Development and Application of a Functional Human Esophageal Mucosa Explant Platform to Eosinophilic Esophagitis.

There is an increasing prevalence of esophageal diseases but intact human tissue platforms to study esophageal function, disease mechanisms, and the interactions between cell types in situ are lacking. To address this, we utilized full thickness human donor esophagi to create and validate the ex vivo function of mucosa and smooth muscle (n = 25). Explanted tissue was tested for contractile responses to carbachol and histamine. We then treated ex vivo human esophageal mucosa with a cytokine cocktail to closely mimic the Th2 and inflammatory milieu of eosinophilic esophagitis (EoE) and assessed alterations in smooth muscle and extracellular matrix function and stiffening. We found that full thickness human esophagus as well as the individual layers of circular and longitudinal muscularis propria developed tension in response to carbachol ex vivo and that mucosa demonstrated squamous cell differentiation. Treatment of mucosa with Th2 and fibrotic cytokines recapitulated the majority of the clinical Eosinophilic Esophagitis Diagnostic Profile (EDP) on fluidic transcriptional microarray. Transforming growth factor-beta-1 (TGFβ1) increased gene expression of fibronectin, smooth muscle actin, and phospholamban (p < 0.001). The EoE cocktail also increased stiffness and decreased mucosal compliance, akin to the functional alterations in EoE (p = 0.001). This work establishes a new, transcriptionally intact and physiologically functional human platform to model esophageal tissue responses in EoE

Unexpected quenching effect on new particle formation from the atmospheric reaction of methanol with SO3

Despite the high abundance in the atmosphere, alcohols in general and methanol in particular are believed to play a small role in atmospheric new particle formation (NPF) largely due to the weak binding abilities of alcohols with the major nucleation precursors, e.g., sulfuric acid (SA) and dimethylamine (DMA). Herein, we identify a catalytic reaction that was previously overlooked, namely, the reaction between methanol and SO3, catalyzed by SA, DMA, or water. We found that alcohols can have unexpected quenching effects on the NPF process, particularly in dry and highly polluted regions with high concentrations of alcohols. Specifically, the catalytic reaction between methanol and SO3 can convert methanol into a less-volatile species-methyl hydrogen sulfate (MHS). The latter was initially thought to be a good nucleation agent for NPF. However, our simulation results suggest that the formation of MHS consumes an appreciable amount of atmospheric SO3, disfavoring further reactions of SO3 with H2O. Indeed, we found that MHS formation can cause a reduction of SA concentration up to 87%, whereas the nucleation ability of MHS toward new particles is not as good as that of SA. Hence, a high abundance of methanol in the atmosphere can lower the particle nucleation rate by as much as two orders of magnitude. Such a quenching effect suggests that the recently identified catalytic reactions between alcohols and SO3 need to be considered in atmospheric modeling in order to predict SA concentration from SO2, while also account for their potentially negative effect on NPF.Peer reviewe

ORMDL3 expression in ASM regulates hypertrophy, hyperplasia via TPM1 and TPM4, and contractility

ORM1-like 3 (ORMDL3) has strong genetic linkage to childhood onset asthma. To determine whether ORMDL3 selective expression in airway smooth muscle (ASM) influences ASM function, we used Cre-loxP techniques to generate transgenic mice (hORMDL3Myh11eGFP-cre), which express human ORMDL3 selectively in smooth muscle cells. In vitro studies of ASM cells isolated from the bronchi of hORMDL3Myh11eGFP-cre mice demonstrated that they developed hypertrophy (quantitated by FACS and image analysis), developed hyperplasia (assessed by BrdU incorporation), and expressed increased levels of tropomysin proteins TPM1 and TPM4. siRNA knockdown of TPM1 or TPM4 demonstrated their importance to ORMDL3-mediated ASM proliferation but not hypertrophy. In addition, ASM derived from hORMDL3Myh11eGFP-cre mice had increased contractility to histamine in vitro, which was associated with increased levels of intracellular Ca2+; increased cell surface membrane Orai1 Ca2+ channels, which mediate influx of Ca2+ into the cytoplasm; and increased expression of ASM contractile genes sarco/endoplasmic reticulum Ca2+ ATPase 2b and smooth muscle 22. In vivo studies of hORMDL3Myh11eGFP-cre mice demonstrated that they had a spontaneous increase in ASM and airway hyperreactivity (AHR). ORMDL3 expression in ASM thus induces changes in ASM (hypertrophy, hyperplasia, increased contractility), which may explain the contribution of ORMDL3 to the development of AHR in childhood onset asthma, which is highly linked to ORMDL3 on chromosome 17q12-21

Can Plasmon Change Reaction Path? : Decomposition of Unsymmetrical Iodonium Salts as an Organic Probe

Plasmon-assisted transformations of organic compounds represent a novel opportunity for conversion of light to chemical energy at room temperature. However, the mechanistic insights of interaction between plasmon energy and organic molecules is still under debate. Herein, we proposed a comprehensive study of the plasmon-assisted reaction mechanism using unsymmetric iodonium salts (ISs) as an organic probe. The experimental and theoretical analysis allow us to exclude the possible thermal effect or hot electron transfer. We found that plasmon interaction with unsymmetrical ISs led to the intramolecular excitation of electron followed by the regioselective cleavage of C–I bond with the formation of electron-rich radical species, which cannot be explained by the hot electron excitation or thermal effects. The high regioselectivity is explained by the direct excitation of electron to LUMO with the formation of a dissociative excited state according to quantum-chemical modeling, which provides novel opportunities for the fine control of reactivity using plasmon energy.Peer reviewe

