Quantifying the efficacy of voltage protocols in characterising ion channel kinetics: A novel information-theoretic approach.

Voltage-clamp experiments are commonly utilised to characterise cellular ion channel kinetics. In these experiments, cells are stimulated using a known time-varying voltage, referred to as the voltage protocol, and the resulting cellular response, typically in the form of current, is measured. Parameters of models that describe ion channel kinetics are then estimated by solving an inverse problem which aims to minimise the discrepancy between the predicted response of the model and the actual measured cell response. In this paper, a novel framework to evaluate the information content of voltage-clamp protocols in relation to ion channel model parameters is presented. Additional quantitative information metrics that allow for comparisons among various voltage protocols are proposed. These metrics offer a foundation for future optimal design frameworks to devise novel, information-rich protocols. The efficacy of the proposed framework is evidenced through the analysis of seven voltage protocols from the literature. By comparing known numerical results for inverse problems using these protocols with the information-theoretic metrics, the proposed approach is validated. The essential steps of the framework are: (i) generate random samples of the parameters from chosen prior distributions; (ii) run the model to generate model output (current) for all samples; (iii) construct reduced-dimensional representations of the time-varying current output using proper orthogonal decomposition (POD); (iv) estimate information-theoretic metrics such as mutual information, entropy equivalent variance, and conditional mutual information using non-parametric methods; (v) interpret the metrics; for example, a higher mutual information between a parameter and the current output suggests the protocol yields greater information about that parameter, resulting in improved identifiability; and (vi) integrate the information-theoretic metrics into a single quantitative criterion, encapsulating the protocol's efficacy in estimating model parameters.

A new model for evaluating pressure-induced vascular tone in small cerebral arteries.

The capacity of small cerebral arteries (SCAs) to adapt to pressure fluctuations has a fundamental physiological role and appears to be relevant in different pathological conditions. Here, we present a new computational model for quantifying the link, and its contributors, between luminal pressure and vascular tone generation in SCAs. This is assembled by combining a chemical sub-model, representing pressure-induced smooth muscle cell (SMC) signalling, with a mechanical sub-model for the tone generation and its transduction at tissue level. The devised model can accurately reproduce the impact of luminal pressure on different cytoplasmic components involved in myogenic signalling, both in the control case and when combined with some specific pharmacological interventions. Furthermore, the model is also able to capture and predict experimentally recorded pressure-outer diameter relationships obtained for vessels under control conditions, both in a Ca 2 + -free bath and under drug inhibition. The modularity of the proposed framework allows the integration of new components for the study of a broad range of processes involved in the vascular function.

On the Ca2＋ elevation in vascular endothelial cells due to inositol trisphosphate-sensitive store receptors activation: A data-driven modeling approach.

Agonist-induced Ca2+ signaling is essential for the regulation of many vital functions in endothelial cells (ECs). A broad range of stimuli elevate the cytosolic Ca2＋ concentration by promoting a pathway mediated by inositol 1,4,5 trisphosphate (IP3) which causes Ca2＋ release from intracellular stores. Despite its importance, there are very few studies focusing on the quantification of such dynamics in the vascular endothelium. Here, by using data from isolated ECs, we established a minimalistic modeling framework able to quantitatively capture the main features (averaged over a cell population) of the cytosolic Ca2＋ response to different IP3 stimulation levels. A suitable description of Ca2＋-regulatory function of inositol 1,4,5 trisphosphate receptors (IP3Rs) and corresponding parameter space are identified by comparing the different model variants against experimental mean population data. The same approach is used to numerically assess the relevance of cytosolic Ca2＋ buffering, as well as Ca2＋ store IP3-sensitivity in the overall cell dynamics. The variability in the dynamics' features observed across the population can be explained (at least in part) through variation of certain model parameters (such as buffering capacity or Ca2＋ store sensitivity to IP3). The results, in terms of experimental fitting and validation, support the proposed minimalistic model as a reference framework for the quantification of the EC Ca2＋ dynamics induced by IP3Rs activation.

