A bioprinted cardiac patch composed of cardiac-specific extracellular matrix and progenitor cells for heart repair

Congenital heart defects are present in 8 of 1000 newborns and palliative surgical therapy has increased survival. Despite improved outcomes, many children develop reduced cardiac function and heart failure requiring transplantation. Human cardiac progenitor cell (hCPC) therapy has potential to repair the pediatric myocardium through release of reparative factors, but therapy suffers from limited hCPC retention and functionality. Decellularized cardiac extracellular matrix hydrogel (cECM) improves heart function in animals, and human trials are ongoing. In the present study, a 3D-bioprinted patch containing cECM for delivery of pediatric hCPCs is developed. Cardiac patches are printed with bioinks composed of cECM, hCPCs, and gelatin methacrylate (GelMA). GelMA-cECM bioinks print uniformly with a homogeneous distribution of cECM and hCPCs. hCPCs maintain >75% viability and incorporation of cECM within patches results in a 30-fold increase in cardiogenic gene expression of hCPCs compared to hCPCs grown in pure GelMA patches. Conditioned media from GelMA-cECM patches show increased angiogenic potential (>2-fold) over GelMA alone, as seen by improved endothelial cell tube formation. Finally, patches are retained on rat hearts and show vascularization over 14 d in vivo. This work shows the successful bioprinting and implementation of cECM-hCPC patches for potential use in repairing damaged myocardium

Effects of a Fluorescent Myosin Light Chain Phosphatase Inhibitor on Prostate Cancer Cells

Myosin light chain phosphatase (MLCP) is an enzyme important to regulation of cell cycle and motility that is shown to be upregulated in aggressive prostate cancer cells and tissue. We developed a fluorescent small molecule inhibitor of MLCP using structure based design in recombinant protein phosphatase 1C. Several best fit compounds were synthesized and evaluated by their inhibition of MLCP/32P-MLC dephosphorylation, which resulted in the identification of novel MLCP inhibitors. Androgen dependent (AD) and castration resistant prostate cancer cell (CRPC) lines were treated with the lead inhibitor resulting in decreased growth rate, reduced DNA synthesis, and G2/M cell cycle arrest. Moreover, CRPC cell lines showed an increased sensitivity to drug treatment having GI50 values four times lower than the AD prostate cancer cell line. This was reinforced by reduced BrdU DNA incorporation into CRPC cells compared to AD cells. β-actin disruption was also seen at much lower drug concentrations in CR cells which caused a dose dependent reduction in cellular chemotaxis of PC-3 cells. Since there are currently few clinical therapeutics targeting CR prostate cancer, MLCP represents a new target for preclinical and clinical development of new potential therapeutics which inhibit this disease phenotype

Noncommutative Complex Scalar Field and Casimir Effect

A noncommutative complex scalar field, satisfying the deformed canonical commutation relations proposed by Carmona et al. [27]-[31], is constructed. Using these noncommutative deformed canonical commutation relations, a model describing the dynamics of the noncommutative complex scalar field is proposed. The noncommutative field equations are solved, and the vacuum energy is calculated to the second order in the parameter of noncommutativity. As an application to this model, the Casimir effect, due to the zero point fluctuations of the noncommutative complex scalar field, is considered. It turns out that in spite of its smallness, the noncommutativity gives rise to a repulsive force at the microscopic level, leading to a modifed Casimr potential with a minimum at the point amin= racine(5/84){\pi}{\theta}.Comment: Revtex style, 28 page

Vacuum fluctuation force on a rigid Casimir cavity in a gravitational field

We discuss the possibility of verifying the equivalence principle for the zero-point energy of quantum electrodynamics, by evaluating the force, produced by vacuum fluctuations, acting on a rigid Casimir cavity in a weak gravitational field. The resulting force has opposite direction with respect to the gravitational acceleration; the order of magnitude for a multi-layer cavity configuration is derived and experimental feasibility is discussed, taking into account current technological resources.Comment: 13 pages, Latex. In the revised version, the presentation has been improve

Taking Blockchain Seriously

In the present techno-political moment it is clear that ignoring or dismissing the hype surrounding blockchain is unwise, and certainly for regulatory authorities and governments who must keep a grip on the technology and those promoting it, in order to ensure democratic accountability and regulatory legitimacy within the blockchain ecosystem and beyond. Blockchain is telling (and showing) us something very important about the evolution of capital and neoliberal economic reason, and the likely impact in the near future on forms and patterns of work, social organization, and, crucially, on communities and individuals who lack influence over the technologies and data that increasingly shape and control their lives. In this short essay I introduce some of the problems in the regulation of blockchain and offer counter-narratives aimed at cutting through the hype fuelling the ascendency of this most contemporary of technologies

Analytic Approach to Perturbative QCD

The two-loop invariant (running) coupling of QCD is written in terms of the Lambert W function. The analyticity structure of the coupling in the complex Q^2-plane is established. The corresponding analytic coupling is reconstructed via a dispersion relation. We also consider some other approximations to the QCD beta-function, when the corresponding couplings are solved in terms of the Lambert function. The Landau gauge gluon propagator has been considered in the renormalization group invariant analytic approach (IAA). It is shown that there is a nonperturbative ambiguity in determination of the anomalous dimension function of the gluon field. Several analytic solutions for the propagator at the one-loop order are constructed. Properties of the obtained analytical solutions are discussed.Comment: Latex-file, 19 pages, 2 tables, 51 references, to be published in Int. J. Mod. Phys.

