Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes. Despite the connection between ILD and autoimmunity, it remains unclear ...whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. We examined a severe form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), and established a strong link between an autoimmune response to the lung-specific protein BPIFB1 (bactericidal/permeability-increasing fold-containing B1) and clinical ILD. Screening of a large cohort of APS1 patients revealed autoantibodies to BPIFB1 in 9.6% of APS1 subjects overall and in 100% of APS1 subjects with ILD. Further investigation of ILD outside the APS1 disorder revealed BPIFB1 autoantibodies present in 14.6% of patients with connective tissue disease-associated ILD and in 12.0% of patients with idiopathic ILD. The animal model for APS1, Aire⁻/⁻ mice, harbors autoantibodies to a similar lung antigen (BPIFB9); these autoantibodies are a marker for ILD. We found that a defect in thymic tolerance was responsible for the production of BPIFB9 autoantibodies and the development of ILD. We also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also led to ILD, consistent with our discovery of BPIFB1 autoantibodies in non-APS1 patients. Overall, our results demonstrate that autoimmunity targeting the lung-specific antigen BPIFB1 may contribute to the pathogenesis of ILD in patients with APS1 and in subsets of patients with non-APS1 ILD, demonstrating the role of lung-specific autoimmunity in the genesis of ILD.
Silicon-carbide (SiC) nanocrystals (NCs) of controlled 2–4 nm size are produced in low-pressure nonthermal plasma from the simple alkylsilane precursor tetramethylsilane (TMS). Generating material on ...the slightly carbon-rich side of 50/50 Si/C, we establish a process for thermally removing residual carbon, which in turn promotes a degree of intrinsic solubility in polar solvents such as isopropanol (IPA). Using the size-dependent Tauc gap of luminescent silicon NCs (Si NCs) as a point of reference, we demonstrate quantum confinement in nanocrystalline β-SiC but without measurable luminescence. Surface-sensitive spectroscopic techniques reveal an oxide shell surrounding a nanocrystalline SiC core, where negative surface charge groups promote solubility while likely acting as efficient trap states for nonradiative recombination. An analytical model is presented that combines electrostatic repulsion with van der Waals attraction to explain experimental observations of concentration-dependent cluster formation and reversible NC aggregation. We anticipate that these materials will be of interest for use as nanofillers in polymer composites and in specialty coatings, while providing a foundation for exploring routes to band gap emission from nanocrystalline SiC.
Regeneration of skeletal muscle after volumetric injury is thought to be impaired by a dysregulated immune microenvironment that hinders endogenous repair mechanisms. Such defects result in fatty ...infiltration, tissue scarring, chronic inflammation, and debilitating functional deficits. Here, we evaluated the key cellular processes driving dysregulation in the injury niche through localized modulation of sphingosine‐1‐phosphate (S1P) receptor signaling. We employ dimensionality reduction and pseudotime analysis on single cell cytometry data to reveal heterogeneous immune cell subsets infiltrating preclinical muscle defects due to S1P receptor inhibition. We show that global knockout of S1P receptor 3 (S1PR3) is marked by an increase of muscle stem cells within injured tissue, a reduction in classically activated relative to alternatively activated macrophages, and increased bridging of regenerating myofibers across the defect. We found that local S1PR3 antagonism via nanofiber delivery of VPC01091 replicated key features of pseudotime immune cell recruitment dynamics and enhanced regeneration characteristic of global S1PR3 knockout. Our results indicate that local S1P receptor modulation may provide an effective immunotherapy for promoting a proreparative environment leading to improved regeneration following muscle injury.
Barrett's esophagus (BE) is a specialized columnar epithelium (SCE) that develops as replacement for damaged squamous epithelium (SqE) in subjects with reflux disease, and as such it is apparently ...more acid resistant than SqE. How SCE resists acid injury is poorly understood; one means may involve altered tight junctions (TJs) since the TJ in SqE is an early target of attack and damage by acid in reflux disease. To assess this possibility, quantitative RT-PCR for 21 claudins was performed on endoscopic biopsies on SCE of BE and from healthy SqE from subjects without esophageal disease. In SCE, Cldn-18 was the most highly expressed at the mRNA level and this finding is paralleled by marked elevation in protein expression on immunoblots. In contrast in SqE, Cldn-18 was minimally expressed at the mRNA level and undetectable at the protein level. Immunofluorescence studies showed membrane localization of Cldn-18 and colocalization with the tight junction protein, zonula occludens-1. When Cldn-18 was overexpressed in MDCK II cells and mounted as monolayers in Ussing chambers, it raised electrical resistance and, as shown by lower dilution potentials to a NaCl gradient and lower diffusion potentials to acidic gradients, selectively reduced paracellular permeability to both Na(+) and H(+) compared with parental MDCK cells. We conclude that Cldn-18 is the dominant claudin in the TJ of SCE and propose that the change from a Cldn-18-deficient TJ in SqE to a Cldn-18-rich TJ in SCE contributes to the greater acid resistance of BE.
A universal cookoff model (UCM) is applied to the melt cast explosive Comp-B composed of RDX and TNT. The UCM uses a simple kinetic mechanism with rates and thermophysical properties determined ...specifically for Comp-B. The success of the UCM is primarily attributed to the flexible form of the rate expression as well as accurate thermophysical properties obtained from small-scale experiments. The rate expressions use distributed activation energies in conjunction with rate multipliers to account for accelerations caused by 1) dissolved RDX, 2) liquid RDX, and 3) pressure. Our finite element model addresses Comp-B cookoff from the pristine state, through melting of the TNT binder, partial dissolution of RDX in the hot TNT, and melting of the remaining RDX as the Comp-B thermally ignites. Typically, the UCM is used for explosives that do not flow. However, we have included a buoyancy-driven flow model to account for multiphase fluid movement. Predicted temperature fields were sensitive to flow, which caused the hotter material to rise. Our predictions of ignition times were also sensitive to RDX dissolving in hot TNT causing an acceleration of the RDX decomposition.
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