Excited-state properties of 6-methoxyflavone in the presence of halide ions in aqueous media.

The present work investigated the influence of different halides on the excited state dynamics of 6-methoxyflavone (6MF) in an aqueous solution with steady-state and time-resolved techniques. On successive addition of I-and Br-ions, the fluorescence of 6MF quenched significantly, whereas the respective ions do not change the maximum fluorescence band. Fluorescence of 6MF was quenched 66% by I-ions and 34% by Br-ions. In a pure aqueous medium, both the H-bonded: CT and protonated species of 6MF participate in the quenching of fluorescence. The quenching process was categorized by Stern-Volmer (S-V) and Lehrer equations. Quenching parameters such as KSV, KSV-Land kqwere higher for I-ions than Br-ions. The decrease in fluorescence intensity and a reduction in fluorescence lifetime suggested the dynamic nature of quenching by I-ions following the electron transfer mechanism. Fluorescence quenching of 6MF has also been observed in the acidic medium in the presence of different halides. Thus, the study reveals that 6MF is responsive towards I-ions in a wide range of pH, specifically in a purely aqueous environment (pH∼7), hence important for sensing/detection applications.

Strain energy density as a Gaussian process and its utilization in stochastic finite element analysis: application to planar soft tissues.

Data-based approaches are promising alternatives to the traditional analytical constitutive models for solid mechanics. Herein, we propose a Gaussian process (GP) based constitutive modeling framework, specifically focusing on planar, hyperelastic and incompressible soft tissues. The strain energy density of soft tissues is modeled as a GP, which can be regressed to experimental stress-strain data obtained from biaxial experiments. Moreover, the GP model can be weakly constrained to be convex. A key advantage of a GP-based model is that, in addition to the mean value, it provides a probability density (i.e. associated uncertainty) for the strain energy density. To simulate the effect of this uncertainty, a non-intrusive stochastic finite element analysis (SFEA) framework is proposed. The proposed framework is verified against an artificial dataset based on the Gasser-Ogden-Holzapfel model and applied to a real experimental dataset of a porcine aortic valve leaflet tissue. Results show that the proposed framework can be trained with limited experimental data and fits the data better than several existing models. The SFEA framework provides a straightforward way of using the experimental data and quantifying the resulting uncertainty in simulation-based predictions.

A Bayesian constitutive model selection framework for biaxial mechanical testing of planar soft tissues: Application to porcine aortic valves.

A variety of constitutive models have been developed for soft tissue mechanics. However, there is no established criterion to select a suitable model for a specific application. Although the model that best fits the experimental data can be deemed the most suitable model, this practice often can be insufficient given the inter-sample variability of experimental observations. Herein, we present a Bayesian approach to calculate the relative probabilities of constitutive models based on biaxial mechanical testing of tissue samples. Forty-six samples of porcine aortic valve tissue were tested using a biaxial stretching setup. For each sample, seven ratios of stresses along and perpendicular to the fiber direction were applied. The probabilities of eight invariant-based constitutive models were calculated based on the experimental data using the proposed model selection framework. The calculated probabilities showed that, out of the considered models and based on the information available through the utilized experimental dataset, the May-Newman model was the most probable model for the porcine aortic valve data. When the samples were further grouped into different cusp types, the May-Newman model remained the most probable for the left- and right-coronary cusps, whereas for non-coronary cusps two models were found to be equally probable: the Lee-Sacks model and the May-Newman model. This difference between cusp types was found to be associated with the first principal component analysis (PCA) mode, where this mode's amplitudes of the non-coronary and right-coronary cusps were found to be significantly different. Our results show that a PCA-based statistical model can capture significant variations in the mechanical properties of soft tissues. The presented framework is applicable to other tissue types, and has the potential to provide a structured and rational way of making simulations population-based.

Effect of halide ions on the fluorescence properties of 3-aminoquinoline in aqueous medium.

