Search

A search has been performed for neutrinos from two sources, the hep reaction in the solar pp fusion chain and the νe component of the diffuse supernova neutrino background (DSNB), using the full dataset of the Sudbury Neutrino Observatory with a total exposure of 2.47 kton-years after fiducialization. The hep search is performed using both a single-bin counting analysis and a likelihood fit. We find a best-fit flux that is compatible with solar model predictions while remaining consistent with zero flux, and set a one-sided upper limit of φhep

Neutrons produced in nuclear interactions initiated by cosmic-ray muons present an irreducible background to many rare-event searches, even in detectors located deep underground. Models for the production of these neutrons have been tested against previous experimental data, but the extrapolation to deeper sites is not well understood. Here we report results from an analysis of cosmogenically produced neutrons at the Sudbury Neutrino Observatory. A specific set of observables are presented, which can be used to benchmark the validity of geant4 physics models. In addition, the cosmogenic neutron yield, in units of 10-4 cm2/(g·μ), is measured to be 7.28±0.09(stat)-1.12+1.59(syst) in pure heavy water and 7.30±0.07(stat)-1.02+1.40(syst) in NaCl-loaded heavy water. These results provide unique insights into this potential background source for experiments at SNOLAB.

The DEAP-3600 experiment is searching for weakly interacting massive particles dark matter with a 3.3 ×103 kg single phase liquid argon (LAr) target, located 2.1 km underground at SNOLAB. The experimental signature of dark matter interactions is kilo electron volt-scale Ar40 nuclear recoils producing 128 nm LAr scintillation photons observed by photomultiplier tubes. The largest backgrounds in DEAP-3600 are electronic recoils (ERs) induced by β and γ rays originating from internal and external radioactivity in the detector material. A background model of the ER interactions in DEAP-3600 was developed and is described in this work. The model is based on several components which are expected from radioisotopes in the LAr, from ex situ material assay measurements, and from dedicated independent in situ analyses. This prior information is used in a Bayesian fit of the ER components to a 247.2 d dataset to model the radioactivity in the surrounding detector materials. Pulse-shape discrimination separates ER and NR events. However, detailed knowledge of the ER background and activity of detector components sets valuable constraints on NR backgrounds including neutrons and alphas. In addition, the activity of Ar42 in LAr in DEAP-3600 is determined by measuring the daughter decay of K42. This cosmogenically activated trace isotope is a relevant background at higher energies for other rare event searches using atmospheric argon, e.g., DarkSide-20k, GERDA, or LEGEND. The specific activity of Ar42 in the atmosphere is found to be 40.4±5.9 μBq/kg of argon.

Neutron production in GeV-scale neutrino interactions is a poorly studiedprocess. We have measured the neutron multiplicities in atmospheric neutrinointeractions in the Sudbury Neutrino Observatory experiment and compared themto the prediction of a Monte Carlo simulation using GENIE and a minimallymodified version of GEANT4. We analyzed 837 days of exposure corresponding toPhase I, using pure heavy water, and Phase II, using a mixture of Cl in heavywater. Neutrons produced in atmospheric neutrino interactions were identifiedwith an efficiency of $15.3\%$ and $44.3\%$, for Phase I and II respectively.The neutron production is measured as a function of the visible energy of theneutrino interaction and, for charged current quasi-elastic interactioncandidates, also as a function of the neutrino energy. This study is alsoperformed classifying the complete sample into two pairs of event categories:charged current quasi-elastic and non charged current quasi-elastic, and$\nu_{\mu}$ and $\nu_e$. Results show good overall agreement between data andMonte Carlo for both phases, with some small tension with a statisticalsignificance below $2\sigma$ for some intermediate energies.

The Hamamatsu R5912-HQE photomultiplier-tube (PMT) is a novel high-quantum efficiency PMT. It is currently used in the DEAP-3600 dark matter detector and is of significant interest for future dark matter and neutrino experiments where high signal yields are needed. We report on the methods developed for in-situ characterization and monitoring of DEAP's 255 R5912-HQE PMTs. This includes a detailed discussion of typical measured single-photoelectron charge distributions, correlated noise (afterpulsing), dark noise, double, and late pulsing characteristics. The characterization is performed during the detector commissioning phase using laser light injected through a light diffusing sphere and during normal detector operation using LED light injected through optical fibres.

The Hamamatsu R5912-HQE photomultiplier-tube (PMT) is a novel high-quantum efficiency PMT. It is currently used in the DEAP-3600 dark matter detector and is of significant interest for future dark matter and neutrino experiments where high signal yields are needed. We report on the methods developed for in-situ characterization and monitoring of DEAP's 255 R5912-HQE PMTs. This includes a detailed discussion of typical measured single-photoelectron charge distributions, correlated noise (afterpulsing), dark noise, double, and late pulsing characteristics. The characterization is performed during the detector commissioning phase using laser light injected through a light diffusing sphere and during normal detector operation using LED light injected through optical fibres.

