Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei.

Topographical cues on cells can, through contact guidance, alter cellular plasticity and accelerate the regeneration of cultured tissue. Here we show how changes in the nuclear and cellular morphologies of human mesenchymal stromal cells induced by micropillar patterns via contact guidance influence the conformation of the cells' chromatin and their osteogenic differentiation in vitro and in vivo. The micropillars impacted nuclear architecture, lamin A/C multimerization and 3D chromatin conformation, and the ensuing transcriptional reprogramming enhanced the cells' responsiveness to osteogenic differentiation factors and decreased their plasticity and off-target differentiation. In mice with critical-size cranial defects, implants with micropillar patterns inducing nuclear constriction altered the cells' chromatin conformation and enhanced bone regeneration without the need for exogenous signalling molecules. Our findings suggest that medical device topographies could be designed to facilitate bone regeneration via chromatin reprogramming.

Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na+ /K+ ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG35-55 -induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG35-55 (PLG-MOG35-55 ) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients.

Supersaturation driven tailoring of photoluminescence efficiency and size distribution: a simplified aqueous approach for producing high-quality, biocompatible quantum dots.

Supersaturation was found to play a pivotal role during nanoparticle-synthesis and its subtle variation helped achieve two prime objectives: (a) high photoluminescence quantum efficiency (PLQE) and (b) narrow size distribution, thereby obviating the need for post-preparative treatments. Degree of supersaturation of initial synthetic mixture was varied by changing the concentration of reagents while keeping their molar ratio constant at 1:2.5:0.5 for [Cd(2+)]:[cysteine]:[chalcogenide]. An eight-fold increase in supersaturation caused a sharp focusing of size distribution by 64% for CdS quantum dots (QDs). The as-prepared CdS and CdTe QDs were found to have size distribution as low as 4% at higher supersaturation. For a four-fold increase in supersaturation, PLQE of as-prepared CdTe QDs (4.3 nm) rose by 5 times to a remarkably high value of 54%. The focusing of size distribution with increasing supersaturation was found to work well even in the absence of any stabilizer. A substantial overlap of nucleation and growth was found at low supersaturation (0.5S(CdTe)), whereas a good separation of the two events is achieved at a higher supersaturation (4S(CdTe)). This study provides a simplified aqueous route for producing highly monodisperse, photoluminescent and biocompatible nanoparticles.

Temperature tunability of size in CdS nanoparticles and size dependent photocatalytic degradation of nitroaromatics.

Size tunability of thiophenol capped CdS nanoparticles (NPs) has been achieved by controlling the temperatures in situ. Synthesis at 5 degrees C produced stable particles of smallest size having narrow size distribution and high photoluminescence quantum yield. The photoluminescence of thiophenol capped CdS NPs was quenched by the nitroaromatic compounds. The Stern-Volmer constant of dinitrobenzene was about 15-fold higher than nitrobenzene, which indicates that introduction of nitro groups in the benzene ring increases the quenching efficiency. Further, the as-prepared CdS NPs were found to display size dependent photocatalytic activity towards degradation of nitroaromatics. The catalytic efficiency of CdS quantum particles was quintupled with decrease in particle size from 5.8 to 3.8 nm. An empirical equation has been derived to correlate the catalytic efficiency of the nanoparticles with the twin factors operating in the quantum confinement regime: (i) change in surface to volume ratio and (ii) shift in conduction band edge.

First-principles analysis of the effects of alloying Pd with Ag for the catalytic hydrogenation of acetylene-ethylene mixtures.

The effect of alloying Pd with Ag on the hydrogenation of acetylene is examined by analyzing the chemisorption of all potential C(1) (atomic carbon, CH, methylene, and methyl) and C(2) (acetylene, vinyl, ethylene, ethyl, ethane, ethylidene, ethylidyne, and vinylidene) surface intermediates and atomic hydrogen along with the reaction energies for the elementary steps that produce these intermediates over Pd(111), Pd(75%)Ag(25%)/Pd(111), Pd(50%)Ag(50%)/Pd(111), and Ag(111) surfaces by using first-principle density functional theoretical (DFT) calculations. All of the calculations reported herein were performed at 25% surface coverage. The adsorption energies for all of the C(1) and C(2) intermediates decreased upon increasing the composition of Ag in the surface. Both geometric as well as electronic factors are responsible for the decreased adsorption strength. The modes of adsorption as well as the strengths of adsorption over the alloy surfaces in a number of cases were characteristically different than those found over pure Pd (111) and Ag (111). Adsorbates tend to minimize their interaction with the Ag atoms in the alloy surface. An electronic analysis of these surfaces shows that there is, in general, a shift in the occupied d-band states away from the Fermi level when Pd is alloyed with Ag. The s and p states also appear to contribute and may be responsible for small deviations from the Hammer-Nørskov model. The effect of alloying is more pronounced on the calculated reaction energies for different possible surface elementary reactions. Alloying Pd with Ag reduces the exothermicity (increases endothermicity) for bond-breaking reactions. This is consistent with experimental results that show a decrease in the decomposition products in moving from pure Pd to Pd-Ag alloys.(2-5) In addition, alloying increases the exothermicity of bond-forming reactions. Alloying therefore not only helps to suppress the unfavorable decomposition (bond-breaking) reaction rates but also helps to enhance the favorable hydrogenation (bond-forming) reaction rates.