Fluorescence (FL) quenching of 3-aminoquinoline (3AQ) by halide ions Cl - Br - and I - has been explored in an aqueous acidic medium using the steady-state and time-domain FL measurement techniques. The halide ions showed no significant change in the absorption spectra of 3AQ in an aqueous acidic medium. The FL intensity was strongly quenched by I - ions and the order of FL quenching by halide ions was I - > Br - > Cl - . The decrease in FL lifetime along with the reduction in FL intensity of 3AQ suggested the dynamic nature of quenching. The obtained K SV values were 328 M - 1 for I - ions and 119 M - 1 for Br - ions and the k q values were ~ 1.66 × 10 10 M - 1 s - 1 and 6.02 × 10 9 M - 1 s - 1 , respectively. The observations suggested that the likely governing mechanism for FL quenching may be an electron transfer process and the involvement of the heavy atom effects.

A low dimensional surrogate model for a fast estimation of strain in the thrombus during a thrombectomy procedure.

BACKGROUND: Intra-arterial thrombectomy is the main treatment for acute ischemic stroke due to large vessel occlusions and can consist in mechanically removing the thrombus with a stent-retriever. A cause of failure of the procedure is the fragmentation of the thrombus and formation of micro-emboli, difficult to remove. This work proposes a methodology for the creation of a low-dimensional surrogate model of the mechanical thrombectomy procedure, trained on realizations from high-fidelity simulations, able to estimate the evolution of the maximum first principal strain in the thrombus. METHOD: A parametric finite-element model was created, composed of a tapered vessel, a thrombus, a stent-retriever and a catheter. A design of experiments was conducted to sample 100 combinations of the model parameters and the corresponding thrombectomy simulations were run and post-processed to extract the maximum first principal strain in the thrombus during the procedure. Then, a surrogate model was built with a combination of principal component analysis and Kriging. RESULTS: The surrogate model was chosen after a sensitivity analysis on the number of principal components and was tested with 10 additional cases. The model provided predictions of the strain curves with correlation above 0.9 and a maximum error of 28%, with an error below 20% in 60% of the test cases. CONCLUSIONS: The surrogate model provides nearly instantaneous estimates and constitutes a valuable tool for evaluating the risk of thrombus rupture during pre-operative planning for the treatment of acute ischemic stroke.

Spectroscopic investigation on the interaction of direct yellow-27 with protein (BSA).

Direct yellow 27 (DY-27) interaction with bovine serum albumin (BSA) was investigated using multi-spectroscopic techniques to understand the toxicity mechanism. Fluorescence quenching of BSA by DY-27 was observed as a result of the formation of a BSA-DY27 complex with a binding constant of 1.19 × 105M-1and followed a static quenching mechanism with a quenching constant Ksvof 7.25 × 104M-1. The far UV circular dichroism spectra revealed the conformational changes in the secondary structure of BSA in the presence of DY-27. The calculated average lifetime of BSA is 6.04 ns and is nearly constant (5.99 ns) in the presence of dye and supports the proposed quenching mechanism. The change in free energy (ΔG) was calculated to be -28.96 kJ mol-1and confirmed the spontaneity of the binding process. Further, docking studies have been conducted to gain more insights into the interactions between DY-27 and serum albumin.

Reliable Numerical Models of Nickel-Titanium Stents: How to Deduce the Specific Material Properties from Testing Real Devices.

The current interest of those dealing with medical research is the preparation of digital twins. In this frame, the first step to accomplish is the preparation of reliable numerical models. This is a challenging task since it is not common to know the exact device geometry and material properties unless in studies performed in collaboration with the manufacturer. The particular case of modeling Ni-Ti stents can be highlighted as a worst-case scenario due to both the complex geometrical features and non-linear material response. Indeed, if the limitations in the description of the geometry can be overcome, many difficulties still exist in the assessment of the material, which can vary according to the manufacturing process and requires many parameters for its description. The purpose of this work is to propose a coupled experimental and computational workflow to identify the set of material properties in the case of commercially-resembling Ni-Ti stents. This has been achieved from non-destructive tensile tests on the devices compared with results from Finite Element Analysis (FEA). A surrogate modeling approach is proposed for the identification of the material parameters, based on a minimization problem on the database of responses of Ni-Ti materials obtained with FEA with a series of different parameters. The reliability of the final result was validated through the comparison with the output of additional experiments.

