First Search for Dark-Trident Processes Using the MicroBooNE Detector.

We present a first search for dark-trident scattering in a neutrino beam using a dataset corresponding to 7.2×10^{20} protons on target taken with the MicroBooNE detector at Fermilab. Proton interactions in the neutrino target at the main injector produce π^{0} and η mesons, which could decay into dark-matter (DM) particles mediated via a dark photon A^{'}. A convolutional neural network is trained to identify interactions of the DM particles in the liquid-argon time projection chamber (LArTPC) exploiting its imagelike reconstruction capability. In the absence of a DM signal, we provide limits at the 90% confidence level on the squared kinematic mixing parameter ϵ^{2} as a function of the dark-photon mass in the range 10≤M_{A^{'}}≤400 MeV. The limits cover previously unconstrained parameter space for the production of fermion or scalar DM particles χ for two benchmark models with mass ratios M_{χ}/M_{A^{'}}=0.6 and 2 and for dark fine-structure constants 0.1≤α_{D}≤1.

First Measurement of η Meson Production in Neutrino Interactions on Argon with MicroBooNE.

We present a measurement of η production from neutrino interactions on argon with the MicroBooNE detector. The modeling of resonant neutrino interactions on argon is a critical aspect of the neutrino oscillation physics program being carried out by the DUNE and Short Baseline Neutrino programs. η production in neutrino interactions provides a powerful new probe of resonant interactions, complementary to pion channels, and is particularly suited to the study of higher-order resonances beyond the Δ(1232). We measure a flux-integrated cross section for neutrino-induced η production on argon of 3.22±0.84(stat)±0.86(syst) 10^{-41} cm^{2}/nucleon. By demonstrating the successful reconstruction of the two photons resulting from η production, this analysis enables a novel calibration technique for electromagnetic showers in GeV accelerator neutrino experiments.

Search for Heavy Neutral Leptons in Electron-Positron and Neutral-Pion Final States with the MicroBooNE Detector.

We present the first search for heavy neutral leptons (HNLs) decaying into νe^{+}e^{-} or νπ^{0} final states in a liquid-argon time projection chamber using data collected with the MicroBooNE detector. The data were recorded synchronously with the NuMI neutrino beam from Fermilab's main injector corresponding to a total exposure of 7.01×10^{20} protons on target. We set upper limits at the 90% confidence level on the mixing parameter |U_{µ4}|^{2} in the mass ranges 10≤m_{HNL}≤150 MeV for the νe^{+}e^{-} channel and 150≤m_{HNL}≤245 MeV for the νπ^{0} channel, assuming |U_{e4}|^{2}=|U_{τ4}|^{2}=0. These limits represent the most stringent constraints in the mass range 35

First Double-Differential Measurement of Kinematic Imbalance in Neutrino Interactions with the MicroBooNE Detector.

We report the first measurement of flux-integrated double-differential quasielasticlike neutrino-argon cross sections, which have been made using the Booster Neutrino Beam and the MicroBooNE detector at Fermi National Accelerator Laboratory. The data are presented as a function of kinematic imbalance variables which are sensitive to nuclear ground-state distributions and hadronic reinteraction processes. We find that the measured cross sections in different phase-space regions are sensitive to different nuclear effects. Therefore, they enable the impact of specific nuclear effects on the neutrino-nucleus interaction to be isolated more completely than was possible using previous single-differential cross section measurements. Our results provide precision data to help test and improve neutrino-nucleus interaction models. They further support ongoing neutrino-oscillation studies by establishing phase-space regions where precise reaction modeling has already been achieved.

First Measurement of Quasielastic Λ Baryon Production in Muon Antineutrino Interactions in the MicroBooNE Detector.

