A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model.

BACKGROUND: Wnt/ß-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease, and although two approved drugs limit functional decline, transplantation is the only treatment that extends survival, highlighting the need for regenerative therapies. METHODS: Using our antibody-based platform of Wnt/ß-catenin modulators, we investigated the ability of a pathway antagonist and pathway activators to reduce pulmonary fibrosis in the acute bleomycin model, and we tested the ability of a WNT mimetic to affect alveolar organoid cultures. RESULTS: A WNT mimetic agonist with broad FZD-binding specificity (FZD1,2,5,7,8) potently expanded alveolar organoids. Upon therapeutic dosing, a broad FZD-binding specific Wnt mimetic decreased pulmonary inflammation and fibrosis and increased lung function in the bleomycin model, and it impacted multiple lung cell types in vivo. CONCLUSIONS: Our results highlight the unexpected capacity of a WNT mimetic to effect tissue repair after lung damage and support the continued development of Wnt/ß-catenin pathway modulation for the treatment of pulmonary fibrosis.

Complete genome sequence of Bradyrhizobium NP1, isolated from forest soil.

We report the complete genome sequence of Bradyrhizobium strain NP1. This bacterium was isolated from forest soil that had been subject to chronic warming. The genome of this novel isolated bacteria is presented as a single circular contig of 7,712,921 base pairs with 64.14% GC content.

How does hydrogen bond network analysis reveal the golden ratio of water-glycerol mixtures?

Properties of water-glycerol mixtures depend closely on the water/glycerol ratio. Around the 30 mol% glycerol concentration mark, the so-called golden ratio of water-glycerol mixtures, several of the mixture's properties have observed maxima or minima, without a clear fundamental explanation. In this work, a series of molecular dynamics simulations have been performed over a wide range of water-glycerol concentrations to analyze the intermolecular hydrogen bond (H-bond) network. The collected values from simulations are justified from both a probabilistic model of H-bonding and from observing the dynamic behavior of each type of H-bonds. The populations of H-bonds that exist at a given concentration of glycerol are largely governed by the probability of one oxygen atom randomly associating with another oxygen atom. However, the H-bonds that glycerol oxygen can form are dependent on the H-bonds that are formed by the other intramolecular glycerol oxygen. Based on the dynamic analysis of each type of H-bonds, there are deviations from randomly associating with another oxygen. Water preferentially donates a hydrogen to a glycerol than to another water molecule. Yet, glycerol has a near-equal likelihood for donating a hydrogen to either another glycerol or a water. This has an effect of increasing the number of H-bonds between water and glycerol molecules and decreasing H-bonds between two water molecules. A maximum contribution of H-bonds between water and glycerol occurs around 30 mol% glycerol which is a concentration where several of the mixture's properties have an observed maxima or minima.

Molecular Dynamics Simulations for Loading-Dependent Diffusion of CO2, SO2, CH4, and Their Binary Mixtures in ZIF-10: The Role of Hydrogen Bond.

The loading-dependent diffusion behavior of CH4, CO2, SO2, and their binary mixtures in ZIF-10 has been investigated in detail by using classical molecular dynamics simulations. Our simulation results demonstrate that the self-diffusion coefficient Di of CH4 molecules decreases sharply and monotonically with the loading while those of both CO2 and SO2 molecules initially display a slight increase at low uptakes and follow a slow decrease at high uptakes. Accordingly, the interaction energies between CH4 molecules and ZIF-10 remain nearly constant regardless of the loading due to the absence of hydrogen bonds (HBs), while the interaction energies between CO2 (or SO2) and ZIF-10 decease rapidly with the loading, especially at small amounts of gas molecules. Such different loading-dependent diffusion and interaction mechanisms can be attributed to the relevant HB behavior between gas molecules and ZIF-10. At low loadings, both the number and strength of HBs between CO2 (or SO2) molecules and ZIF-10 decrease obviously as the loading increases, which is responsible for the slight increase of their diffusion coefficients. However, at high loadings, their HB strength increases with the loading. Similar loading-dependent phenomena of diffusion, interaction, and HB behavior can be observed for CH4, CO2, and SO2 binary mixtures in ZIF-10, only associated with some HB competition between CO2 and SO2 molecules in the case of the CO2/SO2 mixture.

Blockade of patch-based µ opioid receptors in the striatum attenuates methamphetamine-induced conditioned place preference and reduces activation of the patch compartment.

The behavioral effects of methamphetamine (METH) are mediated by the striatum, which is divided into the patch compartment, which mediates limbic and reward functions, and the matrix compartment, which mediates sensorimotor tasks. METH treatment results in repetitive behavior that is related to enhanced relative activation of the patch versus the matrix compartment. The patch, but not the matrix compartment contains a high density of µ opioid receptors, and localized blockade of patch-based µ opioid receptors attenuates METH-induced patch-enhanced activity and repetitive behaviors. Numerous studies have examined patch-enhanced activity and the contribution of patch-associated µ opioid receptors to METH-induced repetitive behavior, but it is not known whether patch-enhanced activity occurs during METH-mediated reward, nor is it known if patch-based µ opioid receptors contribute to METH reward. The goals of this study were to determine if blockade of patch-based µ opioid receptors alters METH-induced conditioned place preference (CPP), as well activation of the patch and matrix compartments following METH-mediated CPP. A biased conditioning paradigm was used to assess CPP, and conditioning occurred over an 8-d period. Animals were bilaterally infused in the striatum with the µ-specific antagonist CTAP or vehicle prior to conditioning. Animals were tested for preference 24h after the last day of conditioning, sacrificed and the brains processed for immunohistochemistry. Blockade of patch-based µ opioid receptors reduced METH-induced CPP, and reduced patch-enhanced c-Fos expression in the striatum following METH-mediated CPP. These data indicate that patch-enhanced activity is associated with METH-mediated reward and patch-based µ opioid receptors contribute to this phenomenon.