Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues

The role of monogenic mutations in the development of 46,XX testicular/ovotesticular disorders of sex development (DSD) remains speculative. Although mutations in NR5A1 are known to cause 46,XY gonadal dysgenesis and 46,XX ovarian insufficiency, such mutations have not been implicated in testicular development of 46,XX gonads. Here, we identified identical NR5A1 mutations in two unrelated Japanese patients with 46,XX testicular/ovotesticular DSD. The p.Arg92Trp mutation was absent from the clinically normal mothers and from 200 unaffected Japanese individuals. In silico analyses scored p.Arg92Trp as probably pathogenic. In vitro assays demonstrated that compared with wild‐type NR5A1, the mutant protein was less sensitive to NR0B1‐induced suppression on the SOX9 enhancer element. Other sequence variants found in the patients were unlikely to be associated with the phenotype. The results raise the possibility that specific mutations in NR5A1 underlie testicular development in genetic females

Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas

Dysregulation of apoptosis plays an important role in tumour progression and resistance to chemotherapy. The X-linked inhibitor of apoptosis ( XIAP) is considered to be the most potent caspase inhibitor of all known inhibitor of apoptosis-family members. Only recently, an antagonist of XIAP has been identified, termed Smac/DIABLO. To explore the relevance of antiapoptotic XIAP and proapoptotic Smac/DIABLO for tumour progression in renal cell carcinomas (RCCs), we analysed XIAP and Smac/DIABLO mRNA and protein expression in the primary tumour tissue from 66 RCCs of all major histological types by quantitative real-time PCR, Western blot and ELISA. X-linked inhibitor of apoptosis and Smac/DIABLO mRNA expression was found in all RCCs. Importantly, the relative XIAP mRNA expression levels significantly increased from early (pT1) to advanced (pT3) tumour stages ( P = 0.0002) and also with tumour dedifferentiation ( P = 0.04). Western blot analysis confirmed the tumour stage-dependent increase of XIAP expression on the protein level. In contrast, mRNA and protein expression levels of Smac/DIABLO did not significantly change between early and advanced tumour stages or between low and high tumour grades. Consequently, the mRNA expression ratio between antiapoptotic XIAP and proapoptotic Smac/DIABLO markedly increased during progression from early ( pT1) to advanced ( pT3) tumour stages. Moreover, RCCs confined within the organ capsule ( pT1 and pT2) exhibited a significantly lower XIAP to Smac/DIABLO expression ratio when compared with RCCs infiltrating beyond the kidney ( pT3; P = 0.01). Thus, our investigation demonstrates that the delicate balance between XIAP and Smac/DIABLO expression is gradually disturbed during progression of RCCs, resulting in a relative increase of antiapoptotic XIAP over proapoptotic Smac/DIABLO, thereby probably contributing to the marked apoptosis resistance of RCC.OncologySCI(E)46ARTICLE71349-13579

Selective inhibitors of cardiac ADPR cyclase as novel anti-arrhythmic compounds

ADP-ribosyl cyclases (ADPRCs) catalyse the conversion of nicotinamide adenine dinucleotide to cyclic adenosine diphosphoribose (cADPR) which is a second messenger involved in Ca2+ mobilisation from intracellular stores. Via its interaction with the ryanodine receptor Ca2+ channel in the heart, cADPR may exert arrhythmogenic activity. To test this hypothesis, we have studied the effect of novel cardiac ADPRC inhibitors in vitro and in vivo in models of ventricular arrhythmias. Using a high-throughput screening approach on cardiac sarcoplasmic reticulum membranes isolated from pig and rat and nicotinamide hypoxanthine dinuleotide as a surrogate substrate, we have identified potent and selective inhibitors of an intracellular, membrane-bound cardiac ADPRC that are different from the two known mammalian ADPRCs, CD38 and CD157/Bst1. We show that two structurally distinct cardiac ADPRC inhibitors, SAN2589 and SAN4825, prevent the formation of spontaneous action potentials in guinea pig papillary muscle in vitro and that compound SAN4825 is active in vivo in delaying ventricular fibrillation and cardiac arrest in a guinea pig model of Ca2+ overload-induced arrhythmia. Inhibition of cardiac ADPRC prevents Ca2+ overload-induced spontaneous depolarizations and ventricular fibrillation and may thus provide a novel therapeutic principle for the treatment of cardiac arrhythmias

Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients

Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium

Molecular Characterization of a Novel Intracellular ADP-Ribosyl Cyclase

Background. ADP-ribosyl cyclases are remarkable enzymes capable of catalyzing multiple reactions including the synthesis of the novel and potent intracellular calcium mobilizing messengers, cyclic ADP-ribose and NAADP. Not all ADP-ribosyl cyclases however have been characterized at the molecular level. Moreover, those that have are located predominately at the outer cell surface and thus away from their cytosolic substrates. Methodology/Principal Findings. Here we report the molecular cloning of a novel expanded family of ADP-ribosyl cyclases from the sea urchin, an extensively used model organism for the study of inositol trisphosphate-independent calcium mobilization. We provide evidence that one of the isoforms (SpARC1) is a soluble protein that is targeted exclusively to the endoplasmic reticulum lumen when heterologously expressed. Catalytic activity of the recombinant protein was readily demonstrable in crude cell homogenates, even under conditions where luminal continuity was maintained. Conclusions/Significance. Our data reveal a new intracellular location for ADP-ribosyl cyclases and suggest that production of calcium mobilizing messengers may be compartmentalized