We present the first measurement of the cross section of Cabibbo-suppressed Λ baryon production, using data collected with the MicroBooNE detector when exposed to the neutrinos from the main injector beam at the Fermi National Accelerator Laboratory. The data analyzed correspond to 2.2×10^{20} protons on target running in neutrino mode, and 4.9×10^{20} protons on target running in anti-neutrino mode. An automated selection is combined with hand scanning, with the former identifying five candidate Λ production events when the signal was unblinded, consistent with the GENIE prediction of 5.3±1.1 events. Several scanners were employed, selecting between three and five events, compared with a prediction from a blinded Monte Carlo simulation study of 3.7±1.0 events. Restricting the phase space to only include Λ baryons that decay above MicroBooNE's detection thresholds, we obtain a flux averaged cross section of 2.0_{-1.7}^{+2.2}×10^{-40} cm^{2}/Ar, where statistical and systematic uncertainties are combined.

First Constraints on Light Sterile Neutrino Oscillations from Combined Appearance and Disappearance Searches with the MicroBooNE Detector.

We present a search for eV-scale sterile neutrino oscillations in the MicroBooNE liquid argon detector, simultaneously considering all possible appearance and disappearance effects within the 3+1 active-to-sterile neutrino oscillation framework. We analyze the neutrino candidate events for the recent measurements of charged-current ν_{e} and ν_{µ} interactions in the MicroBooNE detector, using data corresponding to an exposure of 6.37×10^{20} protons on target from the Fermilab booster neutrino beam. We observe no evidence of light sterile neutrino oscillations and derive exclusion contours at the 95% confidence level in the plane of the mass-squared splitting Δm_{41}^{2} and the sterile neutrino mixing angles θ_{µe} and θ_{ee}, excluding part of the parameter space allowed by experimental anomalies. Cancellation of ν_{e} appearance and ν_{e} disappearance effects due to the full 3+1 treatment of the analysis leads to a degeneracy when determining the oscillation parameters, which is discussed in this Letter and will be addressed by future analyses.

Search for an Excess of Electron Neutrino Interactions in MicroBooNE Using Multiple Final-State Topologies.

We present a measurement of ν_{e} interactions from the Fermilab Booster Neutrino Beam using the MicroBooNE liquid argon time projection chamber to address the nature of the excess of low energy interactions observed by the MiniBooNE Collaboration. Three independent ν_{e} searches are performed across multiple single electron final states, including an exclusive search for two-body scattering events with a single proton, a semi-inclusive search for pionless events, and a fully inclusive search for events containing all hadronic final states. With differing signal topologies, statistics, backgrounds, reconstruction algorithms, and analysis approaches, the results are found to be either consistent with or modestly lower than the nominal ν_{e} rate expectations from the Booster Neutrino Beam and no excess of ν_{e} events is observed.

First Measurement of Energy-Dependent Inclusive Muon Neutrino Charged-Current Cross Sections on Argon with the MicroBooNE Detector.

We report a measurement of the energy-dependent total charged-current cross section σ(E_{ν}) for inclusive muon neutrinos scattering on argon, as well as measurements of flux-averaged differential cross sections as a function of muon energy and hadronic energy transfer (ν). Data corresponding to 5.3×10^{19} protons on target of exposure were collected using the MicroBooNE liquid argon time projection chamber located in the Fermilab booster neutrino beam with a mean neutrino energy of approximately 0.8 GeV. The mapping between the true neutrino energy E_{ν} and reconstructed neutrino energy E_{ν}^{rec} and between the energy transfer ν and reconstructed hadronic energy E_{had}^{rec} are validated by comparing the data and Monte Carlo (MC) predictions. In particular, the modeling of the missing hadronic energy and its associated uncertainties are verified by a new method that compares the E_{had}^{rec} distributions between data and a MC prediction after constraining the reconstructed muon kinematic distributions, energy, and polar angle to those of data. The success of this validation gives confidence that the missing energy in the MicroBooNE detector is well modeled and underpins first-time measurements of both the total cross section σ(E_{ν}) and the differential cross section dσ/dν on argon.

Search for Neutrino-Induced Neutral-Current Δ Radiative Decay in MicroBooNE and a First Test of the MiniBooNE Low Energy Excess under a Single-Photon Hypothesis.

