Probe lifetime around natural satellites with obliquity

The dynamics of a probe orbiting a moon can be significantly influenced by the noncoincidence between the moon’s equatorial and orbital planes. Thus, we performed a general analysis about the effects of the angle (obliquity) between the above-mentioned planes and of the angle (nodal phasing) between the nodal lines of the mother planet’s apparent orbit and the probe orbit on the lifetime of the probe. The lifetime, strictly correlated to the variations in eccentricity of the probe orbit, was evaluated starting from low values of the semi-major axis, moderate eccentricity, and high inclination to offer high ground spatial resolution and extend latitudinal coverage of the natural satellite. This investigation, carried out through numerical simulations, may be useful for identifying the optimal initial conditions of the probe’s orbit elements, leading to an important increase in the probe lifetime in missions devoted to the exploration of natural satellite

Focus on Human Monoamine Transporter Selectivity. New Human DAT and NET Models, Experimental Validation, and SERT Affinity Exploration

The most commonly used antidepressant drugs are the serotonin transporter inhibitors. Their effects depend strongly on the selectivity for a single monoamine transporter compared to other amine transporters or receptors, and the selectivity is roughly influenced by the spatial protein structure. Here, we provide a computational study on three human monoamine transporters, i.e., DAT, NET, and SERT. Starting from the construction of hDAT and hNET models, whose three-dimensional structure is unknown, and the prediction of the binding pose for 19 known inhibitors, 3D-QSAR models of three human transporters were built. The training set variability, which was high in structure and activity profile, was validated using a set of in-house compounds. Results concern more than one aspect. First of all, hDAT and hNET three-dimensional structures were built, validated, and compared to the hSERT one; second, the computational study highlighted the differences in binding site arrangement statistically correlated to inhibitor selectivity; third, the profiling of new inhibitors pointed out a conservation of the inhibitory activity trend between rabbit and human SERT with a difference of about 1 order of magnitude; fourth, binding and functional studies confirmed 4-(benzyloxy)-4-phenylpiperidine 20a-d and 21a-d as potent SERT inhibitors. In particular, one of the compounds (compound 20b) revealed a higher affinity for SERT than paroxetine in human platelets

Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA

Impact of PEGylation on the degradation and pore organization in Mesoporous Silica Nanoparticles: a study of the inner mesoporous structure in physiologically relevant ionic conditions

The degradation of mesoporous silica nanoparticles (MSNs) in the biological milieu due to silica hydrolysis plays a fundamental role for the delivery of encapsulated drugs and therapeutics. However, little is known on the evolution of the pore arrangement in the MSNs in biologically relevant conditions. Small Angle X-ray scattering (SAXS) studies were performed on unmodified and PEGylated MSNs with a MCM-48 pore structure and average sizes of 140 nm, exposed to simulated body fluid solution (SBF) at pH 7.4 for different time intervals from 30 min to 24 h. Experiments were performed with silica concentrations below, at and over 0.14 mg/mL, the saturation concentration of silica in water at physiological temperature. At silica concentrations of 1 mg/mL (oversaturation), unmodified MSNs show variation in interpore distances over 6 h exposure to SBF, remaining constant thereafter. A decrease in radius of gyration is observed over the same time. Mesoporosity and radius of gyration of unmodified MSNs remain then unchanged up to 24 h. PEGylated MSNs at 1 mg/mL concentration show a broader diffraction peak but no change in the position of the peak is observed following 24 h exposure to SBF. PEGylated MSNs at 0.01 mg/mL show no diffraction peaks already after 30 min exposure to SBF, while at 0.14 mg/mL a small diffraction peak is present after 30 min exposure but disappears after 1 h.Fil: Ramirez, Maria de Los Angeles. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martin. Instituto de Nanosistemas; Argentina. Basque Research and Technology Alliance. CIC biomaGUNE; EspañaFil: Bindini, Elisa. Basque Research and Technology Alliance. CIC biomaGUNE; EspañaFil: Moretti, Paolo. Università Politecnica Delle Marche; ItaliaFil: Soler Illia, Galo Juan de Avila Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martin. Instituto de Nanosistemas; ArgentinaFil: Amenitsch, Heinz. Graz University Of Technology.; AustriaFil: Andreozzi, Patrizia. Università degli Studi di Firenze; Italia. Basque Research and Technology Alliance. CIC biomaGUNE; EspañaFil: Ortore, Maria Grazia. Università Politecnica Delle Marche; ItaliaFil: Moya, Sergio E.. Basque Research and Technology Alliance. CIC biomaGUNE; Españ

Salicylaldoximes and anthranylaldoximes as alternatives to phenol-based estrogen receptor ligands