Flyer acceleration experiments using high-power laser

Flyer acceleration technique using high-power lasers has several advantages such as the achieved velocities higher than 10 km/s and non-contamination to the products generated by impacts. In this study, we show that a high-power laser can achieve flyer velocities higher than 10 km/s up to 60 km/s using spherical projectiles with a diameter of 0.1 − 0.3mm. We discuss the projectile condition during the flight based on the results of numerical simulations

Western Pacific Air-Sea Interaction Study

A01: Dynamics of Atmospheric CompositionA Study on the Production and Emission of Marine-Derived Volatile Halocarbons / Y. Yokouchi, A. Ooki, S. Hashimoto and N. Itoh : 05w-pass_001.pdfMeasurements of Gaseous Peroxides in the Oceanic Lower Atmosphere / S. Hatakeyama and T. Akatsuka : 06w-pass_027.pdfPhase Partitioning of NH3 and Gas to Particle Conversion / K. Osada : 07w-pass_033.pdfNew Particle Formation of Marine Aerosols / K. Miura, H. Furutani, Y. Iwamoto, K. Nagano, H. Kobayashi, M. Mochida, H. Mukai, S. Hashimoto, M. Takami and M. Uematsu : 08w-pass_037.pdfA Study of the Chemical Processes in Aerosols and Their Impacts on the Environment Using X-ray Absorption Fine Structure Spectroscopy / Y. Takahashi, M. Higashi, T. Furukawa, T. Miyoshi, M. Fujiwara and M. Uematsu : 09w-pass_043.pdfVariability in Mineral Dust Deposition over the North Pacific and Its Potential Impact on the Ocean Productivity / H. Fukushima : 10w-pass_051.pdfAtmosphere-Ocean Interaction through Atmospheric Aerosol Particles Observed in a Single Nanoparticle Aspect / H. Furutani, J. Jinyoung and M. Uematsu : 11w-pass_061.pdfSimultaneous Measurements of Hygroscopic Property and Cloud Condensation Nucleus Activity of Aerosol Particles of Marine Biogenic Origin / M. Mochida : 12w-pass_071.pdfEruption of Mt. Kilauea Impacted Cloud Droplet and Radiation Budget over North Pacific / I. Uno, K. Eguchi and K. Yumimoto : 13w-pass_083.pdfA02: Variability of Gas Exchanges at the Air-Sea InterfaceHigh-Resolution Measurement of Volatile Organic Compounds Dissolved in Seawater Using Equilibrator Inlet-Proton Transfer Reaction-Mass Spectrometry (EI-PTR-MS) / H. Tanimoto, S. Kameyama, Y. Omori, S. Inomata and U. Tsunogai : 14w-pass_089.pdfStudy of the Production Processes of Marine Biogenic Methane and Carbonyl Sulfide Using Stable Isotope Analysis / S. Toyoda, K. Yamada, Y. Ueno, K. Koba and O. Yoshida : 15w-pass_117.pdfLong-Term Changes of Greenhouse Gases in the Ocean and Their Feedback Effects on the Climate / Y. W. Watanabe, I. Yasuda and N. Tsurushima : 16w-pass_123.pdfTemporal and Spatial Variations in Carbonate System and Air-Sea CO2 Flux in the Kuroshio and Kuroshio Extension / H. Yoshikawa-Inoue, T. Midorikawa and T. R. Takamura : 17w-pass_151.pdfA03: Dynamics of the Marine EcosystemBioavailability and Biogeochemical Processes of Trace Metals in the Surface Ocean / S. Takeda, H. Obata, A. Okubo, M. Sato and Y. Kondo : 18w-pass_163.pdfDetailed Variations in Bioactive Elements in the Surface Ocean and Their Interaction with Microbiological Processes / H. Ogawa, K. Kogure, J. Kanda, F. Hashihama and M. Suzumura : 19w-pass_177.pdfPhotoheterotrophic Process in Surface Seawater Environments / K. Hamasaki, Y. Sato-Takabe, A. Taniguchi and Y. Tada : 20w-pass_199.pdfEcological Study of Bacterial Populations Related to Biogenic Gas Transformation in Marine Environments / K. Hamasaki, R. Kaneko, A. Mouri, Y. Tada, N. Kasamatsu-Takasawa and I. Nagao : 21w-pass_203.pdfA04: Modelling of the Interaction between the Ocean and the AtmosphereModeling for Evaluation and Prediction of Effects of Short-Term Atmospheric Disturbance on Air-Sea Material Cycling / M. Fujii and A. Tanaka : 22w-pass_211.pdfRelating Phytoplankton Pnysiology to North Pacific Biogeochemistry / S. L. Smith, M. N. Aita, M. Shigemitsu and Y. Yamanaka : 23w-pass_223.pdfCoupling of Physical and Bio-Geochemical Process and Monitoring Ocean Circulation Using Data Assimilation System / Y. Ishikawa, T. Awaji, M. Ikeda and T. Toyoda : 24w-pass_237.pdfPart of "Western Pacific Air-Sea Interaction Study

