Effect of Sulindac Sulfide on Metallohydrolases in the Human Colon Cancer Cell Line HT-29

Matrix metalloproteinase 7 (MMP7), a metallohydrolase involved in the development of several cancers, is downregulated in the ApcMin/+ colon cancer mouse model following sulindac treatment. To determine whether this effect is relevant to the human condition, HT-29 human colon cancer cells were treated with sulindac and its metabolites, and compared to results obtained from in vivo mouse studies. The expression of MMP7 was monitored. The results demonstrated that sulindac sulfide effectively downregulated both MMP7 expression and activity. Furthermore, activity-based proteomics demonstrated that sulindac sulfide dramatically decreased the activity of leukotriene A4 hydrolase in HT-29 cells as reflected by a decrease in the level of its product, leukotriene B4. This study demonstrates that the effect of sulindac treatment in a mouse model of colon cancer may be relevant to the human counterpart and highlights the effect of sulindac treatment on metallohydrolases

Evidence for a wide extra-astrocytic distribution of S100B in human brain

BACKGROUND: S100B is considered an astrocytic in-situ marker and protein levels in cerebrospinal fluid (CSF) or serum are often used as biomarker for astrocytic damage or dysfunction. However, studies on S100B in the human brain are rare. Thus, the distribution of S100B was studied by immunohistochemistry in adult human brains to evaluate its cell-type specificity. RESULTS: Contrary to glial fibrillary acidic protein (GFAP), which selectively labels astrocytes and shows only faint ependymal immunopositivity, a less uniform staining pattern was seen in the case of S100B. Cells with astrocytic morphology were primarily stained by S100B in the human cortex, while only 20% (14–30%) or 14% (7–35%) of all immunopositive cells showed oligodendrocytic morphology in the dorsolateral prefrontal and temporal cortices, respectively. In the white matter, however, most immunostained cells resembled oligodendrocytes [frontal: 75% (57–85%); temporal: 73% (59–87%); parietal: 79% (62–89%); corpus callosum: 93% (86–97%)]. S100B was also found in ependymal cells, the choroid plexus epithelium, vascular endothelial cells, lymphocytes, and several neurones. Anti-myelin basic protein (MBP) immunolabelling showed an association of S100B with myelinated fibres, whereas GFAP double staining revealed a distinct subpopulation of cells with astrocytic morphology, which solely expressed S100B but not GFAP. Some of these cells showed co-localization of S100B and A2B5 and may be characterized as O2A glial progenitor cells. However, S100B was not detected in microglial cells, as revealed by double-immunolabelling with HLA-DR. CONCLUSION: S100B is localized in many neural cell-types and is less astrocyte-specific than GFAP. These are important results in order to avoid misinterpretation in the identification of normal and pathological cell types in situ and in clinical studies since S100B is continuously used as an astrocytic marker in animal models and various human diseases

Search for electron antineutrino appearance in a long-baseline muon antineutrino beam

Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions

Measurement and interpretation of same-sign W boson pair production in association with two jets in pp collisions at s = 13 TeV with the ATLAS detector

This paper presents the measurement of fducial and diferential cross sections for both the inclusive and electroweak production of a same-sign W-boson pair in association with two jets (W±W±jj) using 139 fb−1 of proton-proton collision data recorded at a centre-of-mass energy of √s = 13 TeV by the ATLAS detector at the Large Hadron Collider. The analysis is performed by selecting two same-charge leptons, electron or muon, and at least two jets with large invariant mass and a large rapidity diference. The measured fducial cross sections for electroweak and inclusive W±W±jj production are 2.92 ± 0.22 (stat.) ± 0.19 (syst.)fb and 3.38±0.22 (stat.)±0.19 (syst.)fb, respectively, in agreement with Standard Model predictions. The measurements are used to constrain anomalous quartic gauge couplings by extracting 95% confdence level intervals on dimension-8 operators. A search for doubly charged Higgs bosons H±± that are produced in vector-boson fusion processes and decay into a same-sign W boson pair is performed. The largest deviation from the Standard Model occurs for an H±± mass near 450 GeV, with a global signifcance of 2.5 standard deviations

Combination of searches for heavy spin-1 resonances using 139 fb−1 of proton-proton collision data at s = 13 TeV with the ATLAS detector

A combination of searches for new heavy spin-1 resonances decaying into different pairings of W, Z, or Higgs bosons, as well as directly into leptons or quarks, is presented. The data sample used corresponds to 139 fb−1 of proton-proton collisions at = 13 TeV collected during 2015–2018 with the ATLAS detector at the CERN Large Hadron Collider. Analyses selecting quark pairs (qq, bb, , and tb) or third-generation leptons (τν and ττ) are included in this kind of combination for the first time. A simplified model predicting a spin-1 heavy vector-boson triplet is used. Cross-section limits are set at the 95% confidence level and are compared with predictions for the benchmark model. These limits are also expressed in terms of constraints on couplings of the heavy vector-boson triplet to quarks, leptons, and the Higgs boson. The complementarity of the various analyses increases the sensitivity to new physics, and the resulting constraints are stronger than those from any individual analysis considered. The data exclude a heavy vector-boson triplet with mass below 5.8 TeV in a weakly coupled scenario, below 4.4 TeV in a strongly coupled scenario, and up to 1.5 TeV in the case of production via vector-boson fusion

