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Register a new userNanodiamond as a vector for siRNA delivery to Ewing sarcoma cells
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We investigated the ability of diamond nanoparticles (nanodiamonds, NDs) to deliver small interfering RNA (siRNA) in Ewing sarcoma cells, in the perspective of in vivo anti-cancer nucleic acid drug delivery. siRNA was adsorbed onto NDs previously coated with cationic polymer. Cell uptake of NDs has been demonstrated by taking advantage of NDs intrinsic fluorescence coming from embedded color center defects. Cell toxicity of these coated NDs was shown to be low. Consistent with the internalization efficacy, we have shown a specific inhibition of EWS/Fli-1 gene expression at the mRNA and protein level by the ND vectorized siRNA in a serum containing medium.
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Bone is a biomaterial undergoing continuous renewal. The renewal process is known as bone remodelling and is operated by bone-resorbing cells (osteoclasts) and bone-forming cells (osteoblasts). Both biochemical and biomechanical regulatory mechanisms have been identified in the interaction between osteoclasts and osteoblasts. Here we focus on an additional and poorly understood potential regulatory mechanism of bone cells, that involves the morphology of the microstructure of bone. Bone cells can only remove and replace bone at a bone surface. However, the microscopic availability of bone surface depends in turn on the ever-changing bone microstructure. The importance of this geometrical dependence is unknown and difficult to quantify experimentally. Therefore, we develop a sophisticated mathematical model of bone cell interactions that takes into account biochemical, biomechanical and geometrical regulations. We then investigate numerically the influence of bone surface availability in bone remodelling within a representative bone tissue sample. The interdependence between the bone cells activity, which modifies the bone microstructure, and changes in the microscopic bone surface availability, which in turn influences bone cell development and activity, is implemented using a remarkable experimental relationship between bone specific surface and bone porosity. Our model suggests that geometrical regulation of the activation of new remodelling events could have a significant effect on bone porosity and bone stiffness. On the other hand, geometrical regulation of late stages of osteoblast and osteoclast differentiation seems less significant. We conclude that the development of osteoporosis is probably accelerated by this geometrical regulation in cortical bone, but probably slowed down in trabecular bone.
Network theory-based approaches provide valuable insights into the variations in global structural connectivity between differing dynamical states of proteins. Our objective is to review network-based analyses to elucidate such variations, especially in the context of subtle conformational changes. We present technical details of the construction and analyses of protein structure networks, encompassing both the non-covalent connectivity and dynamics. We examine the selection of optimal criteria for connectivity based on the physical concept of percolation. We highlight the advantages of using side-chain based network metrics in contrast to backbone measurements. As an illustrative example, we apply the described network approach to investigate the global conformational change between the closed and partially open states of the SARS-CoV-2 spike protein. This conformational change in the spike protein is crucial for coronavirus entry and fusion into human cells. Our analysis reveals global structural reorientations between the two states of the spike protein despite small changes between the two states at the backbone level. We also observe some differences at strategic locations in the structures, correlating with their functions, asserting the advantages of the side-chain network analysis. Finally we present a view of allostery as a subtle synergistic-global change between the ligand and the receptor, the incorporation of which would enhance the drug design strategies.
We introduce the SPlit-and-conQueR (SPQR) model, a coarse-grained representation of RNA designed for structure prediction and refinement. In our approach, the representation of a nucleotide consists of a point particle for the phosphate group and an anisotropic particle for the nucleoside. The interactions are, in principle, knowledge-based potentials inspired by the ESCORE function, a base-centered scoring function. However, a special treatment is given to base-pairing interactions and certain geometrical conformations which are lost in a raw knowledge-base model. This results in a representation able to describe planar canonical and non-canonical base pairs and base-phosphate interactions and to distinguish sugar puckers and glycosidic torsion conformations. The model is applied to the folding of several structures, including duplexes with internal loops of non-canonical base pairs, tetraloops, junctions and a pseudoknot. For the majority of these systems, experimental structures are correctly predicted at the level of individual contacts. We also propose a method for efficiently reintroducing atomistic detail from the coarse-grained representation.
This chapter reviews the differential geometry-based solvation and electrolyte transport for biomolecular solvation that have been developed over the past decade. A key component of these methods is the differential geometry of surfaces theory, as applied to the solvent-solute boundary. In these approaches, the solvent-solute boundary is determined by a variational principle that determines the major physical observables of interest, for example, biomolecular surface area, enclosed volume, electrostatic potential, ion density, electron density, etc. Recently, differential geometry theory has been used to define the surfaces that separate the microscopic (solute) domains for biomolecules from the macroscopic (solvent) domains. In these approaches, the microscopic domains are modeled with atomistic or quantum mechanical descriptions, while continuum mechanics models (including fluid mechanics, elastic mechanics, and continuum electrostatics) are applied to the macroscopic domains. This multiphysics description is integrated through an energy functional formalism and the resulting Euler-Lagrange equation is employed to derive a variety of governing partial differential equations for different solvation and transport processes; e.g., the Laplace-Beltrami equation for the solvent-solute interface, Poisson or Poisson-Boltzmann equations for electrostatic potentials, the Nernst-Planck equation for ion densities, and the Kohn-Sham equation for solute electron density. Extensive validation of these models has been carried out over hundreds of molecules, including proteins and ion channels, and the experimental data have been compared in terms of solvation energies, voltage-current curves, and density distributions. We also propose a new quantum model for electrolyte transport.
Diamond nanoparticles (nanodiamonds) can transport active drugs in cultured cells as well as in vivo. However, in the latter case, methods allowing to determine their bioavailability accurately are still lacking. Nanodiamond can be made fluorescent with a perfectly stable emission and a lifetime ten times longer than the one of tissue autofluorescence. Taking advantage of these properties, we present an automated quantification method of fluorescent nanodiamonds (FND) in histological sections of mouse organs and tumor, after systemic injection. We use a home-made time-delayed fluorescence microscope comprising a custom pulsed laser source synchronized on the master clock of a gated intensified array detector. This setup allows to obtain ultra-high-resolution images 120 Mpixels of whole mouse organs sections, with subcellular resolution and single-particle sensitivity. As a proof-of-principle experiment, we quantified the biodistribution and aggregation state of new cationic FNDs able to transport small interfering RNA inhibiting the oncogene responsible for Ewing sarcoma. Image analysis showed a low yield of nanodiamonds in the tumor after intravenous injection. Thus, for the in vivo efficacy assay we injected the nanomedicine into the tumor. We achieved a 28-fold inhibition of the oncogene. This method can readily be applied to other nanoemitters with $approx$100 ns lifetime.
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