Spectral and time domain fluorescence spectroscopy of gentisic acid molecule in protic and aprotic polymer matrix.

In the present work, the effect of polymer microenvironment on the photophysics of gentisic acid molecule [2,5-dihydroxybenzoic acid] (GA), steady-state and time-domain fluorescence measurements at different pH conditions were carried out in protic [polyvinyl alcohol PVA] and aprotic [polymethyl methacrylate (PMMA)] polymer matrices. Change in the proticity of the microenvironment of the polymer traps different ionic species along with the neutral form of rotamer P and R conformers of GA molecule, are found to be responsible for the change in the spectral, multi-exponential decay behaviour. In protic polymer, the appearance of a single emission band indicates, dissociation of the GA molecule is very high, and it present as a monoanion along with hydrogen-bonded P and R rotamers. However, in the basic polymer film, most of the conformers of R converted to the anion. In contrast, protonation slows down the dissociation of both P and R forms in the acidic film. Unlike PVA matrix, in PMMA, dual emission band appears due to slow dissociation of GA molecule and hydrogen-bonded rotamer P, and R form exists with monoanion species. The magnitude of large stokes shifted red emission due to excited-state intramolecular proton transfers (ESIPT) found grater in rotamer P compared to its anionic species (green emission) and a blue emission corresponds to rotamer R.

Multiscale modelling of Potts shunt as a potential palliative treatment for suprasystemic idiopathic pulmonary artery hypertension: a paediatric case study.

Potts shunt (PS) was suggested as palliation for patients with suprasystemic pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. PS, however, can result in poorly understood mortality. Here, a patient-specific geometrical multiscale model of PAH physiology and PS is developed for a paediatric PAH patient with stent-based PS. In the model, 7.6mm-diameter PS produces near-equalisation of the aortic and PA pressures and [Formula: see text] (oxygenated vs deoxygenated blood flow) ratio of 0.72 associated with a 16% decrease of left ventricular (LV) output and 18% increase of RV output. The flow from LV to aortic arch branches increases by 16%, while LV contribution to the lower body flow decreases by 29%. Total flow in the descending aorta (DAo) increases by 18% due to RV contribution through the PS with flow into the distal PA branches decreasing. PS induces 18% increase of RV work due to its larger stroke volume pumped against lower afterload. Nonetheless, larger RV work does not lead to increased RV end-diastolic volume. Three-dimensional flow assessment demonstrates the PS jet impinging with a high velocity and wall shear stress on the opposite DAo wall with the most of the shunt flow being diverted to the DAo. Increasing the PS diameter from 5mm up to 10mm results in a nearly linear increase in post-operative shunt flow and a nearly linear decrease in shunt pressure-drop. In conclusion, this model reasonably represents patient-specific haemodynamics pre- and post-creation of the PS, providing insights into physiology of this complex condition, and presents a predictive tool that could be useful for clinical decision-making regarding suitability for PS in PAH patients with drug-resistant suprasystemic PAH.

Solvatochromism and estimation of ground and excited state dipole moments of 6-aminoquinoline.

The spectral behaviour of 6AQ was investigated using fluorescence spectroscopy in several polar and non-polar solvents. Both the absorption and fluorescence spectra displayed solvatochromism. The Stokes shift increased significantly with increasing solvent polarity and signifies a more polar excited state with possible change in the excited state (ES) geometry. The involvement of π→π∗ transition was observed. The ground state (GS) and excited state (ES) dipole moments were determined by the solvatochromic shift method using Bilot-Kawaski, Lippert-Mataga, Kawski-Chamma-Viallet, and Reichardt equations. The experimental value of GS dipole moment matches closely with the theoretical value computed using DFT/B3LYP/6-311G(d,p). The ES dipole moment is higher than the GS dipole moment. Besides, the solvatochromic study reveals that the ES of 6AQ is more polarized than the GS due to intramolecular charge transfer (ICT), possibly aided by a change in the geometry of the molecule in the ES. The influence of the non-specific and specific interactions in the photophysical properties of the titled molecule was analyzed using the Catalan scale. The study shows that 6AQ has reasonable band-gap energy and good CIE chromaticity coordinate in the blue region close to the national television standard committee system (NTSC) for the ideal blue CIE coordinate. Therefore, future research into 6AQ as a source of light-emitting diodes and fluorescent sensors may have potential applications in the field of optoelectronics.

