Showing papers by "Nathan C. Gianneschi published in 2014"
TL;DR: A previously unknown mechanism, phosphate-ATP-adenosine metabolic signaling, by which the CaP-rich mineral environment in bone tissues promotes osteogenic differentiation of human mesenchymal stem cells is unraveled.
Abstract: Synthetic matrices emulating the physicochemical properties of tissue-specific ECMs are being developed at a rapid pace to regulate stem cell fate. Biomaterials containing calcium phosphate (CaP) moieties have been shown to support osteogenic differentiation of stem and progenitor cells and bone tissue formation. By using a mineralized synthetic matrix mimicking a CaP-rich bone microenvironment, we examine a molecular mechanism through which CaP minerals induce osteogenesis of human mesenchymal stem cells with an emphasis on phosphate metabolism. Our studies show that extracellular phosphate uptake through solute carrier family 20 (phosphate transporter), member 1 (SLC20a1) supports osteogenic differentiation of human mesenchymal stem cells via adenosine, an ATP metabolite, which acts as an autocrine/paracrine signaling molecule through A2b adenosine receptor. Perturbation of SLC20a1 abrogates osteogenic differentiation by decreasing intramitochondrial phosphate and ATP synthesis. Collectively, this study offers the demonstration of a previously unknown mechanism for the beneficial role of CaP biomaterials in bone repair and the role of phosphate ions in bone physiology and regeneration. These findings also begin to shed light on the role of ATP metabolism in bone homeostasis, which may be exploited to treat bone metabolic diseases.
297 citations
TL;DR: This paper describes the preparation of the synthetic micellar nanoparticles together with their characterization and motion in liquid water with comparison to conventional electron microscopy analyses, and contends that this technique will quickly become essential in the characterization of analogous systems, especially where dynamics are of interest in the solvated state.
Abstract: In this paper we present in situ transmission electron microscopy of synthetic polymeric nanoparticles with emphasis on capturing motion in a solvated, aqueous state. The nanoparticles studied were obtained from the direct polymerization of a Pt(II)-containing monomer. The resulting structures provided sufficient contrast for facile imaging in situ. We contend that this technique will quickly become essential in the characterization of analogous systems, especially where dynamics are of interest in the solvated state. We describe the preparation of the synthetic micellar nanoparticles together with their characterization and motion in liquid water with comparison to conventional electron microscopy analyses.
93 citations
TL;DR: An untemplated, single-component antisense oligonucleotide delivery system capable of regulating mRNA abundance in live human cells is presented, and these LNA nanoparticles knockdown survivin mRNA, an established target for cancer therapy, in a sequence-specific fashion as analyzed by RT-PCR.
Abstract: We present an untemplated, single-component antisense oligonucleotide delivery system capable of regulating mRNA abundance in live human cells. While most approaches to nucleic acid delivery rely on secondary carriers and complex multicomponent charge-neutralizing formulations, we demonstrate efficient delivery using a simple locked nucleic acid (LNA)-polymer conjugate that assembles into spherical micellar nanoparticles displaying a dense shell of nucleic acid at the surface. Cellular uptake of soft LNA nanoparticles occurs rapidly within minutes as evidenced by flow cytometry and fluorescence microscopy. Importantly, these LNA nanoparticles knockdown survivin mRNA, an established target for cancer therapy, in a sequence-specific fashion as analyzed by RT-PCR.
66 citations
TL;DR: This paper contends that this strategy for rendering peptides resistant to proteolysis by formulating them as high-density brush polymers offers a plausible method of preparing peptides for in vivo use, where rapid digestion by proteases has traditionally restricted their utility.
Abstract: We describe a strategy for rendering peptides resistant to proteolysis by formulating them as high-density brush polymers. The utility of this approach is demonstrated by polymerizing well-established cell-penetrating peptides (CPPs) and showing that the resulting polymers are not only resistant to proteolysis but also maintain their ability to enter cells. The scope of this design concept is explored by studying the proteolytic resistance of brush polymers composed of peptides that are substrates for either thrombin or a metalloprotease. Finally, we demonstrate that the proteolytic susceptibility of peptide brush polymers can be tuned by adjusting the density of the polymer brush and offer in silico models to rationalize this finding. We contend that this strategy offers a plausible method of preparing peptides for in vivo use, where rapid digestion by proteases has traditionally restricted their utility.
59 citations
TL;DR: This paper explored the incorporation of functionality via initiation, termination and propagation employing an array of novel initiators, termination agents and monomers for ROMP to allow the generation of selectively labelled and well-defined polymers that would in turn lead to the formation of labelled nanomaterials.
50 citations
TL;DR: A spherical micelle generated in a three-step sequence in which a farnesyl-pantetheine conjugate is phosphorylated, adenylated, andosphorylated once more to generate a farnesia-CoA amphiphile that self-assembles into spherical micelles is presented.
Abstract: We present a spherical micelle generated in a three-step sequence in which a farnesyl-pantetheine conjugate is phosphorylated, adenylated, and phosphorylated once more to generate a farnesyl-CoA amphiphile that self-assembles into spherical micelles. A sphere-to-fibril morphological switch is achieved by enzymatically transferring the farnesyl group of the farnesyl-CoA micelle onto a peptide via phosphopantetheinyl transferase to generate a peptide amphiphile. Each step in the sequence is followed with characterization by HPLC, MS, TEM, and DLS. This system offers an entry into cofactor-mediated peptide decoration by extending the principles of bioresponsive polymeric materials to sequential enzyme cascades.
9 citations
TL;DR: In this paper, the authors proposed a method to solve a set of computational problems in the field of industrial and manufacturing engineering, using a combination of computational simulation and industrial simulation techniques.
Abstract: 1 Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, California 92093, United States 2 Fundamental Computational Sciences Directorate and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99354, United States 3 Department of Industrial and Manufacturing Engineering, Florida State University, Tallahassee, Florida 32306, United States
1 citations