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

Detection of Crystalline and Fine-grained Calcic Plagioclases on Vesta

Accepted: 2019-06-2

Deciphering sub-micron ice particles on Enceladus surface

The surface of Saturn's moon Enceladus is composed primarily by pure water ice. The Cassini spacecraft has observed present-day geologic activity at the moon's South Polar Region, related with the formation and feeding of Saturn's E-ring. Plumes of micron-sized particles, composed of water ice and other non-ice contaminants (e.g., CO2, NH3, CH4), erupt from four terrain's fractures named Tiger Stripes. Some of this material falls back on Enceladus' surface to form deposits that extend to the North at ∼40°W and ∼220°W, with the highest concentration found at the South Pole. In this work we analyzed VIMS-IR data to identify plumes deposits across Enceladus' surface through the variation in band depth of the main water ice spectral features. To characterize the global variation of water ice band depths across Enceladus, the entire surface was sampled with an angular resolution of 1° in both latitude and longitude, and for each angular bin we averaged the value of all spectral indices as retrieved by VIMS. The position of the plumes' deposits predicted by theoretical models display a good match with water ice band depths' maps on the trailing hemisphere, whereas they diverge significantly on the leading side. Space weathering processes acting on Enceladus' surface ionize and break up water ice molecules, resulting in the formation of particles smaller than one micron. We also mapped the spectral indices for sub-micron particles and we compared the results with the plumes deposits models. Again, a satisfactory match is observed on the trailing hemisphere only. Finally, we investigated the variation of the depth of the water ice absorption bands as a function of the phase angle. In the visible range, some terrains surrounding the Tiger Stripes show a decrease in albedo when the phase angle is smaller than 10°. This unusual effect cannot be confirmed by near infrared data, since observations with a phase angle lower than 10° are not available. For phase angle values greater than 10°, the depth of the water ice features remains quite constant within a broad range of phase angle values

Detection of Crystalline and Fine-grained Calcic Plagioclases on Vesta

Plagioclase feldspars are among the most prevalent minerals in the solar system, and are present in many chondritic and achondritic meteorite families. Nevertheless, spectral features of plagioclases have never been unambiguously and directly observed in remote observations of asteroids. We report here the detection of an absorption band at 12.2 μm on Vesta spectra provided by ground-based spectral observations at the Subaru Telescope. This signature represents the first direct evidence of a widespread presence of crystalline Ca-rich plagioclase on Vesta and reveals that its regolith is comminuted to a very fine grain size, smaller than a few tens of microns, indicating that the mechanical brecciation process has been very effective. The crystalline nature of plagioclase strongly suggests that impacts alone cannot be the sole mechanism for regolith formation on Vesta and a milder process, such as thermal fatigue, should be invoked as an important and concomitant process Thermal fatigue should be considered a very effective process in regolith production and rejuvenation not only for near-Earth asteroids but even for large asteroids located in the main belt

Preliminary estimation of the detection possibilities of Ganymede's water vapor environment with MAJIS

The exosphere of Ganymede is the interface region linking the moon's icy surface to Jupiter's magnetospheric environment. Its characterization is of key importance to achieve a full understanding of the ice alteration processes induced by the radiation environment. Several scientific instruments that will operate on board the upcoming Jupiter Icy Moons Explorer (JUICE) mission, selected by ESA in the context of its Cosmic Vision programme, have the potential to study Ganymede's exosphere. Among them, the Moons And Jupiter Imaging Spectrometer (MAJIS) will have the chance to investigate the composition of the moon's exospheric components and the emission of water molecules. The exospheric water density profile, as obtained from current models, is a crucial parameter for the estimation of the expected signal to noise ratio related to the actual measurement. In lack of an adequate number of Ganymede's observations from past missions, there is a general difficulty in constraining current exosphere models which are based, in general, on different scenarios and considerations and often show large discrepancies in the estimated spatial distribution of the neutral environment. In this work, we make a preliminary estimation of the expected IR emission from exospheric water molecules, using different modelled density profiles, and we speculate on the possibility of JUICE/MAJIS to detect it. An exercise on the potential plume detection capabilities of MAJIS is also performed. The first necessary step for performing these calculations is a rough comparison of the existing models of Ganymede's water vapor exosphere. We discuss the characteristics of the neutral environment as derived from different exospheric models available in literature, the role of the ion-surface interactions in the H2O exosphere generation, and the related implications also in view of future observations. We then use the model outputs to estimate different scenarios for the expected non-Local Thermal Equilibrium (non-LTE) emission from these molecules. The results of this study can be of help during the JUICE observation planning phase

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

Water Vapor Vertical Profiles on Mars in Dust Storms Observed by TGO/NOMAD

It has been suggested that dust storms efficiently transport water vapor from the near‐surface to the middle atmosphere on Mars. Knowledge of the water vapor vertical profile during dust storms is important to understand water escape. During Martian Year 34, two dust storms occurred on Mars: a global dust storm (June to mid‐September 2018) and a regional storm (January 2019). Here we present water vapor vertical profiles in the periods of the two dust storms (Ls = 162–260° and Ls = 298–345°) from the solar occultation measurements by Nadir and Occultation for Mars Discovery (NOMAD) onboard ExoMars Trace Gas Orbiter (TGO). We show a significant increase of water vapor abundance in the middle atmosphere (40–100 km) during the global dust storm. The water enhancement rapidly occurs following the onset of the storm (Ls~190°) and has a peak at the most active period (Ls~200°). Water vapor reaches very high altitudes (up to 100 km) with a volume mixing ratio of ~50 ppm. The water vapor abundance in the middle atmosphere shows high values consistently at 60°S‐60°N at the growth phase of the dust storm (Ls = 195°–220°), and peaks at latitudes greater than 60°S at the decay phase (Ls = 220°–260°). This is explained by the seasonal change of meridional circulation: from equinoctial Hadley circulation (two cells) to the solstitial one (a single pole‐to‐pole cell). We also find a conspicuous increase of water vapor density in the middle atmosphere at the period of the regional dust storm (Ls = 322–327°), in particular at latitudes greater than 60°S

Ibudilast, a Pharmacologic Phosphodiesterase Inhibitor, Prevents Human Immunodeficiency Virus-1 Tat-Mediated Activation of Microglial Cells

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorders (HAND) occur, in part, due to the inflammatory response to viral proteins, such as the HIV-1 transactivator of transcription (Tat), in the central nervous system (CNS). Given the need for novel adjunctive therapies for HAND, we hypothesized that ibudilast would inhibit Tat-induced excess production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα) in microglial cells. Ibudilast is a non-selective cyclic AMP phosphodiesterase inhibitor that has recently shown promise as a treatment for neuropathic pain via its ability to attenuate glial cell activation. Accordingly, here we demonstrate that pre-treatment of both human and mouse microglial cells with increasing doses of ibudilast inhibited Tat-induced synthesis of TNFα by microglial cells in a manner dependent on serine/threonine protein phosphatase activity. Ibudilast had no effect on Tat-induced p38 MAP kinase activation, and blockade of adenosine A2A receptor activation did not reverse ibudilast's inhibition of Tat-induced TNFα production. Interestingly, ibudilast reduced Tat-mediated transcription of TNFα, via modulation of nuclear factor-kappa B (NF-κB) signaling, as shown by transcriptional activity of NF-κB and analysis of inhibitor of kappa B alpha (IκBα) stability. Together, our findings shed light on the mechanism of ibudilast's inhibition of Tat-induced TNFα production in microglial cells and may implicate ibudilast as a potential novel adjunctive therapy for the management of HAND