Indoor dust acts as an adjuvant to promote sensitization to peanut through the airway

Background: There is growing evidence that environmental peanut exposure through non-oral routes, including the skin and respiratory tract, can result in peanut sensitization. Environmental adjuvants in indoor dust can promote sensitization to inhaled antigens, but whether they contribute to peanut allergy development is unclear. Objective: We investigated whether indoor dust promotes airway sensitization to peanut and peanut allergy development in mice. Methods: Female and male C57BL/6J mice were exposed via the airways to peanut, indoor dust extract, or both for 2 weeks. Mice were then challenged with peanut and assessed for anaphylaxis. Peanut-specific immunoglobulins, peanut uptake by lung conventional dendritic cells (cDCs), lung innate cytokines, and T cell differentiation in lung-draining lymph nodes were quantified. Innate cytokine production by primary human bronchial epithelial cells exposed to indoor dust was also determined. Results: Inhalational exposure to low levels of peanut in combination with indoor dust, but neither alone, resulted in production of peanut-specific IgE and development of anaphylaxis upon peanut challenge. Indoor dust triggered production of innate cytokines in murine lungs and in primary human bronchial epithelial cells. Additionally, inhaled indoor dust stimulated maturation and migration of peanut-laden lung type 1 cDCs to draining lymph nodes. Inhalational exposure to peanut and indoor dust induced peanut-specific T helper 2 cell differentiation and accumulation of T follicular helper cells in draining lymph nodes, which were associated with increased B cell numbers and peanut-specific immunoglobulin production. Conclusions & clinical relevance: Indoor dust promotes airway sensitization to peanut and development of peanut allergy in mice. Our findings suggest that environmental adjuvants in indoor dust may be determinants of peanut allergy development in children

Ultrafast Spectroscopic Signatures of Coherent Electron-Transfer Mechanisms in a Transition Metal Complex

The prevalence of ultrafast electron-transfer processes in light-harvesting materials has motivated a deeper understanding of coherent reaction mechanisms. Kinetic models based on the traditional (equilibrium) form of Fermi's Golden Rule are commonly employed to understand photoinduced electron-transfer dynamics. These models fail in two ways when the electron-transfer process is fast compared to solvation dynamics and vibrational dephasing. First, electron-transfer dynamics may be accelerated if the photoexcited wavepacket traverses the point of degeneracy between donor and acceptor states in the solvent coordinate. Second, traditional kinetic models fail to describe electron-transfer transitions that yield products which undergo coherent nuclear motions. We address the second point in this work. Transient absorption spectroscopy and a numerical model are used to investigate coherent back-electron-transfer mechanisms in a transition metal complex composed of titanium and catechol, [Ti(cat)3]2-. The transient absorption experiments reveal coherent wavepacket motions initiated by the back-electron-transfer process. Model calculations suggest that the vibrationally coherent product states may originate in either vibrational populations or coherences of the reactant. That is, vibrational coherence may be produced even if the reactant does not undergo coherent nuclear motions. The analysis raises a question of broader significance: can a vibrational population-to-coherence transition (i.e., a nonsecular transition) accelerate electron-transfer reactions even when the rate is slower than vibrational dephasing

Communication: Uncovering correlated vibrational cooling and electron transfer dynamics with multidimensional spectroscopy

Analogues of 2D photon echo methods in which two population times are sampled have recently been used to expose heterogeneity in chemical kinetics. In this work, the two population times sampled for a transition metal complex are transformed into a 2D rate spectrum using the maximum entropy method. The 2D rate spectrum suggests heterogeneity in the vibrational cooling (VC) rate within the ensemble. In addition, a cross peak associated with VC and back electron transfer (BET) dynamics reveals correlation between the two processes. We hypothesize that an increase in the strength of solute-solvent interactions, which accelerates VC, drives the system toward the activationless regime of BET

Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome.

AIMS: Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Na(v)1.5. Here, we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation. METHODS AND RESULTS: SCN5A was screened for mutations in a male patient with type-1 BrS pattern ECG. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. Sodium currents (I(Na)) were analysed using the whole-cell patch-clamp technique at 37 degrees C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (I(to)) was incorporated. A new mutation (C1850S) was identified in the Na(v)1.5 C-terminal domain. In HEK293 cells, mutant I(Na) density was decreased by 62% at -20 mV. Inactivation of mutant I(Na) was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 mV towards negative potentials. No change was observed regarding activation characteristics. Altogether, these biophysical alterations decreased the availability of I(Na). In the simulations, the I(to) density necessary to precipitate repolarization differed minimally between the two genotypes. In contrast, the mutation greatly affected conduction across a structural heterogeneity and precipitated conduction block. CONCLUSION: Our data confirm that mutations of the C-terminal domain of Na(v)1.5 alter the inactivation of the channel and support the notion that conduction alterations may play a significant role in the pathogenesis of BrS