Strategic options development and analysis

Strategic Options Development and Analysis (SODA) enables a group or individual to construct a graphical representation (map) or a problematic situation, and thus explore options and their ramifications with respect to a complex system of goals or objectives. In addition the approach aims to help groups arrive at a negotiated agreement about how to act to resolve the situation. It is based upon the use of causal mapping – a formally constructed means-ends network. Because the map has been constructed using the natural language of the problem owners it becomes a model of the situation that is ‘owned’ by those who define the problem. The use of formalities for the construction of the model makes it amenable to a range of analyses encouraging reflection and a deeper understanding. These analyses can be used in a ‘rough and ready’ manner by visual inspection or through the use of specialist causal mapping software. Each of the analyses helps a group or individual discover important features of the problem situation. And these features facilitate agreeing a good solution. The SODA process is aimed at helping a group learn about the situation they face before they reach agreements. Most significantly the exploration through the causal map leads to a higher probability of more creative solutions and promotes solutions that are more likely to be implemented because the problem construction process is more likely to include richer social dimensions about the blockages to action and organizational change. The basic theories that inform SODA derive from cognitive psychology and social negotiation, where the model acts as a continuously changing representation of the problematic situation (a transitional object) – changing as the views of a person or group shift through learning and exploration. This chapter jointly written by two leading practitioner academics and the original developers of SODA, Colin Eden and Fran Ackermann, describe the SODA approach as it is applied in practice

Search for light sterile neutrinos with the T2K far detector Super-Kamiokande at a baseline of 295 km

We perform a search for light sterile neutrinos using the data from the T2K far detector at a baseline of 295 km, with an exposure of 14.7ð7.6Þ × 1020 protons on target in neutrino (antineutrino) mode. A selection of neutral-current interaction samples is also used to enhance the sensitivity to sterile mixing. No evidence of sterile neutrino mixing in the 3 þ 1 model was found from a simultaneous fit to the charged-current muon, electron and neutral-current neutrino samples. We set the most stringent limit on the sterile oscillation amplitude sin2 θ24 for the sterile neutrino mass splitting Δm241 < 3 × 10−3 eV2=c4

Search for neutral-current induced single photon production at the ND280 near detector in T2K

Neutrino neutral-current (NC) induced single photon production is a sub-leading order process for accelerator-based neutrino beam experiments including T2K. It is, however, an important process to understand because it is a background for electron (anti)neutrino appearance oscillation experiments. Here, we performed the first search of this process below 1 GeV using the fine-grained detector at the T2K ND280 off-axis near detector. By reconstructing single photon kinematics from electron-positron pairs, we achieved 95% pure gamma ray sample from 5.738 x 10(20) protons-on-targets neutrino mode data. We do not find positive evidence of NC induced single photon production in this sample. We set the model-dependent upper limit on the cross-section for this process, at 0.114 x 10(-38) cm(2) (90% C.L.) per nucleon, using the J-PARC off-axis neutrino beam with an average energy of similar to 0.6 GeV. This is the first limit on this process below 1 GeV which is important for current and future oscillation experiments looking for electron neutrino appearance oscillation signals

Constraint on the matter-antimatter symmetry-violating phase in neutrino oscillations

The charge-conjugation and parity-reversal (CP) symmetry of fundamental particles is a symmetry between matter and antimatter. Violation of this CP symmetry was first observed in 19641, and CP violation in the weak interactions of quarks was soon established2. Sakharov proposed3 that CP violation is necessary to explain the observed imbalance of matter and antimatter abundance in the Universe. However, CP violation in quarks is too small to support this explanation. So far, CP violation has not been observed in non-quark elementary particle systems. It has been shown that CP violation in leptons could generate the matter–antimatter disparity through a process called leptogenesis4. Leptonic mixing, which appears in the standard model’s charged current interactions5,6, provides a potential source of CP violation through a complex phase δCP, which is required by some theoretical models of leptogenesis7,8,9. This CP violation can be measured in muon neutrino to electron neutrino oscillations and the corresponding antineutrino oscillations, which are experimentally accessible using accelerator-produced beams as established by the Tokai-to-Kamioka (T2K) and NOvA experiments10,11. Until now, the value of δCP has not been substantially constrained by neutrino oscillation experiments. Here we report a measurement using long-baseline neutrino and antineutrino oscillations observed by the T2K experiment that shows a large increase in the neutrino oscillation probability, excluding values of δCP that result in a large increase in the observed antineutrino oscillation probability at three standard deviations (3σ). The 3σ confidence interval for δCP, which is cyclic and repeats every 2π, is [−3.41, −0.03] for the so-called normal mass ordering and [−2.54, −0.32] for the inverted mass ordering. Our results indicate CP violation in leptons and our method enables sensitive searches for matter–antimatter asymmetry in neutrino oscillations using accelerator-produced neutrino beams. Future measurements with larger datasets will test whether leptonic CP violation is larger than the CP violation in quarks

Search for heavy neutrinos with the T2K near detector ND280

International audienceThis paper reports on the search for heavy neutrinos with masses in the range 140<MN<493  MeV/c2 using the off-axis near detector ND280 of the T2K experiment. These particles can be produced from kaon decays in the standard neutrino beam and then subsequently decay in ND280. The decay modes under consideration are N→ℓα±π∓ and N→ℓα+ℓβ-ν(−)(α,β=e,μ). A search for such events has been made using the Time Projection Chambers of ND280, where the background has been reduced to less than two events in the current dataset in all channels. No excess has been observed in the signal region. A combined Bayesian statistical approach has been applied to extract upper limits on the mixing elements of heavy neutrinos to electron-, muon- and tau- flavored currents (Ue2, Uμ2, Uτ2) as a function of the heavy neutrino mass, e.g., Ue2<10-9 at 90% C.L. for a mass of 390  MeV/c2. These constraints are competitive with previous experiments