We report results from a search for neutrino-induced neutral current (NC) resonant Δ(1232) baryon production followed by Δ radiative decay, with a ⟨0.8⟩ GeV neutrino beam. Data corresponding to MicroBooNE's first three years of operations (6.80×10^{20} protons on target) are used to select single-photon events with one or zero protons and without charged leptons in the final state (1γ1p and 1γ0p, respectively). The background is constrained via an in situ high-purity measurement of NC π^{0} events, made possible via dedicated 2γ1p and 2γ0p selections. A total of 16 and 153 events are observed for the 1γ1p and 1γ0p selections, respectively, compared to a constrained background prediction of 20.5±3.65(syst) and 145.1±13.8(syst) events. The data lead to a bound on an anomalous enhancement of the normalization of NC Δ radiative decay of less than 2.3 times the predicted nominal rate for this process at the 90% confidence level (C.L.). The measurement disfavors a candidate photon interpretation of the MiniBooNE low-energy excess as a factor of 3.18 times the nominal NC Δ radiative decay rate at the 94.8% C.L., in favor of the nominal prediction, and represents a greater than 50-fold improvement over the world's best limit on single-photon production in NC interactions in the sub-GeV neutrino energy range.

Electron-beam energy reconstruction for neutrino oscillation measurements.

Neutrinos exist in one of three types or 'flavours'-electron, muon and tau neutrinos-and oscillate from one flavour to another when propagating through space. This phenomena is one of the few that cannot be described using the standard model of particle physics (reviewed in ref. 1), and so its experimental study can provide new insight into the nature of our Universe (reviewed in ref. 2). Neutrinos oscillate as a function of their propagation distance (L) divided by their energy (E). Therefore, experiments extract oscillation parameters by measuring their energy distribution at different locations. As accelerator-based oscillation experiments cannot directly measure E, the interpretation of these experiments relies heavily on phenomenological models of neutrino-nucleus interactions to infer E. Here we exploit the similarity of electron-nucleus and neutrino-nucleus interactions, and use electron scattering data with known beam energies to test energy reconstruction methods and interaction models. We find that even in simple interactions where no pions are detected, only a small fraction of events reconstruct to the correct incident energy. More importantly, widely used interaction models reproduce the reconstructed energy distribution only qualitatively and the quality of the reproduction varies strongly with beam energy. This shows both the need and the pathway to improve current models to meet the requirements of next-generation, high-precision experiments such as Hyper-Kamiokande (Japan)3 and DUNE (USA)4.

Search for a Higgs Portal Scalar Decaying to Electron-Positron Pairs in the MicroBooNE Detector.

We present a search for the decays of a neutral scalar boson produced by kaons decaying at rest, in the context of the Higgs portal model, using the MicroBooNE detector. We analyze data triggered in time with the Fermilab NuMI neutrino beam spill, with an exposure of 1.93×10^{20} protons on target. We look for monoenergetic scalars that come from the direction of the NuMI hadron absorber, at a distance of 100 m from the detector, and decay to electron-positron pairs. We observe one candidate event, with a standard model background prediction of 1.9±0.8. We set an upper limit on the scalar-Higgs mixing angle of θ<(3.3-4.6)×10^{-4} at the 95% confidence level for scalar boson masses in the range (100-200) MeV/c^{2}. We exclude, at the 95% confidence level, the remaining model parameters required to explain the central value of a possible excess of K_{L}^{0}→π^{0}νν[over ¯] decays reported by the KOTO collaboration. We also provide a model-independent limit on a new boson X produced in K→πX decays and decaying to e^{+}e^{-}.

First Measurement of Differential Charged Current Quasielasticlike ν_{µ}-Argon Scattering Cross Sections with the MicroBooNE Detector.

We report on the first measurement of flux-integrated single differential cross sections for charged-current (CC) muon neutrino (ν_{µ}) scattering on argon with a muon and a proton in the final state, ^{40}Ar (ν_{µ},µp)X. The measurement was carried out using the Booster Neutrino Beam at Fermi National Accelerator Laboratory and the MicroBooNE liquid argon time projection chamber detector with an exposure of 4.59×10^{19} protons on target. Events are selected to enhance the contribution of CC quasielastic (CCQE) interactions. The data are reported in terms of a total cross section as well as single differential cross sections in final state muon and proton kinematics. We measure the integrated per-nucleus CCQE-like cross section (i.e., for interactions leading to a muon, one proton, and no pions above detection threshold) of (4.93±0.76_{stat}±1.29_{sys})×10^{-38} cm^{2}, in good agreement with theoretical calculations. The single differential cross sections are also in overall good agreement with theoretical predictions, except at very forward muon scattering angles that correspond to low-momentum-transfer events.