The Dark matter Experiment using Argon Pulse-shape discrimination (DEAP) has been designed for a direct detection search for particle dark matter using a single-phase liquid argon target. The projected cross section sensitivity for DEAP-3600 to the spin-independent scattering of Weakly Interacting Massive Particles (WIMPs) on nucleons is 10−46cm2 for a 100 GeV/c2 WIMP mass with a fiducial exposure of 3 tonne-years. This paper describes the physical properties and construction of the DEAP-3600 detector.

The Dark matter Experiment using Argon Pulse-shape discrimination (DEAP) has been designed for a direct detection search for particle dark matter using a single-phase liquid argon target. The projected cross section sensitivity for DEAP-3600 to the spin-independent scattering of Weakly Interacting Massive Particles (WIMPs) on nucleons is 10−46cm2 for a 100 GeV/c2 WIMP mass with a fiducial exposure of 3 tonne-years. This paper describes the physical properties and construction of the DEAP-3600 detector.

The long baseline between Earth and the Sun makes solar neutrinos an excellent test beam for exploring possible neutrino decay. The signature of such decay would be an energy-dependent distortion of the traditional survival probability which can be fit for using well-developed and high-precision analysis methods. Here a model including neutrino decay is fit to all three phases of B8 solar neutrino data taken by the Sudbury Neutrino Observatory (SNO). This fit constrains the lifetime of neutrino mass state ν2 to be >8.08×10-5 s/eV at 90% confidence. An analysis combining this SNO result with those from other solar neutrino experiments results in a combined limit for the lifetime of mass state ν2 of >1.92×10-3 s/eV at 90% confidence.

Experimental tests of Lorentz symmetry in systems of all types are critical for ensuring that the basic assumptions of physics are well founded. Data from all phases of the Sudbury Neutrino Observatory, a kiloton-scale heavy water Cherenkov detector, are analyzed for possible violations of Lorentz symmetry in the neutrino sector. Such violations would appear as one of eight possible signal types in the detector: six seasonal variations in the solar electron neutrino survival probability differing in energy and time dependence and two shape changes to the oscillated solar neutrino energy spectrum. No evidence for such signals is observed, and limits on the size of such effects are established in the framework of the standard model extension, including 38 limits on previously unconstrained operators and improved limits on 16 additional operators. This makes limits on all minimal, Dirac-type Lorentz violating operators in the neutrino sector available for the first time.

Tests on B-L symmetry breaking models are important probes to search for new physics. One proposed model with Δ(B-L)=2 involves the oscillations of a neutron to an antineutron. In this paper, a new limit on this process is derived for the data acquired from all three operational phases of the Sudbury Neutrino Observatory experiment. The search concentrated on oscillations occurring within the deuteron, and 23 events were observed against a background expectation of 30.5 events. These translated to a lower limit on the nuclear lifetime of 1.48×1031 yr at 90% C.L. when no restriction was placed on the signal likelihood space (unbounded). Alternatively, a lower limit on the nuclear lifetime was found to be 1.18×1031 yr at 90% C.L. when the signal was forced into a positive likelihood space (bounded). Values for the free oscillation time derived from various models are also provided in this article. This is the first search for neutron-Antineutron oscillation with the deuteron as a target.

Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK β1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPKβ1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPKβ1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.