Fluorescence Spectral Properties of Methyl Orange in Homogeneous Media.

The methyl orange [C14H14N3SO3Na], an azo dye exhibited strong emission and large Stokes shift in various solvents, and the largest shift (Δλ = 125.51nm or Δν = 9297cm-1) was obtained in the water. The UV-visible spectra of the dye showed the absorption in the range (33,333 - 20,000) cm-1. We found that solvent effects on the absorption wavelength are consistent. The bathochromic shift in water and the hypsochromic shift in methanol observed in the absorption (43 nm) as well as in the fluorescence (42 nm) spectra predict the strong solute-solvent interaction. The fluorescence quantum yield (ɸf) was decreased from 24% in DMSO to 5% in water. The fluorescent properties of this dye are strongly solvent dependent, the wavelength of minimum fluorescence emission (λem = 435.51nm) shifts to the red. The maximum and minimum calculated oscillator strength is 32% with (Ɛmax = 29011 M-1cm-1) and 11% (Ɛmax = 6682 M-1cm-1) in methanol and DMSO, respectively. Protonated solvents without exception give a shorter lifetime and lower quantum yield. The average excited-state lifetime of the dye was found maximum (τav = 5.36 ns) in DMSO. Also, fluorescence lifetime was combined to deduce the radiative and non-radiative decay rate.

A proof of concept study for machine learning application to stenosis detection.

This proof of concept (PoC) assesses the ability of machine learning (ML) classifiers to predict the presence of a stenosis in a three vessel arterial system consisting of the abdominal aorta bifurcating into the two common iliacs. A virtual patient database (VPD) is created using one-dimensional pulse wave propagation model of haemodynamics. Four different machine learning (ML) methods are used to train and test a series of classifiers-both binary and multiclass-to distinguish between healthy and unhealthy virtual patients (VPs) using different combinations of pressure and flow-rate measurements. It is found that the ML classifiers achieve specificities larger than 80% and sensitivities ranging from 50 to 75%. The most balanced classifier also achieves an area under the receiver operative characteristic curve of 0.75, outperforming approximately 20 methods used in clinical practice, and thus placing the method as moderately accurate. Other important observations from this study are that (i) few measurements can provide similar classification accuracies compared to the case when more/all the measurements are used; (ii) some measurements are more informative than others for classification; and (iii) a modification of standard methods can result in detection of not only the presence of stenosis, but also the stenosed vessel. Graphical Abstract An overview of methodology fo the creation of virtual patients and their classification.

Structural, Electronic and NLO Properties of 6-aminoquinoline: A DFT/TD-DFT Study.

A computational study based on the DFT/TD-DFT approach was performed to explore various properties of 6-aminoquinoline (6AQ). The geometrical parameters, molecular orbitals (MOs), electronic spectra, electrostatic potential, molecular surface, reactivity parameters and thermodynamic properties of 6AQ were explored. The absorption and emission spectra of 6AQ in solvents have been estimated by TD-DFT coupled with the PCM model and correlated with the available experimental results. Depending on the solvents, the computed absorption maxima of 6AQ were noticed between 327 nm - 340 nm and ascribed to [Formula: see text] transition. The simulated emission maxima were obtained between 389 to 407 nm and ascribed to [Formula: see text] transition. On increasing the solvent polarity, both the emission and absorption maxima showed a bathochromic shift. The LUMO and HOMO were localized on the entire molecule. It was observed that the lowest excited state is possibly the [Formula: see text] charge-transfer (CT) state. The natural bonding orbital (NBO) study points out that ICT plays a significant role in stabilizing the molecular system. Moreover, the NLO (nonlinear optical) properties (polarizability, first-order hyperpolarizability and dipole moment) were computed using different hybrid functionals. The estimated values indicate that 6AQ can be considered a desirable molecule for further studies of the NLO applications.