First Measurement of Inclusive Muon Neutrino Charged Current Differential Cross Sections on Argon at E_{ν}∼0.8 GeV with the MicroBooNE Detector.

We report the first measurement of the double-differential and total muon neutrino charged current inclusive cross sections on argon at a mean neutrino energy of 0.8 GeV. Data were collected using the MicroBooNE liquid argon time projection chamber located in the Fermilab Booster neutrino beam and correspond to 1.6×10^{20} protons on target of exposure. The measured differential cross sections are presented as a function of muon momentum, using multiple Coulomb scattering as a momentum measurement technique, and the muon angle with respect to the beam direction. We compare the measured cross sections to multiple neutrino event generators and find better agreement with those containing more complete treatment of quasielastic scattering processes at low Q^{2}. The total flux integrated cross section is measured to be 0.693±0.010(stat)±0.165(syst)×10^{-38} cm^{2}.

TRAF2 is a biologically important necroptosis suppressor.

Tumor necrosis factor α (TNFα) triggers necroptotic cell death through an intracellular signaling complex containing receptor-interacting protein kinase (RIPK) 1 and RIPK3, called the necrosome. RIPK1 phosphorylates RIPK3, which phosphorylates the pseudokinase mixed lineage kinase-domain-like (MLKL)-driving its oligomerization and membrane-disrupting necroptotic activity. Here, we show that TNF receptor-associated factor 2 (TRAF2)-previously implicated in apoptosis suppression-also inhibits necroptotic signaling by TNFα. TRAF2 disruption in mouse fibroblasts augmented TNFα-driven necrosome formation and RIPK3-MLKL association, promoting necroptosis. TRAF2 constitutively associated with MLKL, whereas TNFα reversed this via cylindromatosis-dependent TRAF2 deubiquitination. Ectopic interaction of TRAF2 and MLKL required the C-terminal portion but not the N-terminal, RING, or CIM region of TRAF2. Induced TRAF2 knockout (KO) in adult mice caused rapid lethality, in conjunction with increased hepatic necrosome assembly. By contrast, TRAF2 KO on a RIPK3 KO background caused delayed mortality, in concert with elevated intestinal caspase-8 protein and activity. Combined injection of TNFR1-Fc, Fas-Fc and DR5-Fc decoys prevented death upon TRAF2 KO. However, Fas-Fc and DR5-Fc were ineffective, whereas TNFR1-Fc and interferon α receptor (IFNAR1)-Fc were partially protective against lethality upon combined TRAF2 and RIPK3 KO. These results identify TRAF2 as an important biological suppressor of necroptosis in vitro and in vivo.

New insights into apoptosis signaling by Apo2L/TRAIL.

Apoptosis ligand 2 tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to a small subset of proapoptotic protein ligands in the TNF superfamily. This subset, which also includes Fas ligand and TNF-alpha, can activate the extrinsic apoptotic cell death pathway on binding to cognate death receptors at the cell surface. Over the past 10 years, Apo2L/TRAIL has emerged as a promising candidate for cancer therapy, on the basis of its unique ability to trigger apoptosis in various types of cancer cells without significant toxicity toward normal cells. Herein, we review key advances in understanding the molecular events that control apoptosis signaling by Apo2L/TRAIL, which may aid in the development of cancer therapies based on the extrinsic apoptotic pathway.

Ictal and interictal phonophobia in migraine-a quantitative controlled study.

