Interferon-Induced Ifit2/ISG54 Protects Mice from Lethal VSV Neuropathogenesis

Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2−/−) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1−/− mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2−/− mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2−/− mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2−/− mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2−/− mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2−/− mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2−/− mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon

Multidifferential cross section measurements of νμ -argon quasielasticlike reactions with the MicroBooNE detector

We report on a flux-integrated multidifferential measurement of charged-current muon neutrino scattering on argon with one muon and one proton in the final state using the Booster Neutrino Beam and MicroBooNE detector at Fermi National Accelerator Laboratory. The data are studied as a function of various kinematic imbalance variables and of a neutrino energy estimator, and are compared to a number of event generator predictions. We find that the measured cross sections in different phase-space regions are sensitive to nuclear effects. Our results provide precision data to test and improve the neutrino-nucleus interaction models needed to perform high-accuracy oscillation analyses. Specific regions of phase space are identified where further model refinements are most needed

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 demonstration of O (1 ns) timing resolution in the MicroBooNE liquid argon time projection chamber

MicroBooNE is a neutrino experiment located in the Booster Neutrino Beamline (BNB) at Fermilab, which collected data from 2015 to 2021. MicroBooNE's liquid argon time projection chamber (LArTPC) is accompanied by a photon detection system consisting of 32 photomultiplier tubes used to measure the argon scintillation light and determine the timing of neutrino interactions. Analysis techniques combining light signals and reconstructed tracks are applied to achieve a neutrino interaction time resolution of O(1 ns). The result obtained allows MicroBooNE to access the nanosecond beam structure of the BNB for the first time. The timing resolution achieved will enable significant enhancement of cosmic background rejection for all neutrino analyses. Furthermore, the ns timing resolution opens new avenues to search for long-lived-particles such as heavy neutral leptons in MicroBooNE, as well as in future large LArTPC experiments, namely the SBN program and DUNE

TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2K923E) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein’s stability. An inhibitory function was only observed upon over-expression of TYK2K923E in vitro. Tyk2K923E mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy

New CC0\pi\ GENIE Model Tune for MicroBooNE

A novel tune has been made for the MicroBooNE experiment. The fit uses 4 new parameters within the GENIE v3.0.6 Monte Carlo program. Charged current pionless data from the T2K experiment was used. New uncertainties were obtained. These results will be used in future MicroBooNE analyses.Comment: 24 pages, 14 figure

Measurement of triple-differential inclusive muon-neutrino charged-current cross section on argon with the MicroBooNE detector

We report the first measurement of the differential cross section $d^{2}\sigma (E_{\nu})/ d\cos(\theta_{\mu}) dP_{\mu}$ for inclusive muon-neutrino charged-current scattering on argon. This measurement utilizes data from 6.4$\times10^{20}$ protons on target of exposure collected using the MicroBooNE liquid argon time projection chamber located along the Fermilab Booster Neutrino Beam with a mean neutrino energy of approximately 0.8~GeV. The mapping from reconstructed kinematics to truth quantities, particularly from reconstructed to true neutrino energy, is validated by comparing the distribution of reconstructed hadronic energy in data to that of the model prediction in different muon scattering angle bins after conditional constraint from the muon momentum distribution in data. The success of this validation gives confidence that the missing energy in the MicroBooNE detector is well-modeled in simulation, enabling the unfolding to a triple-differential measurement over muon momentum, muon scattering angle, and neutrino energy. The unfolded measurement covers an extensive phase space, providing a wealth of information useful for future liquid argon time projection chamber experiments measuring neutrino oscillations. Comparisons against a number of commonly used model predictions are included and their performance in different parts of the available phase-space is discussed

First demonstration of O(1 ns)\mathcal{O}(1\,\text{ns}) timing resolution in the MicroBooNE liquid argon time projection chamber

MicroBooNE is a neutrino experiment located in the Booster Neutrino Beamline (BNB) at Fermilab, which collected data from 2015 to 2021. MicroBooNE's liquid argon time projection chamber (LArTPC) is accompanied by a photon detection system consisting of 32 photomultiplier tubes used to measure the argon scintillation light and determine the timing of neutrino interactions. Analysis techniques combining light signals and reconstructed tracks are applied to achieve a neutrino interaction time resolution of $\mathcal{O}(1\,\text{ns})$. The result obtained allows MicroBooNE to access the ns neutrino pulse structure of the BNB for the first time. The timing resolution achieved will enable significant enhancement of cosmic background rejection for all neutrino analyses. Furthermore, the ns timing resolution opens new avenues to search for long-lived-particles such as heavy neutral leptons in MicroBooNE, as well as in future large LArTPC experiments, namely the SBN program and DUNE