The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72. Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS

Observation of Large CP Violation in the Neutral B Meson System

We present a measurement of the Standard Model CP violation parameter sin 2phi_1 based on a 29.1 fb^{-1} data sample collected at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider. One neutral B meson is fully reconstructed as a J/psi Ks, psi(2S) Ks, chi_c1 Ks, eta_c Ks, J/psi K_L or J/psi K^{*0} decay and the flavor of the accompanying B meson is identified from its decay products. From the asymmetry in the distribution of the time intervals between the two B meson decay points, we determine sin 2phi_1 = 0.99 +- 0.14(stat) +- 0.06(syst). We conclude that we have observed CP violation in the neutral B meson system.Comment: 4 figures, to appear in Phys. Rev. Letter

Measurement of the CP Violation Parameter sin(2phi_1) in B^0_d Meson Decays

We present a measurement of the Standard Model CP violation parameter sin(2phi_1) based on a 10.5 fb^{-1} data sample collected at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric e+e- collider. One neutral B meson is reconstructed in the J/psi K_S, psi(2S) K_S, chi_{c1} K_S, eta_c K_S, J/psi K_L or J/psi pi^0 CP-eigenstate decay channel and the flavor of the accompanying B meson is identified from its charged particle decay products. From the asymmetry in the distribution of the time interval between the two B-meson decay points, we determine sin(2phi_1) = 0.58 +0.32-0.34 (stat) +0.09-0.10 (syst).Comment: LaTex, 13 pages, 3 figures, submitted to P.R.

An Improved Measurement of Mixing-induced CP Violation in the Neutral B Meson System

We present an improved measurement of the standard model CP violation parameter sin2phi_1 (also known as sin2beta) based on a sample of 85 times 10^6 B Bbar pairs collected at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider. One neutral B meson is reconstructed in a J/psi K_S, psi(2S) K_S, chi_{c1} K_S, eta_c K_S, J/psi K^{*0}, or J/psi K_L CP-eigenstate decay channel and the flavor of accompanying B meson is identified from itsdecay products. From the asymmetry in the distribution of the time intervals between the two B meson decay points, we obtain sin2phi_1 = 0.719 +/- 0.074(stat) +/- 0.035(syst). We also report measurements of CP violation parameters for the related B^0 -> J/psi pi^0 decay mode and the penguin-dominated processes B^0 -> eta' K_S, phi K_S and K^+K^- K_S.Comment: 11 pages, 4 figures, 4 tables, contributed to ICHEP200

Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease

Background:Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease. Methodology/Principal Findings:We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge) and drastic decline of Aβ production. Conclusions/Significance:These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation

Neuropeptide Receptor Transcriptome Reveals Unidentified Neuroendocrine Pathways

Neuropeptides are an important class of molecules involved in diverse aspects of metazoan development and homeostasis. Insects are ideal model systems to investigate neuropeptide functions, and the major focus of insect neuropeptide research in the last decade has been on the identification of their receptors. Despite these vigorous efforts, receptors for some key neuropeptides in insect development such as prothoracicotropic hormone, eclosion hormone and allatotropin (AT), remain undefined. In this paper, we report the comprehensive cloning of neuropeptide G protein-coupled receptors from the silkworm, Bombyx mori, and systematic analyses of their expression. Based on the expression patterns of orphan receptors, we identified the long-sought receptor for AT, which is thought to stimulate juvenile hormone biosynthesis in the corpora allata (CA). Surprisingly, however, the AT receptor was not highly expressed in the CA, but instead was predominantly transcribed in the corpora cardiaca (CC), an organ adjacent to the CA. Indeed, by using a reverse-physiological approach, we purified and characterized novel allatoregulatory peptides produced in AT receptor-expressing CC cells, which may indirectly mediate AT activity on the CA. All of the above findings confirm the effectiveness of a systematic analysis of the receptor transcriptome, not only in characterizing orphan receptors, but also in identifying novel players and hidden mechanisms in important biological processes. This work illustrates how using a combinatorial approach employing bioinformatic, molecular, biochemical and physiological methods can help solve recalcitrant problems in neuropeptide research

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

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C