Estrogens play a crucial role in the development and function of female reproductive tissues. They have positive effects on the maintenance of bone mineral density, on the liver, and on the cardiovascular and central nervous systems. Selective Estrogen Receptor Modulators (SERMs) are particularly attractive as therapeutic agents because they are able to block estrogen action at those sites where stimulation would be undesirable, such as the breast and uterus, but at the same time stimulate estrogen actions in other tissues where they are desired, such as the bone and liver. Most synthetic estrogen receptor ligands possess a phenolic ring, mimicking the phenolic "Aring" of the natural ligand estradiol. In an attempt to increase the structural diversity of estrogen receptor (ER) ligands, we designed and synthesized molecules containing unprecedented replacements of the prototypical phenolic "A-ring" of estrogens with an oxime and a hydroxy- (salicylaldoximes) or aminomoieties (anthranylaldoximes), forming intramolecularly H-bonded pseudocycles. These new classes of compounds showed interesting ER binding properties on both receptor subtypes (ERα and ERβ). These results proved that the six-membered ring formed by an intramolecular hydrogen bond, and containing an exocyclic oxime OH, is an effective stereoelectronic replacement of the phenolic ring of typical ER ligands

Modeling complex metabolic reactions, ecological systems, and financial and legal networks with MIANN models based on Markov-Wiener node descriptors

[Abstract] The use of numerical parameters in Complex Network analysis is expanding to new fields of application. At a molecular level, we can use them to describe the molecular structure of chemical entities, protein interactions, or metabolic networks. However, the applications are not restricted to the world of molecules and can be extended to the study of macroscopic nonliving systems, organisms, or even legal or social networks. On the other hand, the development of the field of Artificial Intelligence has led to the formulation of computational algorithms whose design is based on the structure and functioning of networks of biological neurons. These algorithms, called Artificial Neural Networks (ANNs), can be useful for the study of complex networks, since the numerical parameters that encode information of the network (for example centralities/node descriptors) can be used as inputs for the ANNs. The Wiener index (W) is a graph invariant widely used in chemoinformatics to quantify the molecular structure of drugs and to study complex networks. In this work, we explore for the first time the possibility of using Markov chains to calculate analogues of node distance numbers/W to describe complex networks from the point of view of their nodes. These parameters are called Markov-Wiener node descriptors of order kth (Wk). Please, note that these descriptors are not related to Markov-Wiener stochastic processes. Here, we calculated the Wk(i) values for a very high number of nodes (>100,000) in more than 100 different complex networks using the software MI-NODES. These networks were grouped according to the field of application. Molecular networks include the Metabolic Reaction Networks (MRNs) of 40 different organisms. In addition, we analyzed other biological and legal and social networks. These include the Interaction Web Database Biological Networks (IWDBNs), with 75 food webs or ecological systems and the Spanish Financial Law Network (SFLN). The calculated Wk(i) values were used as inputs for different ANNs in order to discriminate correct node connectivity patterns from incorrect random patterns. The MIANN models obtained present good values of Sensitivity/Specificity (%): MRNs (78/78), IWDBNs (90/88), and SFLN (86/84). These preliminary results are very promising from the point of view of a first exploratory study and suggest that the use of these models could be extended to the high-throughput re-evaluation of connectivity in known complex networks (collation)

A Small Satellite Constellation for a Continuous Coverage of Mid-Low Earth Latitudes

Abstract When located on a geostationary orbit, a satellite keeps a steady position with respect to a generic point on the Earth’s surface and this characteristic allows for important advantages. A continuous longitudinal coverage of the Earth’s surface (higher latitudes excluded) is a result of using a three geo-satellite constellation. Nevertheless, there are also several drawbacks related to the geostationary orbit employment. The need to consider alternative satellite constellations has begun to arise from these disadvantages; these constellations, in spite of having very similar characteristics to the geostationary system, are able to overcome the complexity, the costs and the launching site problems connected with a geostationary satellite. For equatorial orbits, the Four-Leaf Clover System represents a profitable alternative compared to the traditional geostationary system. As far as high Earth latitudes are concerned, there are different operational constellations, such as Molniya and Tundra, capable of ensuring the continuous coverage of a region and generally taking orbits with a critical inclination into account (63.43 deg). The aim of this paper is to demonstrate that it is possible to create a satellite constellation capable of ensuring a continuous coverage of mid-low Earth latitudes. After a general study of the orbits employed to date, followed by a general graphical representation, a constellation of eight small satellites in multi-synchronous orbits makes the achievement of this paper’s aim possible. Several possibilities for application follow, both for telecommunications and remote sensing missions