Efficient Delivery of MicroRNA and AntimiRNA Molecules Using an Argininocalix[4]arene Macrocycle

MicroRNAs (miRNAs) are short non-coding RNA molecules acting as gene regulators by repressing translation or by inducing degradation of the target RNA transcripts. Altered expression of miRNAs may be involved in the pathogenesis of many severe human diseases, opening new avenues in the field of therapeutic strategies, i.e., miRNA targeting or miRNA mimicking. In this context, the efficient and non-toxic delivery of premiRNA and antimiRNA molecules might be of great interest. The aim of the present paper is to determine whether an argininocalix[4]arene is able to efficiently deliver miRNA, premiRNA, and antimiRNA molecules to target cells, preserving their biological activity. This study points out that (1) the toxicity of argininocalix[4]arene 1 is low, and it can be proposed for long-term treatment of target cells, being that this feature is a pre-requisite for the development of therapeutic protocols; (2) the delivery of premiRNA and antimiRNA molecules is efficient, being higher when compared with reference gold standards available; and (3) the biological activity of the premiRNAs and antimiRNAs is maintained. This was demonstrated using the argininocalix[4]arene 1 in miRNA therapeutic approaches performed on three well-described experimental model systems: (1) the induction of apoptosis by antimiR-221 in glioma U251 cells; (2) the induction of apoptosis by premiR-124 in U251 cells; and (3) the inhibition of pro-inflammatory IL-8 and IL-6 genes in cystic fibrosis IB3-1 cells. Our results demonstrate that the argininocalix[4]arene 1 should be considered a very useful delivery system for efficient transfer to target cells of both premiRNA and antimiRNA molecules, preserving their biological activity

A database of aerosols and gases coefficients for VIS-NIR radiative transfer in the Solar System planetary atmospheres

Radiative transfer (RT) modelling of planetary atmospheres allows to obtain extremely valuable information about these environments. The computation of optical properties of the aerosols and gases, that is heavily time consuming, is always required as input for both forward models and inversion algorithms. We provide look up tables for these coefficients, ready to be ingested in RT solvers, in the visible and near infrared spectral ranges and covering the main species of the Solar System planets' atmospheres. Gases absorption coefficients have been computed with the line-by-line approach from the HITRAN 2012 spectral database and an improved method to interpolate them is suggested. Aerosols single scattering properties have been computed using the Mie and Rayleigh models for a set of selected species relevant for planetary atmospheres. Optimization in terms of tabulated wavelengths and maximum number of Legendre polynomial expansion terms has been performed for each species

The spectrum of a Saturn ring spoke from Cassini/VIMS

On 2008, July, the Cassini/VIMS spectrometer detected spokes on the Saturn's B ring for the first time. These are the first measurements of the complete reflectance spectrum of the spokes in a wide spectral range (0.35–0.51 μm). Here we will focus on a single broad‐shaped spoke, imaged by VIMS on July, 9. Radiative transfer modeling supports a pure water ice composition for the spoke's grains, but their size distribution is found to be wider than previously thought: preliminary results yields a modal value of about 1.90 μm (reff = 3.5 μm, veff = 0.3) and a number density of about 0.01–0.1 grains/cm3. The unexpected abundance of micron‐sized grains in the spoke may have implications for the formation models since the energy requirement increases by at least one order of magnitude. These kind of observations may also constrain the size selection effects thought to be produced by the forces governing the spokes' evolution

Large Abundances of Polycyclic Aromatic Hydrocarbons in Titan's Upper Atmosphere

In this paper, we analyze the strong unidentified emission near 3.28 micron in Titan's upper daytime atmosphere recently discovered by Dinelli et al.We have studied it by using the NASA Ames PAH IR Spectroscopic Database. The polycyclic aromatic hydrocarbons (PAHs), after absorbing UV solar radiation, are able to emit strongly near 3.3 micron. By using current models for the redistribution of the absorbed UV energy, we have explained the observed spectral feature and have derived the vertical distribution of PAH abundances in Titan's upper atmosphere. PAHs have been found to be present in large concentrations, about (2-3) 10(exp 4) particles / cubic cm. The identified PAHs have 9-96 carbons, with a concentration-weighted average of 34 carbons. The mean mass is approx 430 u; the mean area is about 0.53 sq. nm; they are formed by 10-11 rings on average, and about one-third of them contain nitrogen atoms. Recently, benzene together with light aromatic species as well as small concentrations of heavy positive and negative ions have been detected in Titan's upper atmosphere. We suggest that the large concentrations of PAHs found here are the neutral counterpart of those positive and negative ions, which hence supports the theory that the origin of Titan main haze layer is located in the upper atmosphere