A physiologically realistic virtual patient database for the study of arterial haemodynamics.

This study creates a physiologically realistic virtual patient database (VPD), representing the human arterial system, for the primary purpose of studying the effects of arterial disease on haemodynamics. A low dimensional representation of an anatomically detailed arterial network is outlined, and a physiologically realistic posterior distribution for its parameters constructed through the use of a Bayesian approach. This approach combines both physiological/geometrical constraints and the available measurements reported in the literature. A key contribution of this work is to present a framework for including all such available information for the creation of virtual patients (VPs). The Markov Chain Monte Carlo (MCMC) method is used to sample random VPs from this posterior distribution, and the pressure and flow-rate profiles associated with each VP computed through a physics based model of pulse wave propagation. This combination of the arterial network parameters (representing a virtual patient) and the haemodynamics waveforms of pressure and flow-rates at various locations (representing functional response and potential measurements that can be acquired in the virtual patient) makes up the VPD. While 75,000 VPs are sampled from the posterior distribution, 10,000 are discarded as the initial burn-in period of the MCMC sampler. A further 12,857 VPs are subsequently removed due to the presence of negative average flow-rate, reducing the VPD to 52,143. Due to undesirable behaviour observed in some VPs-asymmetric under- and over-damped pressure and flow-rate profiles in left and right sides of the arterial system-a filter is proposed to remove VPs showing such behaviour. Post application of the filter, the VPD has 28,868 subjects. It is shown that the methodology is appropriate by comparing the VPD statistics to those reported in literature across real populations. Generally, a good agreement between the two is found while respecting physiological/geometrical constraints.

A framework for incorporating 3D hyperelastic vascular wall models in 1D blood flow simulations.

We present a novel framework for investigating the role of vascular structure on arterial haemodynamics in large vessels, with a special focus on the human common carotid artery (CCA). The analysis is carried out by adopting a three-dimensional (3D) derived, fibre-reinforced, hyperelastic structural model, which is coupled with an axisymmetric, reduced order model describing blood flow. The vessel transmural pressure and lumen area are related via a Holzapfel-Ogden type of law, and the residual stresses along the thickness and length of the vessel are also accounted for. After a structural characterization of the adopted hyperelastic model, we investigate the link underlying the vascular wall response and blood-flow dynamics by comparing the proposed framework results against a popular tube law. The comparison shows that the behaviour of the model can be captured by the simpler linear surrogate only if a representative value of compliance is applied. Sobol's multi-variable sensitivity analysis is then carried out in order to identify the extent to which the structural parameters have an impact on the CCA haemodynamics. In this case, the local pulse wave velocity (PWV) is used as index for representing the arterial transmission capacity of blood pressure waveforms. The sensitivity analysis suggests that some geometrical factors, such as the stress-free inner radius and opening angle, play a major role on the system's haemodynamics. Subsequently, we quantified the differences in haemodynamic variables obtained from different virtual CCAs, tube laws and flow conditions. Although each artery presents a distinct vascular response, the differences obtained across different flow regimes are not significant. As expected, the linear tube law is unable to accurately capture all the haemodynamic features characterizing the current model. The findings from the sensitivity analysis are further confirmed by investigating the axial stretching effect on the CCA fluid dynamics. This factor does not seem to alter the pressure and flow waveforms. On the contrary, it is shown that, for an axially stretched vessel, the vascular wall exhibits an attenuation in absolute distension and an increase in circumferential stress, corroborating the findings of previous studies. This analysis shows that the new model offers a good balance between computational complexity and physics captured, making it an ideal framework for studies aiming to investigate the profound link between vascular mechanobiology and blood flow.