO2 was completely desorbed at 333 K because the disolved carbamate ion releases CO2 at low temperature. The reusability of IPDA under CO2 adsorption-and-desorption cycles without degradation, the >95% efficinecy kept for 100 hours under direct air capture condition, and high CO2 capture rate (214 mmol/h for 1 mol amine) suggest that the phase separation system using IPDA is robust and durable for practical use.

It is known that the bone matrix plays an important role in the response to physical stresses such as hypergravity and microgravity. In order to accurately analyze the response of bone to hypergravity and microgravity, a culture system under the conditions of coexistence of osteoclasts, osteoblasts, and bone matrix was earnestly desired. The teleost scale is a unique calcified organ in which osteoclasts, osteoblasts, and the two layers of bone matrix, i.e., a bony layer and a fibrillary layer, coexist. Therefore, we have developed in vitro organ culture systems of osteoclasts and osteoblasts with the intact bone matrix using goldfish scales. Using the scale culture system, we examined the effects of hypergravity with a centrifuge and simulated ground microgravity (g-µG) with a three-dimensional clinostat on osteoclasts and osteoblasts. Under 3-gravity (3G) loading for 1 day, osteoclastic marker mRNA expression levels decreased, while the mRNA expression of the osteoblastic marker increased. Upon 1 day of exposure, the simulated g-µG induced remarkable enhancement of osteoclastic marker mRNA expression, whereas the osteoblastic marker mRNA expression decreased. In response to these gravitational stimuli, osteoclasts underwent major morphological changes. By simulated g-µG treatments, morphological osteoclastic activation was induced, while osteoclastic deactivation was observed in the 3G-treated scales. In space experiments, the results that had been obtained with simulated g-µG were reproduced. RNA-sequencing analysis showed that osteoclastic activation was induced by the down-regulation of Wnt signaling under flight-microgravity. Thus, goldfish scales can be utilized as a bone model to analyze the responses of osteoclasts and osteoblasts to gravity.

In hemodialysis (HD), the patient's blood is purified via circulation in an extracorporeal circuit containing a dialyzer. In the manufacturing process of polysulfone (PSu) membrane dialyzers, the membranes are hydrophilized via the addition of the hydrophilic agent polyvinylpyrrolidone (PVP) to increase their hydraulic permeability. The elution of PVP from the membrane reduces the membrane's hydraulic permeability, and the eluted PVP could cause adverse effects in the human body. Therefore, it is important to identify the factors that induce PVP elution from PSu dialyzer membranes to improve the efficiency and safety of HD. In the present study, experimental circuits connecting each of the three types of PSu membrane dialyzers that had been sterilized, using gamma irradiation, autoclaving, or in-line steam methods, were prepared. After the dialyzers were primed, saline was circulated in the circuits at a flow rate of 100 mL/min or 200 mL/min. At 0, 2, 4, 6, and 8 h after circulation was initiated, the amount of PVP eluted from the PSu membranes in vitro was determined. In this experimental setting, longer the circulation duration, greater the amount of PVP eluted from the PSu membranes of the tested dialyzers; however, the flow rate did not influence the in vitro elution of PVP. Furthermore, the immersion of the dialyzer membranes in saline for 24 h strongly facilitated the in vitro elution of PVP. In sum, these results suggest that the duration of PSu membrane incubation in saline is a determinant of the level of PVP elution from the PSu membrane dialyzers., Graphical abstract Image 1, Highlights • The flow rate did not influence the in vitro PVP elution from PSu membrane dialyzers. • The time of PSu membrane incubation in saline is a determinant of PVP elution level. • Substances other than PVP are eluted from PSu membrane dialyzers.

The circadian clock is a highly conserved 24 h biological oscillation mechanism and is affected by environmental stimuli such as light, food and temperature. Disruption of the circadian clock results in disorders of diverse biological processes, including the sleep-wake cycle and metabolism. Although we previously identified several components of the circadian clock in zebrafish, our understanding of the relationship between light-inducible clock genes and metabolism remains incomplete. To investigate how light-inducible clock genes regulate metabolism, we performed transcriptomic and metabolomic analyses of the light-inducible clock genes zPer2, zCry1a, and zCry2a in zebrafish. Transcriptomic analysis of zPer2/zCry1a double knockout (DKO) and zPer2/zCry1a/zCry2a triple knockout (TKO) mutants showed that their gene expression profiles differed from that of wild type (WT) zebrafish. In particular, mRNA levels of zKeap1a, which encodes an oxidative stress sensor, were increased in DKO and TKO mutants. Metabolomic analysis showed genotype-dependent alteration of metabolomic profiles. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) showed the alteration of cysteine/methionine metabolism and glutathione metabolism. Specifically, cysteine and glutathione were decreased but methionine sulfoxide was increased in TKO zebrafish. These results indicate that the light-inducible genes zPer2, zCry1a, and zCry2a are involved in regulating the oxidative status of zebrafish.

