Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase/Visfatin Enzymatic Activity Identifies a New Inflammatory Pathway Linked to NAD

Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFα levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders

Methods of model reduction for large-scale biological systems: a survey of current methods and trends

Complex models of biochemical reaction systems have become increasingly common in the systems biology literature. The complexity of such models can present a number of obstacles for their practical use, often making problems difficult to intuit or computationally intractable. Methods of model reduction can be employed to alleviate the issue of complexity by seeking to eliminate those portions of a reaction network that have little or no effect upon the outcomes of interest, hence yielding simplified systems that retain an accurate predictive capacity. This review paper seeks to provide a brief overview of a range of such methods and their application in the context of biochemical reaction network models. To achieve this, we provide a brief mathematical account of the main methods including timescale exploitation approaches, reduction via sensitivity analysis, optimisation methods, lumping, and singular value decomposition-based approaches. Methods are reviewed in the context of large-scale systems biology type models, and future areas of research are briefly discussed

The poly-omics of ageing through individual-based metabolic modelling

Abstract Background Ageing can be classified in two different ways, chronological ageing and biological ageing. While chronological age is a measure of the time that has passed since birth, biological (also known as transcriptomic) ageing is defined by how time and the environment affect an individual in comparison to other individuals of the same chronological age. Recent research studies have shown that transcriptomic age is associated with certain genes, and that each of those genes has an effect size. Using these effect sizes we can calculate the transcriptomic age of an individual from their age-associated gene expression levels. The limitation of this approach is that it does not consider how these changes in gene expression affect the metabolism of individuals and hence their observable cellular phenotype. Results We propose a method based on poly-omic constraint-based models and machine learning in order to further the understanding of transcriptomic ageing. We use normalised CD4 T-cell gene expression data from peripheral blood mononuclear cells in 499 healthy individuals to create individual metabolic models. These models are then combined with a transcriptomic age predictor and chronological age to provide new insights into the differences between transcriptomic and chronological ageing. As a result, we propose a novel metabolic age predictor. Conclusions We show that our poly-omic predictors provide a more detailed analysis of transcriptomic ageing compared to gene-based approaches, and represent a basis for furthering our knowledge of the ageing mechanisms in human cells

On the non-linear response of piezoelectric slabs under weak electric fields: experimental and analytical modelling

Piezoceramic materials exhibit different types of non-linearities depending on the magnitude of the mechanical and electric field strength in the piezoelectric continuum. Some of the non-linearities observed under weak electric fields are the presence of superharmonics in the response spectra, jump phenomena, and so on, especially if the system is excited near resonance. In this article, an analytical solution (in the two-dimensional plane stress domain) for the non-linear response of a rectangular piezoceramic slab has been obtained by the use of Rayleigh-Ritz method and perturbation technique. The eigenfunction obtained from the solution of differential equations of the linear problem has been used as the shape function in the Rayleigh-Ritz method. Forced vibration experiments have been conducted on rectangular piezoceramic slabs of two different materials (e.g. PIC 181 and PIC 255) by applying varying electric field strengths across the thickness, and the displacement and current responses have been measured. Experiments have also been conducted for the first two free in-plane modes in the case of the piezoceramic PIC 181. Analytical solutions have been obtained by using the current formulations and they are found to compare well with those of the experiment. These solutions should serve as a method to validate the finite-element formulations as well as to help in the determination of non-linear material property coefficients for these materials

Analytical solution in 2D domain for nonlinear response of piezoelectric slabs under weak electric fields

Piezoceramic materials exhibit different types of nonlinearities depending upon the magnitude of the mechanical and electric field strength in the continuum. Some of the nonlinearities observed under weak electric fields are: presence Of superharmonics in the response spectra and jump phenomena etc. especially if the system is excited near resonance. In this paper, an analytical Solution (in 2D plane stress domain) for the nonlinear response of a rectangular piezoceramic slab has been obtained by use of Rayleigh-Ritz method and perturbation technique. The eigenfunction obtained from Solution of the differential equation of the linear problem has been Used as the shape function in the Rayleigh-Ritz method. Forced vibration experiments have been conducted oil a rectangular piezoceramic slab by applying varying electric field strengths across the thickness and the results have been compared with those of analytical Solution. The analytical solutions compare well with those of experimental results. These solutions should serve as a method to validate the FE formulations as well as help in the determination of nonlinear material property coefficients for these materials. (C) 200

Time evolution of resistance in response to magnetic field: Evidence of glassy transport in La0.85Sr0.15CoO3

We demonstrate the distinct glassy transport phenomena associated with the phase separated and spin-glass-like phases of La0.85Sr0.15CoO3, prepared under different heat-treatment conditions. The low-temperature annealed (phase-separated) sample, exhibits a small change in resistance, with evolution of time, as compared to the high-temperature annealed (spin glass) one. However, the resistance change as a function of time, in both cases, is well described by a stretched exponential fit, signifying the slow dynamics. Moreover, the ultraviolet spectroscopy study evidences a relatively higher density of states in the vicinity of EF for low-temperature annealed sample and this correctly points to its less semiconducting behavior