The transition probability density function of the low-pass filtered random telegraph signal†

The transition probability density function p(y/y₀) of the output y(t) of an RC filter driven by the random telegraph signal is derived. The results extend the previous work of Wonham (1959) who treated the special case y_o = 0. An alternate method of solution to Wonham's procedure is given whereby the transition density is obtained from the solution of a set of Fokker-Planck-Kolmogorov equations.     

Fixed-order FIR approximation of linear systems from quantized input and output data

The problem of identifying a fixed-order FIR approximation of linear systems with unknown structure, assuming that both input and output measurements are subjected to quantization, is dealt with in this paper. A fixed-order FIR model providing the best approximation of the input–output relationship is sought by minimizing the worst-case distance between the output of the true system and the modeled output, for all possible values of the input and output data consistent with their quantized measurements. The considered problem is firstly formulated in terms of robust optimization. Then, two different algorithms to compute the optimum of the formulated problem by means of linear programming techniques are presented. The effectiveness of the proposed approach is illustrated by means of a simulation example.     

Polymers used to influence cell fate in 3D geometry: New trends

The extracellular matrix (ECM) is a hydrogel-like structure comprised of several different biopolymers, encompassing a wide range of biological, chemical, and mechanical properties. The composition, organization, and assembly of the ECM play a critical role in cell function. Cellular behavior is guided by interactions that occur between cells and their local microenvironment, and this interrelationship plays a significant role in determining physiological functions. Bioengineering approaches have been developed to mimic native tissue microenvironments by fabricating novel bioactive hydrogel scaffolds. This review explores material designs and fabrication approaches that are guiding the design of hydrogels as tissue engineered scaffolds. As the fundamental biology of the cellular microenvironment is often the inspiration for material design, the review focuses on modifications to control bioactive cues such as adhesion molecules and growth factors, and summarizes the current applications of biomimetic scaffolds that have been used in vitro as well as in vivo.     

An improved damage diagnostic technique based on Singular Spectrum Analysis and time series models

An approach to enhance the sensitivity of the damage index using the prediction errors of autoregressive – autoregressive exogenous models by augmenting Singular Spectrum Analysis (SSA) to detect and locate minor damage is presented. Numerical simulation studies are carried out by considering a simply supported beam with single and multiple cracks. An experimental study on a reinforced cement concrete beam has been carried out to validate the technique using different levels of damage. The studies emphasise that the SSA improves the sensitivity of the damage index for detection and also localisation, handling environmental/operational variability and measurement noise.     

Modelling the combined effects of salt,sorbic acid and nisin on the probability of growth of Clostridium sporogenes in a controlled environment (nutrient broth)

The safe preservation of new generation foods (high moisture, low salt, high pH and shelf stable under ambient conditions) is microbiologically challenging. The growth of Clostridium botulinum in low acid foods is a hazard for consumers. In this study the combined effect of salt (sodium chloride) (0–4% w/v), potassium sorbate (0–4% w/v) and nisin (0–300 ppm) at two different pHs (5.5 and 7) on the probability of growth of Clostridium sporogenes spores, as a non-toxigenic surrogate of C. botulinum, was evaluated in nutrient broth. Nutrient broth was used as it can easily and accurately be adjusted and controlled in terms of composition, and allows more rapid growth than is observed in food. The aims of this study were to develop probability of growth models in which the logit is expressed as a function of the concentrations of the selected preservatives. The developed models fit the data adequately. The c-values models were close to 1, indicating good predictive power. This indicates the performance of models would be satisfactory. The results of this study indicated that salt, potassium sorbate and nisin had significant inhibitory effects on the growth of C. sporogenes in high moisture (>95%) and high pH conditions (pH > 4.5). Combinations of the selected preservatives were more effective than any of them individually. The inhibitory effects of all three preservatives in the current study were pH dependent. Less stringent combinations of preservative concentrations were required experimentally to stop growth at pH 5.5 compared with pH 7.     

Development of in vitro models to demonstrate the ability of PecSys®, an in situ nasal gelling technology,to reduce nasal run-off and drip

Many of the increasing number of intranasal products available for either local or systemic action can be considered sub-optimal, most notably where nasal drip or run-off give rise to discomfort/tolerability issues or reduced/variable efficacy. PecSys, an in situ gelling technology, contains low methoxy (LM) pectin which gels due to interaction with calcium ions present in nasal fluid. PecSys is designed to spray readily, only forming a gel on contact with the mucosal surface. The present study employed two in vitro models to confirm that gelling translates into a reduced potential for drip/run-off: (i) Using an inclined TLC plate treated with a simulated nasal electrolyte solution (SNES), mean drip length [±SD, n = 10] was consistently much shorter for PecSys (1.5?±?0.4?cm) than non-gelling control (5.8?±?1.6?cm); (ii) When PecSys was sprayed into a human nasal cavity cast model coated with a substrate containing a physiologically relevant concentration of calcium, PecSys solution was retained at the site of initial deposition with minimal redistribution, and no evidence of run-off/drip anteriorly or down the throat. In contrast, non-gelling control was significantly more mobile and consistently redistributed with run-off towards the throat. Conclusion: In both models PecSys significantly reduced the potential for run-off/drip ensuring that more solution remained at the deposition site. In vivo, this enhancement of retention will provide optimum patient acceptability, modulate drug absorption and maximize the ability of drugs to be absorbed across the nasal mucosa and thus reduce variability in drug delivery.     

Crystal Structure Determination and Mutagenesis Analysis of the Ene Reductase NCR

The crystal structure of the “ene” nicotinamide‐dependent cyclohexenone reductase (NCR) from Zymomonas mobilis (PDB ID: 4A3U) has been determined in complex with acetate ion, FMN, and nicotinamide, to a resolution of 1.95 Å. To study the activity and enantioselectivity of this enzyme in the bioreduction of activated α,β‐unsaturated alkenes, the rational design methods site‐ and loop‐directed mutagenesis were applied. Based on a multiple sequence alignment of various members of the Old Yellow Enzyme family, eight single‐residue variants were generated and investigated in asymmetric bioreduction. Furthermore, a structural alignment of various ene reductases predicted four surface loop regions that are located near the entrance of the active site. Four NCR loop variants, derived from loop‐swapping experiments with OYE1 from Saccharomyces pastorianus, were analysed for bioreduction. The three enzyme variants, P245Q, D337Y and F314Y, displayed increased activity compared to wild‐type NCR towards the set of substrates tested. The active‐site mutation Y177A demonstrated a clear influence on the enantioselectivity. The loop‐swapping variants retained reduction efficiency, but demonstrated decreased enzyme activity compared with the wild‐type NCR ene reductase enzyme.     

Modeling Human Liver Biology Using Stem Cell-Derived Hepatocytes

Stem cell-derived hepatocytes represent promising models to study human liver biology and disease. This concise review discusses the recent progresses in the field, with a focus on human liver disease, drug metabolism and virus infection.