As long-lived post-mitotic cells, neurons employ unique strategies to resist pathogen infection while preserving cellular function. Here, using a murine model of Zika virus (ZIKV) infection, we identified an innate immune pathway that restricts ZIKV replication in neurons and is required for survival upon ZIKV infection of the central nervous system (CNS). We found that neuronal ZIKV infection activated the nucleotide sensor ZBP1 and the kinases RIPK1 and RIPK3, core components of virus-induced necroptotic cell death signaling. However, activation of this pathway in ZIKV-infected neurons did not induce cell death. Rather, RIPK signaling restricted viral replication by altering cellular metabolism via upregulation of the enzyme IRG1 and production of the metabolite itaconate. Itaconate inhibited the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes. These findings demonstrate an immunometabolic mechanism of viral restriction during neuroinvasive infection.

We have developed an efficient iterative inversion method applicable to both two‐dimensional (2D) and three‐dimensional magnetotelluric data. The method approximates horizontal derivative terms with their values calculated from the fields of the previous iteration. The equations at each horizontal coordinate then become uncoupled. At each iteration this allows separate inversions for the improved conductivity profile beneath each measurement site. Resultant profiles are interpolated to form a new multidimensional model for which the fields for the next iteration are calculated. The method is extremely fast, and tests with 2D data show very promising results.

The physics governing galvanic distortion of natural source electromagnetic induction measurements is reexamined beginning from first principles. The conditions under which a decomposition of measured magnetotelluric response tensors and magnetic transfer functions is applicable are described, and the form of the decomposition describing distortion of the electric and magnetic fields is derived directly from the integral equation defining the scattering of electric and magnetic fields by surface heterogeneities. The inclusion of magnetic field galvanic distortion leads to indeterminacy of the regional magnetotelluric response in the form of scaling by frequency‐dependent, complex factors controlled by two unknown real constants. This is a generalization of the well‐known static shift effect from electric field galvanic distortion and can in principal be removed if the magnitude and phase of the regional response are known at some frequency. Distortion of the magnetic transfer function is shown to be even more indeterminate, containing a term proportional to one of the regional magnetotelluric responses which is inseparably additive to the regional magnetic transfer function, as well as the complex scaling seen for magnetotellurics. A set of simultaneous nonlinear equations describing the full electric and magnetic field galvanic distortion decomposition of the magnetotelluric response tensor and magnetic transfer function is derived, and methods for their solution are described, including implementation of jackknife error estimates. The full magnetotelluric decomposition is applied to severely distorted data from the Canadian shield and seafloor data from the EMSLAB experiment. In both cases, magnetic field galvanic distortion is important at periods under a few thousand seconds. This suggests that greater attention to galvanic distortion of the magnetic field is needed during magnetotelluric surveys.

We have developed a robust and efficient finite difference algorithm for computing the magnetotelluric response of general three‐dimensional (3‐D) models using the minimum residual relaxation method. The difference equations that we solve are second order in H and are derived from the integral forms of Maxwell's equations on a staggered grid. The boundary H field values are obtained from two‐dimensional transverse magnetic mode calculations for the vertical planes in the 3‐D model. An incomplete Cholesky decomposition of the diagonal subblocks of the coefficient matrix is used as a preconditioner, and corrections are made to the H fields every few iterations to ensure there are no H divergences in the solution. For a plane wave source field, this algorithm reduces the errors in the H field for simple 3‐D models to around the 0.01% level compared to their fully converged values in a modest number of iterations, taking only a few minutes of computation time on our desktop workstation. The E fields can then be determined from discretized versions of the curl of H equations.

Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/ β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4 + T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.blood-brain barrier | endothelial cell | Wnt/β-catenin signaling | MS | EAE I n both multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), leukocytes infiltrate the central nervous system (CNS) across a damaged blood-brain barrier (BBB) to mediate myelin destruction and neuronal damage (1). BBB breakdown is a contributing factor to the pathogenesis of both MS and EAE (2-4). Structural and functional BBB degradation precedes lesion development in both MS and EAE (5-9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7, 11) and coincides with early infiltration of neutrophils before the onset of EAE (12). Although the severity of barrier leakage decreases over time for most relapsing-remitting MS lesions, as assessed by gadoliniumenhancing magnetic resonance imaging (7, 13-15), whether BBB recovery is an active process and, if so, which pathways mediate its repair, remain unclear.The BBB achieves its highly selective permeability through the presence of (i) tight junctions (TJs) that prevent paracellular diffusion of small molecules and immune cells between endothelial cells (ECs), (ii) very few endocytotic vesicles that restrict movement of large mo...

SUMMARY Telluric distortion occurs when electric charges accumulate along near‐surface inhomogeneities. Practical parametrizations of a telluric distortion matrix separate it into recoverable and non‐recoverable parameters. A very simple parametrization used by Bahr (1988) does this, and is easily interpreted in terms of rotations and amplifications of the regional electric field components aligned with the regional strike directions. Groom & Bailey's (1989) parametrization is equivalent, but more complicated. Optimal estimates of the electric field rotations, the regional strike, and scaled regional impedances are made easily using the simple parametrization advocated here. The regional impedance estimates have a variance that is modestly improved over those obtained by simply rotating the measured impedance matrix. Optimal esitmates of Groom & Bailey's parameters are obtained easily from the parametrization used here. The recoverable 3‐D distortion parameters do not characterize distorting bodies very well as their values depend to varying degree on the orientation of the regional strike. Owing to inherent non‐uniqueness, any measured impedance matrix that can be represented as a 3‐D distortion of a regional 2‐D impedance can equally well be represented as a 2‐D distortion of a regional 2‐D impedance in the form given by Zhang, Roberts & Pedersen (1987). The superficial 2‐D strike and anisotropy are easily recovered from the parametrization used here, and characterize 2‐D distortion well, as they are coordinate‐independent for 2‐D distortions. The optimal estimates are straightforward even for the realistic case of measurement errors that are correlated between elements of a measured impedance matrix.

SUMMARY Lymphocytes cross vascular boundaries via either disrupted tight junctions (TJs) or caveolae to induce tissue inflammation. In the central nervous system (CNS), Th17 lymphocytes cross the blood-brain barrier (BBB) prior to Th1 cells, yet this differential crossing is poorly understood. We have used intravital two-photon imaging of the spinal cord in wild-type and caveolae-deficient mice with fluorescently labeled endothelial TJs, to determine how TJ remodeling and caveolae regulate CNS entry of lymphocytes during the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis. We find that dynamic TJ remodeling occurs early in EAE but does not depend upon caveolar transport. Moreover, Th1 but not Th17 lymphocytes are significantly reduced in the inflamed CNS of mice lacking caveolae. Therefore, TJ remodeling facilitates Th17 migration across the BBB, whereas caveolae promote Th1 entry into the CNS. Moroever, therapies that target both TJ degradation and caveolar transcytosis may limit lymphocyte infiltration during inflammation.

The preceding paper derives a staggered‐grid, finite‐difference approximation applicable to electromagnetic induction in the Earth. The staggered‐grid, finite‐difference approximation results in a linear system of equations [Formula: see text]x = b, where [Formula: see text] is symmetric but not Hermitian. This is solved using the biconjugate gradient method, preconditioned with a modified, partial Cholesky decomposition of [Formula: see text]. This method takes advantage of the sparsity of [Formula: see text], and converges much more quickly than methods used previously to solve the 3-D induction problem. When simulating a conductivity model at a number of frequencies, the rate of convergence slows as frequency approaches 0. The convergence rate at low frequencies can be improved by an order of magnitude, by alternating the incomplete Cholesky preconditioned biconjugate gradient method with a procedure designed to make the approximate solutions conserve current.