Identification and Characterization of a New Tubulin-Binding

We studied the mechanism of action of 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (JG-03-14) and found that it is a potent microtubule depolymerizer. JG-03-14 caused a dose-dependent loss of cellular microtubules, formation of aberrant mitotic spindles, accumulation of cells in the G2/M phase of the cell cycle, and Bcl-2 phosphorylation. These events culminated in the initiation of apoptosis, as evidenced by the caspase 3-dependent cleavage of poly(ADP-ribose) polymerase (PARP). JG-03-14 has antiproliferative activity against a wide range of cancer cell lines, with an average IC50 value of 62 nM, and it is a poor substrate for transport by P-glycoprotein. JG-03-14 inhibited the polymerization of purified tubulin in vitro, consistent with a direct interaction between the compound and tubulin. JG-03-14 potently inhibited the binding of [3H]colchicine to tubulin, suggesting that it bound to tubulin at a site overlapping the colchicine site. JG-03-14 had antitumor effects in the PC3 xenograft model, in which it caused greater than 50% reduction in tumor burden after 14 days of treatment. Molecular modeling studies indicated that the dimethoxyphenyl group of JG-03-14 occupies a space similar to that of the trimethoxyphenyl group of colchicine. However, the 2,3,5-trisubstituted pyrrole group, which is connected to the dimethoxyphenyl moiety, interacted with both α and β tubulin in space not shared with colchicine, suggesting significant differences compared with colchicine in the mechanism of binding to tubulin. Our results suggest that this tetransubstituted pyrrole represents a new, biologically active chemotype for the colchicine site on tubulin

Infrared renormalons and analyticity structure in pQCD

Relation between the infrared renormalons, the Borel resummation prescriptions, and the analyticity structure of Green functions in perturbative QCD (pQCD) is investigated. A specific recently suggested Borel resummation prescription resulted in the Principal Value and an additional power-suppressed correction that is consistent with the Operator Product Expansion. Arguments requiring the finiteness of the result for any power coefficient of the leading infrared renormalon, and the consistency in the case of the absence of that renormalon, require that this prescription be modified. The apparently most natural modification leads to the result represented by the Principal Value. The analytic structure of the amplitude in the complex coupling plane, obtained in this way, is consistent with that obtained in the literature by other methods.Comment: 6 pages, revtex4, 1 eps-figure; improved version - the paragraph containing Eqs.(18) and (19) is new, as well as the next paragraph; the Title modified; some references added; version to appear in Phys. Rev.

Transport properties of heterogeneous materials derived from Gaussian random fields: Bounds and Simulation

We investigate the effective conductivity ($\sigma_e$) of a class of amorphous media defined by the level-cut of a Gaussian random field. The three point solid-solid correlation function is derived and utilised in the evaluation of the Beran-Milton bounds. Simulations are used to calculate $\sigma_e$ for a variety of fields and volume fractions at several different conductivity contrasts. Relatively large differences in $\sigma_e$ are observed between the Gaussian media and the identical overlapping sphere model used previously as a `model' amorphous medium. In contrast $\sigma_e$ shows little variability between different Gaussian media.Comment: 15 pages, 14 figure

Designing bioinspired green nanosilicas using statistical and machine learning approaches

The in vitro bioinspired synthesis of silica, inspired from in vivo biosilicification, is a sustainable alternative to the conventional production of high value porous silicas. The short reaction time, mild reaction conditions of room temperature and its use of benign precursors make this an eco-friendly, economical and scalable route with great industrial potential. However, a systematic optimisation of critical process parameters and material attributes of bioinspired silica is lacking. Specifically, statistical approaches such as design of experiments (DoE) and global sensitivity analysis (GSA) using machine learning could be highly effective but have not been applied to this “green” nanomaterial yet. Herein, for the first time, a sequential DoE strategy was developed with pre-screening experiments to outline the feasible design space. A successive screening using 23 full factorial design determined that from the initially investigated three factors (the ratio of the reactant concentrations, pH, and precursor concentration), only the first two were statistically significant for silica yield and surface area. The subsequent concatenated optimisation using central composite design located a maximum yield of 90 mol% and a maximum surface area of 300–400 m2 g−1. Since for successful commercialisation, high yields and large specific surface areas are desirable, their simultaneous optimisation was also achieved with high predictability regression models. For complementation, a variance-based GSA was successfully applied to bioinspired silica for the first time. This method rapidly identified key parameters and interactions that control the physicochemical properties and provided insights in the wide parameter space, which was validated by the extensive DoE campaign. This work is the starting point in holistically modelling the multidimensional factor–response relationship over a large experimental space in order to complement efforts for resource-efficient product and process development and optimisation of bioinspired silica and beyond