Measurement of Neutrino Oscillation with KamLAND: Evidence of Spectral Distortion

We present results of a study of neutrino oscillation based on a 766 ton-year exposure of KamLAND to reactor anti-neutrinos. We observe 258 \nuebar\ candidate events with energies above 3.4 MeV compared to 365.2 events expected in the absence of neutrino oscillation. Accounting for 17.8 expected background events, the statistical significance for reactor \nuebar disappearance is 99.998%. The observed energy spectrum disagrees with the expected spectral shape in the absence of neutrino oscillation at 99.6% significance and prefers the distortion expected from \nuebar oscillation effects. A two-neutrino oscillation analysis of the KamLAND data gives \DeltaMSq = 7.9$^{+0.6}_{-0.5}\times10^{-5}$ eV$^2$. A global analysis of data from KamLAND and solar neutrino experiments yields \DeltaMSq = 7.9$^{+0.6}_{-0.5}\times10^{-5}$ eV$^2$ and \ThetaParam = 0.40$^{+0.10}_{-0.07}$, the most precise determination to date.Comment: 5 pages, 4 figures; submitted to Phys.Rev.Letter

First Results from KamLAND: Evidence for Reactor Anti-Neutrino Disappearance

KamLAND has been used to measure the flux of $\bar{\nu}_e$'s from distant nuclear reactors. In an exposure of 162 ton$\cdot$yr (145.1 days) the ratio of the number of observed inverse $\beta$-decay events to the expected number of events without disappearance is $0.611\pm 0.085 {\rm (stat)} \pm 0.041 {\rm (syst)}$ for $\bar{\nu}_e$ energies $>$ 3.4 MeV. The deficit of events is inconsistent with the expected rate for standard $\bar{\nu}_e$ propagation at the 99.95% confidence level. In the context of two-flavor neutrino oscillations with CPT invariance, these results exclude all oscillation solutions but the `Large Mixing Angle' solution to the solar neutrino problem using reactor $\bar{\nu}_e$ sources.Comment: 6 pages, 6 figure

Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex

It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. Diabetes 61:2823-2832, 201

Activation of Wnt/β-catenin signalling pathway induces chemoresistance to interferon-α/5-fluorouracil combination therapy for hepatocellular carcinoma

Type I IFN receptor type 2 (IFNAR2) expression correlates significantly with clinical response to interferon (IFN)-α/5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC). However, some IFNAR2-positive patients show no response to the therapy. This result suggests the possibility of other factors, which would be responsible for resistance to IFN-α/5-FU therapy. The aim of this study was to examine the mechanism of anti-proliferative effects of IFN-α/5-FU therapy and search for a biological marker of chemoresistance to such therapy. Gene expression profiling and molecular network analysis were used in the analysis of non-responders and responders with IFNAR2-positive HCC. The Wnt/β-catenin signalling pathway contributed to resistance to IFN-α/5-FU therapy. Immunohistochemical analysis showed positive epithelial cell adhesion molecule (Ep-CAM) expression, the target molecule of Wnt/β-catenin signalling, only in non-responders. In vitro studies showed that activation of Wnt/β-catenin signalling by glycogen synthesis kinase-3 inhibitor (6-bromoindirubin-3′-oxime (BIO)) induced chemoresistance to IFN-α/5-FU. BrdU-based cell proliferation ELISA and cell cycle analysis showed that concurrent addition of BIO and IFN-α/5-FU significantly to hepatoma cell cultures reduced the inhibitory effects of the latter two on DNA synthesis and accumulation of cells in the S-phase. The results indicate that activation of Wnt/β-catenin signalling pathway induces chemoresistance to IFN-α/5-FU therapy and suggest that Ep-CAM is a potentially useful marker for resistance to such therapy, especially in IFNAR2-positive cases

EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice

Background We have previously shown that EphrinA1/EphA expression profile changes in response to myocardial infarction (MI), exogenous EphrinA1-Fc administration following MI positively influences wound healing, and that deletion of the EphA2 Receptor (EphA2-R) exacerbates injury and remodeling. To determine whether or not ephrinA1-Fc would be of therapeutic value in the hyperglycemic infarcted heart, it is critical to evaluate how ephrinA1/EphA signaling changes in the hyperglycemic myocardium in response to MI. Methods Streptozotocin (STZ)-induced hyperglycemia in wild type (WT) and EphA2-receptor mutant (EphA2-R-M) mice was initiated by an intraperitoneal injection of STZ (150 mg/kg) 10 days before surgery. MI was induced by permanent ligation of the left anterior descending coronary artery and analyses were performed at 4 days post-MI. ANOVAs with Student-Newman Keuls multiple comparison post-hoc analysis illustrated which groups were significantly different, with significance of at least p < 0.05. Results Both WT and EphA2-R-M mice responded adversely to STZ, but only hyperglycemic EphA2-R-M mice had lower ejection fraction (EF) and fractional shortening (FS). At 4 days post-MI, we observed greater post-MI mortality in EphA2-R-M mice compared with WT and this was greater still in the EphA2-R-M hyperglycemic mice. Although infarct size was greater in hyperglycemic WT mice vs normoglycemic mice, there was no difference between hyperglycemic EphA2-R-M mice and normoglycemic EphA2-R-M mice. The hypertrophic response that normally occurs in viable myocardium remote to the infarct was noticeably absent in epicardial cardiomyocytes and cardiac dysfunction worsened in hyperglycemic EphA2-R-M hearts post-MI. The characteristic interstitial fibrotic response in the compensating myocardium remote to the infarct also did not occur in hyperglycemic EphA2-R-M mouse hearts to the same extent as that observed in the hyperglycemic WT mouse hearts. Differences in neutrophil and pan-leukocyte infiltration and serum cytokines implicate EphA2-R in modulation of injury and the differences in ephrinA1 and EphA6-R expression in governing this are discussed. Conclusions We conclude that EphA2-mutant mice are more prone to hyperglycemia-induced increased injury, decreased survival, and worsened LV remodeling due to impaired wound healing

Neonatal Colonisation Expands a Specific Intestinal Antigen-Presenting Cell Subset Prior to CD4 T-Cell Expansion, without Altering T-Cell Repertoire

Interactions between the early-life colonising intestinal microbiota and the developing immune system are critical in determining the nature of immune responses in later life. Studies in neonatal animals in which this interaction can be examined are central to understanding the mechanisms by which the microbiota impacts on immune development and to developing therapies based on manipulation of the microbiome. The inbred piglet model represents a system that is comparable to human neonates and allows for control of the impact of maternal factors. Here we show that colonisation with a defined microbiota produces expansion of mucosal plasma cells and of T-lymphocytes without altering the repertoire of alpha beta T-cells in the intestine. Importantly, this is preceded by microbially-induced expansion of a signal regulatory protein α-positive (SIRPα+) antigen-presenting cell subset, whilst SIRPα−CD11R1+ antigen-presenting cells (APCs) are unaffected by colonisation. The central role of intestinal APCs in the induction and maintenance of mucosal immunity implicates SIRPα+ antigen-presenting cells as orchestrators of early-life mucosal immune development

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 &gt;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

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