Objective: Salsalate is a prodrug of salicylate that lowers blood glucose in people with type 2 diabetes. AMP-activated protein kinase (AMPK) is an αβγ heterotrimer which inhibits macrophage inflammation and the synthesis of fatty acids and cholesterol in the liver through phosphorylation of acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (HMGCR), respectively. Salicylate binds to and activates AMPKβ1-containing heterotrimers that are highly expressed in both macrophages and liver, but the potential importance of AMPK and ability of salsalate to reduce atherosclerosis have not been evaluated., Methods: ApoE -/- and LDLr -/- mice with or without (-/-) germline or bone marrow AMPKβ1, respectively, were treated with salsalate, and atherosclerotic plaque size was evaluated in serial sections of the aortic root. Studies examining the effects of salicylate on markers of inflammation, fatty acid and cholesterol synthesis and proliferation were conducted in bone marrow-derived macrophages (BMDMs) from wild-type mice or mice lacking AMPKβ1 or the key AMPK-inhibitory phosphorylation sites on ACC (ACC knock-in (KI)-ACC KI) or HMGCR (HMGCR-KI)., Results: Salsalate reduced atherosclerotic plaques in the aortic roots of ApoE -/- mice, but not ApoE -/- AMPKβ1 -/- mice. Similarly, salsalate reduced atherosclerosis in LDLr -/- mice receiving wild-type but not AMPKβ1 -/- bone marrow. Reductions in atherosclerosis by salsalate were associated with reduced macrophage proliferation, reduced plaque lipid content and reduced serum cholesterol. In BMDMs, this suppression of proliferation by salicylate required phosphorylation of HMGCR and the suppression of cholesterol synthesis., Conclusions: These data indicate that salsalate suppresses macrophage proliferation and atherosclerosis through an AMPKβ1-dependent pathway, which may involve HMGCR phosphorylation and cholesterol synthesis. Since rapidly-proliferating macrophages are a hallmark of atherosclerosis, these data indicate further evaluation of salsalate as a potential therapeutic agent for treating atherosclerotic cardiovascular disease., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The DEAP-3600 detector searches for the scintillation signal from dark matter particles scattering on a 3.3 tonne liquid argon target. The largest background comes from 39 Ar beta decays and is suppressed using pulse-shape discrimination (PSD). We use two types of PSD estimator: the prompt-fraction, which considers the fraction of the scintillation signal in a narrow and a wide time window around the event peak, and the log-likelihood-ratio, which compares the observed photon arrival times to a signal and a background model. We furthermore use two algorithms to determine the number of photons detected at a given time: (1) simply dividing the charge of each PMT pulse by the mean single-photoelectron charge, and (2) a likelihood analysis that considers the probability to detect a certain number of photons at a given time, based on a model for the scintillation pulse shape and for afterpulsing in the light detectors. The prompt-fraction performs approximately as well as the log-likelihood-ratio PSD algorithm if the photon detection times are not biased by detector effects. We explain this result using a model for the information carried by scintillation photons as a function of the time when they are detected., (© The Author(s) 2021.)

Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules 1 . LCFA-CoA esters promote their own oxidation by acting as allosteric inhibitors of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA and relieves inhibition of carnitine palmitoyl-transferase 1, thereby promoting LCFA-CoA transport into the mitochondria for β-oxidation 2-6 . Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) β1-containing isoforms to increase fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase. Activation of AMPK by LCFA-CoA esters requires the allosteric drug and metabolite site formed between the α-subunit kinase domain and the β-subunit. β1 subunit mutations that inhibit AMPK activation by the small-molecule activator A769662, which binds to the allosteric drug and metabolite site, also inhibit activation by LCFA-CoAs. Thus, LCFA-CoA metabolites act as direct endogenous AMPK β1-selective activators and promote LCFA oxidation.

Sodium-glucose cotransporter 2 inhibitors such as canagliflozin lower blood glucose and reduce cardiovascular events in people with type 2 diabetes through mechanisms that are not fully understood. Canagliflozin has been shown to increase the activity of the AMP-activated protein kinase (AMPK), a metabolic energy sensor important for increasing fatty acid oxidation and energy expenditure and suppressing lipogenesis and inflammation, but whether AMPK activation is important for mediating some of the beneficial metabolic effects of canagliflozin has not been determined. We, therefore, evaluated the effects of canagliflozin in female ApoE-/- and ApoE-/-AMPK β1-/- mice fed a western diet. Canagliflozin increased fatty acid oxidation and energy expenditure and lowered adiposity, blood glucose and the respiratory exchange ratio independently of AMPK β1. Canagliflozin also suppressed liver lipid synthesis and the expression of ATP-citrate lyase, acetyl-CoA carboxylase and sterol response element-binding protein 1c independently of AMPK β1. Canagliflozin lowered circulating IL-1β and studies in bone marrow-derived macrophages indicated that in contrast with the metabolic adaptations, this effect required AMPK β1. Canagliflozin had no effect on the size of atherosclerotic plaques in either ApoE-/- and ApoE-/-AMPK β1-/- mice. Future studies investigating whether reductions in liver lipid synthesis and macrophage IL-1β are important for the cardioprotective effects of canagliflozin warrant further investigation., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3 ). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood 1-3 . Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system 4 . Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.

The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss-of-function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites on acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation in human liver cancer cells. Consistent with these findings, a novel, liver-specific ACC inhibitor (ND-654) that mimics the effects of ACC phosphorylation inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Knowledge of programmed death ligand 1 (PD-L1) expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might identify biomarkers that predict the efficacy of immunotherapy with anti-programmed death-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in nongerminal center B cell-derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found that that BCR-mediated NFATc1 activation upregulates IL-10 chemokine expression in PD-L1 + B-cell lymphoma cells. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. We also found that BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks NFATc1 and STAT3 activation, thereby inhibiting IL-10 and PD-L1 expression. Finally, we validated the PD-L1 signaling network in 2 primary DLBCL cohorts consisting of 428 and 350 cases and showed significant correlations among IL-10, STAT3, and PD-L1. Thus, our findings reveal a complex signaling network regulating PD-L1 expression in B-cell lymphoma cells and suggest that PD-L1 expression can be modulated by small molecule inhibitors to potentiate immunotherapies., (© 2018 by The American Society of Hematology.)