402 research outputs found
Cationic carbosilane dendrimers and oligonucleotide binding: an energetic affair
GENERATION 2 CATIONIC CARBOSILANE DENDRIMERS HOLD GREAT PROMISE AS INTERNALIZING AGENTS FOR GENE THERAPY AS THEY PRESENT LOW TOXICITY AND RETAIN AND INTERNALIZE GENETIC MATERIAL AS OLIGONUCLEOTIDE OR SIRNA. IN THIS WORK WE CARRIED OUT A COMPLETE IN SILICO STRUCTURAL AND ENERGETICAL CHARACTERIZATION OF THE INTERACTIONS OF A SET OF 2G CARBOSILANE DENDRIMERS, SHOWING DIFFERENT AFFINITY TOWARDS TWO SINGLE STRAND OLIGONUCLEOTIDE (ODN) SEQUENCES IN VITRO. OUR SIMULATIONS PREDICT THAT THESE FOUR DENDRIMERS AND THE RELEVANT ODN COMPLEXES ARE CHARACTERIZED BY SIMILAR SIZE AND SHAPE, AND THAT THE MOLECULE-SPECIFIC ODN BINDING ABILITY CAN BE RATIONALIZED ONLY CONSIDERING A CRITICAL MOLECULAR DESIGN PARAMETER: THE NORMALIZED EFFECTIVE BINDING ENERGY \u394GBIND,EFF/NEFF I.E., THE PERFORMANCE OF EACH ACTIVE INDIVIDUAL DENDRIMER BRANCH DIRECTLY INVOLVED IN A BINDING INTERACTIO
A Molecular Dynamics approach to investigate the tribological behaviour of Al-Si and α-Al2O3-Si interfaces at the nanoscale
The evolution of Information and Communications Technology (ICT) and Micro-Nano Electromechanical System (MEMS/NEMS) makes evident the trend towards the
progressive miniaturisation of devices. The energy efficiencies at the nanoscale are, in turn, significantly lowered by friction force. The friction force depends not only
on the tribological pair parameters and normal loads, but also on the crystalline structure of the materials in contact, their surface chemistry and roughness. Our
research focuses on the nanometric friction force using Molecular Dynamics (MD) simulations. An investigation of a system comprising a hemispheric silicon tip
sliding on an aluminium oxide flat surface, aiming at understanding the interactions between the materials from an atomistic standpoint, was thus conducted
Nanopercolation
We investigate through direct molecular mechanics calculations the
geometrical properties of hydrocarbon mantles subjected to percolation
disorder. We show that the structures of mantles generated at the critical
percolation point have a fractal dimension . In addition,
the solvent access surface and volume of these molecules follow
power-law behavior, and ,
where is the system size, and with both critical exponents and
being significantly dependent on the radius of the accessing probing
molecule, . Our results from extensive simulations with two distinct
microscopic topologies (i.e., square and honeycomb) indicate the consistency of
the statistical analysis and confirm the self-similar characteristic of the
percolating hydrocarbons. Due to their highly branched topology, some of the
potential applications for this new class of disordered molecules include drug
delivery, catalysis, and supramolecular structures.Comment: 4 pages, 5 figure
Peculiarities in the structure - properties relationship of epoxy-silica hybrids with highly organic siloxane domains
Epoxy-silica hybrids were produced from a diglycidyl ether of bisphenol-A resin using Jeffamine 230 hardener with a two-step in situ generation of siloxane domains. The siloxane component was obtained by hydrolysis and condensation of a mixture of Îł-glycidoxypropyl-trimethoxysilane and tetraethoxysilane, which was added to the epoxy resin after removal of the formed alcohols and water. The morphological structure of the hybrids was examined by TEM, SAXS and WAXS analysis, and confirmation of the identified co-continuity of the constitutive phases for nominal silica contents greater than 18%wt was obtained by TGA and DMA analysis. While the loss modulus was found to increase monotonically over the entire range of siloxane content, the glass transition temperature exhibited a stepwise increase upon reaching the conditions for phase co-continuity. Molecular dynamics simulations were used to produce model structures for silsequioxanes cage-like structures, as main constituents of the siloxane phase. The predicted interdomain distance between the silsequioxane structures was in agreement with the SAXS experimental data
An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile
Gene therapy using small interfering RNA (siRNA) is emerging as a novel therapeutic approach to treat various diseases. However, safe and efficient siRNA delivery still constitutes the major obstacle for clinical implementation of siRNA therapeutics. Here we report an ionizable supramolecular dendrimer vector, formed via self-assembly of a small amphiphilic dendrimer, as an effective siRNA delivery system with a favorable safety profile. By virtue of the ionizable tertiary amine terminals, the supramolecular dendrimer has a low positively charged surface potential and no notable cytotoxicity at physiological pH. Nonetheless, this ionizable feature imparted sufficient surface charge to the supramolecular dendrimer to enable formation of a stable complex with siRNA via electrostatic interactions. The resulting siRNA/dendrimer delivery system had a surface charge that was neither neutral, thus avoiding aggregation, nor too high, thus avoiding cytotoxicity, but was sufficient for favorable cellular uptake and endosomal release of the siRNA. When tested in different cancer cell lines and patient-derived cancer organoids, this dendrimer-mediated siRNA delivery system effectively silenced the oncogenes Myc and Akt2 with a potent antiproliferative effect, outperforming the gold standard vector, Lipofectamine 2000. Therefore, this ionizable supramolecular dendrimer represents a promising vector for siRNA delivery. The concept of supramolecular dendrimer nanovectors via self-assembly is new, yet easy to implement in practice, offering a new perspective for supramolecular chemistry in biomedical applications. [Figure not available: see fulltext.
Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins
Given the clinical impact of LMNA cardiomyopathies, understanding lamin function will fulfill a clinical need and will lead to advancement in the treatment of heart failure. A multidisciplinary approach combining cell biology, atomic force microscopy (AFM) and molecular modeling was used to analyze the biomechanical properties of human lamin A/C gene (LMNA) mutations (E161K, D192G, N195K) using an in vitro neonatal rat ventricular myocyte (NRVM) model
Hindered nucleoside analogs as antiflaviviridae agents
Abstract
Flaviviridae are an important family of viruses, responsible for widely spread diseases such as dengue and West Nile fever and hepatitis C. Despite the severity of the related diseases, no effective antiviral treatments for infection are available. Following our discovery of adenosine-hindered analogs as potent antiflaviviridae agents, we have continued our investigation on guanosine and inosine derivatives, which were evaluated for activity against BVDV, YFV, DENV, and WNV viruses in cell-based assays. The present study allowed us to identify some newer features that led to improve the antiviral potency (down to the ”M range) and to selectively inhibit BVDV and YFV viruses. The molecular modeling results were consistent with the hypothesis that test analogs act as RNA-dependent RNA polymerase (RdRp) inhibitors by interacting with a surface allosteric binding pocket
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