Large methane releases lead to strong aerosol forcing and reduced cloudiness

The release of vast quantities of methane into the atmosphere as a result of clathrate destabilization is a potential mechanism for rapid amplification of global warming. Previous studies have calculated the enhanced warming based mainly on the radiative effect of the methane itself, with smaller contributions from the associated carbon dioxide or ozone increases. Here, we study the effect of strongly elevated methane (CH4) levels on oxidant and aerosol particle concentrations using a combination of chemistry-transport and general circulation models. A 10-fold increase in methane concentrations is predicted to significantly decrease hydroxyl radical (OH) concentrations, while moderately increasing ozone (O3). These changes lead to a 70 % increase in the atmospheric lifetime of methane, and an 18 % decrease in global mean cloud droplet number concentrations (CDNC). The CDNC change causes a radiative forcing that is comparable in magnitude to the longwave radiative forcing ("enhanced greenhouse effect") of the added methane. Together, the indirect CH4-O3 and CH4-OH-aerosol forcings could more than double the warming effect of large methane increases. Our findings may help explain the anomalously large temperature changes associated with historic methane releases

EOS: a software for flavor physics phenomenology

EOS is an open-source software for a variety of computational tasks in flavor physics. Its use cases include theory predictions within and beyond the Standard Model of particle physics, Bayesian inference of theory parameters from experimental and theoretical likelihoods, and simulation of pseudo events for a number of signal processes. EOS ensures high-performance computations through a C++ back-end and ease of usability through a Python front-end. To achieve this flexibility, EOS enables the user to select from a variety of implementations of the relevant decay processes and hadronic matrix elements at run time. In this article, we describe the general structure of the software framework and provide basic examples. Further details and in-depth interactive examples are provided as part of the EOS online documentation

Causes and importance of new particle formation in the present-day and preindustrial atmospheres

New particle formation has been estimated to produce around half of cloud-forming particles in the present-day atmosphere, via gas-to-particle conversion. Here we assess the importance of new particle formation (NPF) for both the present-day and the preindustrial atmospheres. We use a global aerosol model with parametrizations of NPF from previously published CLOUD chamber experiments involving sulfuric acid, ammonia, organic molecules, and ions. We find that NPF produces around 67% of cloud condensation nuclei at 0.2% supersaturation (CCN0.2%) at the level of low clouds in the preindustrial atmosphere (estimated uncertainty range 45-84%) and 54% in the present day (estimated uncertainty range 38-66%). Concerning causes, we find that the importance of biogenic volatile organic compounds (BVOCs) in NPF and CCN formation is greater than previously thought. Removing BVOCs and hence all secondary organic aerosol from our model reduces low-cloud-level CCN concentrations at 0.2% supersaturation by 26% in the present-day atmosphere and 41% in the preindustrial. Around three quarters of this reduction is due to the tiny fraction of the oxidation products of BVOCs that have sufficiently low volatility to be involved in NPF and early growth. Furthermore, we estimate that 40% of preindustrial CCN0.2% are formed via ion-induced NPF, compared with 27% in the present day, although we caution that the ion-induced fraction of NPF involving BVOCs is poorly measured at present. Our model suggests that the effect of changes in cosmic ray intensity on CCN is small and unlikely to be comparable to the effect of large variations in natural primary aerosol emissions. Plain Language Summary New particle formation in the atmosphere is the process by which gas molecules collide and stick together to form atmospheric aerosol particles. Aerosols act as seeds for cloud droplets, so the concentration of aerosols in the atmosphere affects the properties of clouds. It is important to understand how aerosols affect clouds because they reflect a lot of incoming solar radiation away from Earth's surface, so changes in cloud properties can affect the climate. Before the Industrial Revolution, aerosol concentrations were significantly lower than they are today. In this article, we show using global model simulations that new particle formation was a more important mechanism for aerosol production than it is now. We also study the importance of gases emitted by vegetation, and of atmospheric ions made by radon gas or cosmic rays, in preindustrial aerosol formation. We find that the contribution of ions and vegetation to new particle formation was also greater in the preindustrial period than it is today. However, the effect on particle formation of variations in ion concentration due to changes in the intensity of cosmic rays reaching Earth was small.Peer reviewe

Atmospheric nucleation: highlights of the EUCAARI project and future directions

Within the project EUCAARI (European Integrated project on Aerosol Cloud Climate and Air Quality interactions), atmospheric nucleation was studied by (i) developing and testing new air ion and cluster spectrometers, (ii) conducting homogeneous nucleation experiments for sulphate and organic systems in the laboratory, (iii) investigating atmospheric nucleation mechanism under field conditions, and (iv) applying new theoretical and modelling tools for data interpretation and development of parameterisations. The current paper provides a synthesis of the obtained results and identifies the remaining major knowledge gaps related to atmospheric nucleation. The most important technical achievement of the project was the development of new instruments for measuring sub-3 nm particle populations, along with the extensive application of these instruments in both the laboratory and the field. All the results obtained during EUCAARI indicate that sulphuric acid plays a central role in atmospheric nucleation. However, also vapours other than sulphuric acid are needed to explain the nucleation and the subsequent growth processes, at least in continental boundary layers. Candidate vapours in this respect are some organic compounds, ammonia, and especially amines. Both our field and laboratory data demonstrate that the nucleation rate scales to the first or second power of the nucleating vapour concentration(s). This agrees with the few earlier field observations, but is in stark contrast with classical thermodynamic nucleation theories. The average formation rates of 2-nm particles were found to vary by almost two orders of magnitude between the different EUCAARI sites, whereas the formation rates of charged 2-nm particles varied very little between the sites. Overall, our observations are indicative of frequent, yet moderate, ion-induced nucleation usually outweighed by much stronger neutral nucleation events in the continental lower troposphere. The most concrete outcome of the EUCAARI nucleation studies are the new semi-empirical nucleation rate parameterizations based on field observations, along with updated aerosol formation parameterizations