The solid base catalysis of sodium salts of Lindqvist-type metal oxide clusters was investigated using a Knoevenagel condensation reaction. We successfully synthesized the sodium salts of Ta and Nb mixed-oxide clusters Na8−nHn[(Ta6−xNbx)O19]·15H2O (Na-Ta6−xNbx, n = 0, 1, x = 0–6) and found them to exhibit activity for proton abstraction from nitrile substrates with a pKa value of 23.8, which is comparable to that of the conventional solid base MgO. The Ta-rich Na-Ta6 and Na-Ta4Nb2 exhibited high activity among Ta and Nb mixed-oxide clusters. Synchrotron X-ray diffraction (SXRD) measurements, Fourier-transform infrared (FT-IR) spectroscopy, and X-ray absorption spectroscopy (XAS) revealed the structure of Na-Ta6−xNbx: (1) The crystal structure changed from Na7H[M6O19]·15H2O to Na8[M6O19]·15H2O (M = Ta or Nb) by the anisotropic expansion of the unit cell with an increase in Ta content, (2) Highly symmetrical Lindqvist [Ta6−xNbxO19]8− was generated in Na-Ta4Nb2 and Na-Ta6 because of the symmetrical association of Na+ ions with [Ta6−xNbxO19]8− in the structure. DFT calculation revealed that the Lindqvist structures with high symmetry have large NBO charges on surface oxygen species, which are strongly related to base catalytic activity, whereas the composition hardly affects the NBO charges. The above results showed that the Brønsted base catalysis was sensitive to the symmetry of the Lindqvist [Ta6−xNbxO19]8− structure. These findings contribute to the design of solid base catalysts composed of anionic metal oxide clusters with alkaline-metal cations.

Circadian clocks are intrinsic, time-tracking systems that bestow upon organisms a survival advantage. Under natural conditions, organisms are trained to follow a 24-h cycle under environmental time cues such as light to maximize their physiological efficiency. The exact timing of this rhythm is established via cell-autonomous oscillators called cellular clocks, which are controlled by transcription/ translation-based negative feedback loops. Studies using cell-based systems and genetic techniques have identified the molecular mechanisms that establish and maintain cellular clocks. One such mechanism, known as post-translational modification, regulates several aspects of these cellular clock components, including their stability, subcellular localization, transcriptional activity, and interaction with other proteins and signaling pathways. In addition, these mechanisms contribute to the integration of external signals into the cellular clock machinery. Here, we describe the post-translational modifications of cellular clock regulators that regulate circadian clocks in vertebrates.

In the present study, we investigated the influence of the addition of O₂ to the H₂ reactant stream during the hydrogenation of NO₂⁻ in water on the catalytic performances of Al₂O₃-supported precious metal catalysts including Pd, Pt, Ir, Rh, and Ru with 0.3 mmol g-¹ of the metal. Pd/Al₂O₃ showed high selectivity for N₂ irrespective of the presence and absence of O₂, and Rh and Ru/Al₂O₃ were inactive towards the hydrogenation of NO₂⁻ even in the absence of O₂. In contrast, while Pt/Al₂O₃ showed high selectivity for NH₃ (90%) in the absence of O₂ (P-H2 = 0.2 atm and P-O2 = 0 atm), the product drastically changed to N₂ with 93% selectivity when O₂ was added (P-H2 = 0.2 atm and P-O2 = 0.1 atm). Since Pt/Al₂O₃ was completely inactive towards the oxidation of NH₃ with O₂ in water under the reaction conditions, oxidative decomposition of the formed NH₃ was not the reason for the high selectivity for N₂ in the presence of O₂. Kinetic analysis of the reaction in the absence and presence of O₂ and studies on the effects of the Pt size suggested that hydrogen atoms activated on the Pt particles were mainly consumed by O₂ upon H₂O formation in the presence of O₂. We concluded that the inactivation of the Pt sites active for NH₃ formation and furthermore the change in the function of the sites to N₂ formation caused by the O₂ addition lead to the drastic change in the selectivity from NH₃ to N₂ in the presence of O₂.