Detection of Crystalline and Fine-grained Calcic Plagioclases on Vesta

Accepted: 2019-06-2

Artifacts reduction in VIR/Dawn data

Remote sensing images are generally affected by different types of noise that degrade the quality of the spectral data (i.e., stripes and spikes). Hyperspectral images returned by a Visible and InfraRed (VIR) spectrometer onboard the NASA Dawn mission exhibit residual systematic artifacts. VIR is an imaging spectrometer coupling high spectral and spatial resolutions in the visible and infrared spectral domain (0.25-5.0 μm). VIR data present one type of noise that may mask or distort real features (i.e., spikes and stripes), which may lead to misinterpretation of the surface composition. This paper presents a technique for the minimization of artifacts in VIR data that include a new instrument response function combining ground and in-flight radiometric measurements, correction of spectral spikes, odd-even band effects, systematic vertical stripes, high-frequency noise, and comparison with ground telescopic spectra of Vesta and Ceres. We developed a correction of artifacts in a two steps process: creation of the artifacts matrix and application of the same matrix to the VIR dataset. In the approach presented here, a polynomial function is used to fit the high frequency variations. After applying these corrections, the resulting spectra show improvements of the quality of the data. The new calibrated data enhance the significance of results from the spectral analysis of Vesta and Ceres

MTOR and STAT3 pathway hyper-activation is associated with elevated interleukin-6 levels in patients with shwachman-diamond syndrome: Further evidence of lymphoid lineage impairment

Shwachman–Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome, resulting in neutropenia and a risk of myeloid neoplasia. A mutation in a ribosome maturation factor accounts for almost all of the cases. Lymphoid involvement in SDS has not been well characterized. We recently reported that lymphocyte subpopulations are reduced in SDS patients. We have also shown that the mTOR-STAT3 pathway is hyper-activated in SDS myeloid cell populations. Here we show that mTOR-STAT3 signaling is markedly upregulated in the lymphoid compartment of SDS patients. Furthermore, our data reveal elevated IL-6 levels in cellular supernatants obtained from lymphoblasts, bone marrow mononuclear and mesenchymal stromal cells, and plasma samples obtained from a cohort of 10 patients. Of note, everolimus-mediated inhibition of mTOR signaling is associated with basal state of phosphorylated STAT3. Finally, inhibition of mTOR-STAT3 pathway activation leads to normalization of IL-6 expression in SDS cells. Altogether, our data strengthen the hypothesis that SDS affects both lymphoid and myeloid blood compartment and suggest everolimus as a potential therapeutic agent to reduce excessive mTOR-STAT3 activation in SDS

Nuclear Factor-Kappa B Family Member RelB Inhibits Human Immunodeficiency Virus-1 Tat-Induced Tumor Necrosis Factor-Alpha Production

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is likely neuroinflammatory in origin, believed to be triggered by inflammatory and oxidative stress responses to cytokines and HIV protein gene products such as the HIV transactivator of transcription (Tat). Here we demonstrate increased messenger RNA for nuclear factor-kappa B (NF-κB) family member, transcription factor RelB, in the brain of doxycycline-induced Tat transgenic mice, and increased RelB synthesis in Tat-exposed microglial cells. Since genetic ablation of RelB in mice leads to multi-organ inflammation, we hypothesized that Tat-induced, newly synthesized RelB inhibits cytokine production by microglial cells, possibly through the formation of transcriptionally inactive RelB/RelA complexes. Indeed, tumor necrosis factor-alpha (TNFα) production in monocytes isolated from RelB deficient mice was significantly higher than in monocytes isolated from RelB expressing controls. Moreover, RelB overexpression in microglial cells inhibited Tat-induced TNFα synthesis in a manner that involved transcriptional repression of the TNFα promoter, and increased phosphorylation of RelA at serine 276, a prerequisite for increased RelB/RelA protein interactions. The Rel-homology-domain within RelB was necessary for this interaction. Overexpression of RelA itself, in turn, significantly increased TNFα promoter activity, an effect that was completely blocked by RelB overexpression. We conclude that RelB regulates TNFα cytokine synthesis by competitive interference binding with RelA, which leads to downregulation of TNFα production. Moreover, because Tat activates both RelB and TNFα in microglia, and because Tat induces inflammatory TNFα synthesis via NF-κB, we posit that RelB serves as a cryoprotective, anti-inflammatory, counter-regulatory mechanism for pathogenic NF-κB activation. These findings identify a novel regulatory pathway for controlling HIV-induced microglial activation and cytokine production that may have important therapeutic implications for the management of HAND