Western Pacific Air-Sea Interaction Study

A01: Dynamics of Atmospheric CompositionA Study on the Production and Emission of Marine-Derived Volatile Halocarbons / Y. Yokouchi, A. Ooki, S. Hashimoto and N. Itoh : 05w-pass_001.pdfMeasurements of Gaseous Peroxides in the Oceanic Lower Atmosphere / S. Hatakeyama and T. Akatsuka : 06w-pass_027.pdfPhase Partitioning of NH3 and Gas to Particle Conversion / K. Osada : 07w-pass_033.pdfNew Particle Formation of Marine Aerosols / K. Miura, H. Furutani, Y. Iwamoto, K. Nagano, H. Kobayashi, M. Mochida, H. Mukai, S. Hashimoto, M. Takami and M. Uematsu : 08w-pass_037.pdfA Study of the Chemical Processes in Aerosols and Their Impacts on the Environment Using X-ray Absorption Fine Structure Spectroscopy / Y. Takahashi, M. Higashi, T. Furukawa, T. Miyoshi, M. Fujiwara and M. Uematsu : 09w-pass_043.pdfVariability in Mineral Dust Deposition over the North Pacific and Its Potential Impact on the Ocean Productivity / H. Fukushima : 10w-pass_051.pdfAtmosphere-Ocean Interaction through Atmospheric Aerosol Particles Observed in a Single Nanoparticle Aspect / H. Furutani, J. Jinyoung and M. Uematsu : 11w-pass_061.pdfSimultaneous Measurements of Hygroscopic Property and Cloud Condensation Nucleus Activity of Aerosol Particles of Marine Biogenic Origin / M. Mochida : 12w-pass_071.pdfEruption of Mt. Kilauea Impacted Cloud Droplet and Radiation Budget over North Pacific / I. Uno, K. Eguchi and K. Yumimoto : 13w-pass_083.pdfA02: Variability of Gas Exchanges at the Air-Sea InterfaceHigh-Resolution Measurement of Volatile Organic Compounds Dissolved in Seawater Using Equilibrator Inlet-Proton Transfer Reaction-Mass Spectrometry (EI-PTR-MS) / H. Tanimoto, S. Kameyama, Y. Omori, S. Inomata and U. Tsunogai : 14w-pass_089.pdfStudy of the Production Processes of Marine Biogenic Methane and Carbonyl Sulfide Using Stable Isotope Analysis / S. Toyoda, K. Yamada, Y. Ueno, K. Koba and O. Yoshida : 15w-pass_117.pdfLong-Term Changes of Greenhouse Gases in the Ocean and Their Feedback Effects on the Climate / Y. W. Watanabe, I. Yasuda and N. Tsurushima : 16w-pass_123.pdfTemporal and Spatial Variations in Carbonate System and Air-Sea CO2 Flux in the Kuroshio and Kuroshio Extension / H. Yoshikawa-Inoue, T. Midorikawa and T. R. Takamura : 17w-pass_151.pdfA03: Dynamics of the Marine EcosystemBioavailability and Biogeochemical Processes of Trace Metals in the Surface Ocean / S. Takeda, H. Obata, A. Okubo, M. Sato and Y. Kondo : 18w-pass_163.pdfDetailed Variations in Bioactive Elements in the Surface Ocean and Their Interaction with Microbiological Processes / H. Ogawa, K. Kogure, J. Kanda, F. Hashihama and M. Suzumura : 19w-pass_177.pdfPhotoheterotrophic Process in Surface Seawater Environments / K. Hamasaki, Y. Sato-Takabe, A. Taniguchi and Y. Tada : 20w-pass_199.pdfEcological Study of Bacterial Populations Related to Biogenic Gas Transformation in Marine Environments / K. Hamasaki, R. Kaneko, A. Mouri, Y. Tada, N. Kasamatsu-Takasawa and I. Nagao : 21w-pass_203.pdfA04: Modelling of the Interaction between the Ocean and the AtmosphereModeling for Evaluation and Prediction of Effects of Short-Term Atmospheric Disturbance on Air-Sea Material Cycling / M. Fujii and A. Tanaka : 22w-pass_211.pdfRelating Phytoplankton Pnysiology to North Pacific Biogeochemistry / S. L. Smith, M. N. Aita, M. Shigemitsu and Y. Yamanaka : 23w-pass_223.pdfCoupling of Physical and Bio-Geochemical Process and Monitoring Ocean Circulation Using Data Assimilation System / Y. Ishikawa, T. Awaji, M. Ikeda and T. Toyoda : 24w-pass_237.pdfPart of "Western Pacific Air-Sea Interaction Study