Neuropilin-2 regulates airway inflammatory responses to inhaled lipopolysaccharide

Neuropilins are multifunctional receptors that play important roles in immune regulation. Neuropilin-2 (NRP2) is expressed in the lungs, but whether it regulates airway immune responses is unknown. Here, we report that Nrp2 is weakly expressed by alveolar macrophages (AMs) in the steady state but is dramatically upregulated following in vivo lipopolysaccharide (LPS) inhalation. Ex vivo treatment of human AMs with LPS also increased NRP2 mRNA expression and cell-surface display of NRP2 protein. LPS-induced Nrp2 expression in AMs was dependent upon the myeloid differentiation primary response 88 signaling pathway and the transcription factor NF-κB. In addition to upregulating display of NRP2 on the cell membrane, inhaled LPS also triggered AMs to release soluble NRP2 into the airways. Finally, myeloid-specific ablation of NRP2 resulted in increased expression of the chemokine (C-C motif) ligand 2 (Ccl2) in the lungs and prolonged leukocyte infiltration in the airways following LPS inhalation. These findings suggest that NRP2 expression by AMs regulates LPS-induced inflammatory cell recruitment to the airways and reveal a novel role for NRP2 during innate immune responses in the lungs

Signaling pathway of ginsenoside-Rg1 leading to nitric oxide production in endothelial cells.

We here provide definitive evidence that ginsenoside-Rg1, the pharmacologically active component of ginseng, is a functional ligand of the glucocorticoid receptor (GR) as determined by fluorescence polarization assay. Rg1 increased the phosphorylation of GR, phosphatidylinositol-3 kinase (PI3K), Akt/PKB and endothelial nitric oxide synthase (eNOS) leading to increase nitric oxide (NO) production in human umbilical vein endothelial cell. Rg1-induced eNOS phosphorylation and NO production were significantly reduced by RU486, LY294,002, or SH-6. Also, knockdown of GR completely eliminated the Rg1-induced NO production. This study revealed that Rg1 can indeed serve as an agonist ligand for GR and the activated GR can induce rapid NO production from eNOS via the non-transcriptional PI3K/Akt pathway

The Photon Ring in M87*

We report measurements of the gravitationally lensed secondary image—the first in an infinite series of so-called “photon rings”—around the supermassive black hole M87* via simultaneous modeling and imaging of the 2017 Event Horizon Telescope (EHT) observations. The inferred ring size remains constant across the seven days of the 2017 EHT observing campaign and is consistent with theoretical expectations, providing clear evidence that such measurements probe spacetime and a striking confirmation of the models underlying the first set of EHT results. The residual diffuse emission evolves on timescales comparable to one week. We are able to detect with high significance a southwestern extension consistent with that expected from the base of a jet that is rapidly rotating in the clockwise direction. This result adds further support to the identification of the jet in M87* with a black hole spin-driven outflow, launched via the Blandford-Znajek process. We present three revised estimates for the mass of M87* based on identifying the modeled thin ring component with the bright ringlike features seen in simulated images, one of which is only weakly sensitive to the astrophysics of the emission region. All three estimates agree with each other and previously reported values. Our strongest mass constraint combines information from both the ring and the diffuse emission region, which together imply a mass-to-distance ratio of 4.20 − 0.06 + 0.12 μ as and a corresponding black hole mass of (7.13 \ub1 0.39) 7 109 M ⊙, where the error on the latter is now dominated by the systematic uncertainty arising from the uncertain distance to M87*

THEMIS: A Parameter Estimation Framework for the Event Horizon Telescope

The Event Horizon Telescope (EHT) provides the unprecedented ability to directly resolve the structure and dynamics of black hole emission regions on scales smaller than their horizons. This has the potential to critically probe the mechanisms by which black holes accrete and launch outflows, and the structure of supermassive black hole spacetimes. However, accessing this information is a formidable analysis challenge for two reasons. First, the EHT natively produces a variety of data types that encode information about the image structure in nontrivial ways; these are subject to a variety of systematic effects associated with very long baseline interferometry and are supplemented by a wide variety of auxiliary data on the primary EHT targets from decades of other observations. Second, models of the emission regions and their interaction with the black hole are complex, highly uncertain, and computationally expensive to construct. As a result, the scientific utilization of EHT observations requires a flexible, extensible, and powerful analysis framework. We present such a framework, Themis, which defines a set of interfaces between models, data, and sampling algorithms that facilitates future development. We describe the design and currently existing components of Themis, how Themis has been validated thus far, and present additional analyses made possible by Themis that illustrate its capabilities. Importantly, we demonstrate that Themis is able to reproduce prior EHT analyses, extend these, and do so in a computationally efficient manner that can efficiently exploit modern high-performance computing facilities. Themis has already been used extensively in the scientific analysis and interpretation of the first EHT observations of M87