The aim of the study was to evaluate quantitatively ictal and interictal phonophobia in episodic migraine (EM). We included subjects with EM and age- and gender-matched controls. Sound stimuli were pure tones at frequencies of 1000, 4000 and 8000 Hz. Sound aversion thresholds (SATs) were determined as the minimal sound intensity perceived as unpleasant or painful. Migraineurs were examined both between and during attacks. We compared interictal SATs in migraineurs with those in controls. We also compared ictal and interictal SATs in migraineurs. Sixty migraineurs and 52 controls were included. Interictal mean SAT of migraineurs, averaged for the three frequencies, was significantly lower than that of controls [90.4 (0.8) dB vs. 105.9 (1.1) dB, respectively, P < 0.0001]. In migraineurs, mean ictal SAT, averaged for the three frequencies, was significantly lower than interictal SAT [76.0 (0.9) dB vs. 91.0 (0.8) dB, respectively, P < 0.0001]. Patients with EM exhibit increased sound aversion between attacks that is further augmented during an acute attack.

Highly sensitive amperometric immunosensor for the detection of Escherichia coli.

With the aim of detecting rapidly the presence of Escherichia coli (E. coli), a disposable amperometric immunosensor was developed based on a double layered configuration at the transducer surface, consisting first of a polypyrrole-NH(2)-anti-E. coli antibody (PAE) inner layer followed by an alginate-polypyrrole (Alg-Ppy) outer packing layer. In the presence of the substrate p-aminophenyl beta-D-galactopyranoside (PAPG), the bacterial enzyme, beta-D-galactosidase produces the p-aminophenol (PAP) product, also generating an amperometric signal due to PAP electrooxidation by potentiostating the glassy carbon (GC) electrode at 0.22V. The operational procedure consists in first adding the test sample containing the bacteria, then coating it with Alg-Ppy to ensure the confinement of the released enzyme and the analyte (being generated by the enzymatic catalysis) to the electrode active surface. This procedure facilitates the diffusion of the substrate within the complex and thus creates a higher oxidation level of the PAP enabling a detection limit of 10 colony forming units (CFU)/ml. The immunosensor setup demonstrates an improved detection limit of more than 10 times less bacteria detected than other immunosensing techniques without the need for multi step pretreatments of the test sample and/or incubation as found in some of the existing methods.

Electrochemistry and chemiluminescence techniques compared in the detection of NADPH oxidase activity in phagocyte cells.

Several methodologies have been used in clinical chemistry for real-time assessment of NADPH oxidase primary product superoxide anion which dismutases to hydrogen peroxide. Among these methodologies, isoluminol chemiluminescence (CL) is considered to be one of the more sensitive and reliable techniques for the assessment of NADPH oxidase activity in neutrophils. The electrochemical technique was recently designed and also applied for real-time detection of NADPH oxidase activity in neutrophils but its reliability and sensitivity has not been investigated so far. In this study, isoluminol CL and electrochemical techniques were investigated and compared by monitoring the generation of superoxide and hydrogen peroxide in both PLB 985 cell line differentiated into neutrophil-like cells and human neutrophils. The electrochemical technique was shown to be as sensitive as that of CL and able to detect the reactive oxygen species (ROS) release of as low as 500 cells. Thus, the electrochemical technique could be used as an alternative to optical techniques for the evaluation of extracellular ROS in phagocyte cells.

Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5.

Activation of the proapoptotic receptor death receptor5 (DR5) in various cancer cells triggers programmed cell death through the extrinsic pathway. We have generated a fully human monoclonal antibody (Apomab) that induces tumor cell apoptosis through DR5 and investigated the structural features of its interaction with DR5. Biochemical studies showed that Apomab binds DR5 tightly and selectively. X-ray crystallographic analysis of the complex between the Apomab Fab fragment and the DR5 ectodomain revealed an interaction epitope that partially overlaps with both regions of the Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand binding site. Apomab induced DR5 clustering at the cell surface and stimulated a death-inducing signaling complex containing the adaptor molecule Fas-associated death domain and the apoptosis-initiating protease caspase-8. Fc crosslinking further augmented Apomab's proapoptotic activity. In vitro, Apomab triggered apoptosis in cancer cells, while sparing normal hepatocytes even upon anti-Fc crosslinking. In vivo, Apomab exerted potent antitumor activity as a single agent or in combination with chemotherapy in xenograft models, including those based on colorectal, non-small cell lung and pancreatic cancer cell lines. These results provide structural and functional insight into the interaction of Apomab with DR5 and support further investigation of this antibody for cancer therapy.

Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.

Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. Here we report that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.