Bridging experiments, models and simulations : an integrative approach to validation in computational cardiac electrophysiology

Computational models in physiology often integrate functional and structural information from a large range of spatio-temporal scales from the ionic to the whole organ level. Their sophistication raises both expectations and scepticism concerning how computational methods can improve our understanding of living organisms and also how they can reduce, replace and refine animal experiments. A fundamental requirement to fulfil these expectations and achieve the full potential of computational physiology is a clear understanding of what models represent and how they can be validated. The present study aims at informing strategies for validation by elucidating the complex interrelations between experiments, models and simulations in cardiac electrophysiology. We describe the processes, data and knowledge involved in the construction of whole ventricular multiscale models of cardiac electrophysiology. Our analysis reveals that models, simulations, and experiments are intertwined, in an assemblage that is a system itself, namely the model-simulation-experiment (MSE) system. Validation must therefore take into account the complex interplay between models, simulations and experiments. Key points for developing strategies for validation are: 1) understanding sources of bio-variability is crucial to the comparison between simulation and experimental results; 2) robustness of techniques and tools is a pre-requisite to conducting physiological investigations using the MSE system; 3) definition and adoption of standards facilitates interoperability of experiments, models and simulations; 4) physiological validation must be understood as an iterative process that defines the specific aspects of electrophysiology the MSE system targets, and is driven by advancements in experimental and computational methods and the combination of both.

Development of a new index of balance in adults with intellectual and developmental disabilities

Purposes: The first objective was to propose a new model representing the balance level of adults with intellectual and developmental disabilities (IDD) using Principal Components Analysis (PCA); and the second objective was to use the results from the PCA recorded by regression method to construct and validate summative scales of the standardized values of the index, which may be useful to facilitate a balance assessment in adults with IDD. Methods: A total of 801 individuals with IDD (509 males) mean 33.1±8.5 years old, were recruited from Special Olympic Games in Spain 2009 to 2012. The participants performed the following tests: the timed-stand test, the single leg stance test with open and closed eyes, the Functional Reach Test, the Expanded Timed-Get-up-and-Go Test. Data was analyzed using principal components analysis (PCA) with Oblimin rotation and Kaiser normalization. We examined the construct validity of our proposed two-factor model underlying balance for adults with IDD. The scores from PCA were recorded by regression method and were standardized. Results: The Component Plot and Rotated Space indicated that a two-factor solution (Dynamic and Static Balance components) was optimal. The PCA with direct Oblimin rotation revealed a satisfactory percentage of total variance explained by the two factors: 51.6 and 21.4%, respectively. The median score standardized for component dynamic and static of the balance index for adults with IDD is shown how references values. Conclusions: Our study may lead to improvements in the understanding and assessment of balance in adults with IDD. First, it confirms that a two-factor model may underlie the balance construct, and second, it provides an index that may be useful for identifying the balance level for adults with IDD.

Directional persistence and the optimality of run-and-tumble chemotaxis

E. coli does chemotaxis by performing a biased random walk composed of alternating periods of swimming (runs) and reorientations (tumbles). Tumbles are typically modelled as complete directional randomisations but it is known that in wild type E. coli, successive run directions are actually weakly correlated, with a mean directional difference of ∼63°. We recently presented a model of the evolution of chemotactic swimming strategies in bacteria which is able to quantitatively reproduce the emergence of this correlation. The agreement between model and experiments suggests that directional persistence may serve some function, a hypothesis supported by the results of an earlier model. Here we investigate the effect of persistence on chemotactic efficiency, using a spatial Monte Carlo model of bacterial swimming in a gradient, combined with simulations of natural selection based on chemotactic efficiency. A direct search of the parameter space reveals two attractant gradient regimes, (a) a low-gradient regime, in which efficiency is unaffected by directional persistence and (b) a high-gradient regime, in which persistence can improve chemotactic efficiency. The value of the persistence parameter that maximises this effect corresponds very closely with the value observed experimentally. This result is matched by independent simulations of the evolution of directional memory in a population of model bacteria, which also predict the emergence of persistence in high-gradient conditions. The relationship between optimality and persistence in different environments may reflect a universal property of random-walk foraging algorithms, which must strike a compromise between two competing aims: exploration and exploitation. We also present a new graphical way to generally illustrate the evolution of a particular trait in a population, in terms of variations in an evolvable parameter.

Some comparison on whole-proteome phylogeny of large dsDNA viruses based on dynamical language approach and feature frequency profiles method

There has been a growing interest in alignment-free methods for phylogenetic analysis using complete genome data. Among them, CVTree method, feature frequency profiles method and dynamical language approach were used to investigate the whole-proteome phylogeny of large dsDNA viruses. Using the data set of large dsDNA viruses from Gao and Qi (BMC Evol. Biol. 2007), the phylogenetic results based on the CVTree method and the dynamical language approach were compared in Yu et al. (BMC Evol. Biol. 2010). In this paper, we first apply dynamical language approach to the data set of large dsDNA viruses from Wu et al. (Proc. Natl. Acad. Sci. USA 2009) and compare our phylogenetic results with those based on the feature frequency profiles method. Then we construct the whole-proteome phylogeny of the larger dataset combining the above two data sets. According to the report of The International Committee on the Taxonomy of Viruses (ICTV), the trees from our analyses are in good agreement to the latest classification of large dsDNA viruses.

Stability and convergence of a new finite volume method for a two-sided space-fractional diffusion equation

In this paper, we consider a two-sided space-fractional diffusion equation with variable coefficients on a finite domain. Firstly, based on the nodal basis functions, we present a new fractional finite volume method for the two-sided space-fractional diffusion equation and derive the implicit scheme and solve it in matrix form. Secondly, we prove the stability and convergence of the implicit fractional finite volume method and conclude that the method is unconditionally stable and convergent. Finally, some numerical examples are given to show the effectiveness of the new numerical method, and the results are in excellent agreement with theoretical analysis.

An improved computational method in structural dynamics

Purpose – In structural, earthquake and aeronautical engineering and mechanical vibration, the solution of dynamic equations for a structure subjected to dynamic loading leads to a high order system of differential equations. The numerical methods are usually used for integration when either there is dealing with discrete data or there is no analytical solution for the equations. Since the numerical methods with more accuracy and stability give more accurate results in structural responses, there is a need to improve the existing methods or develop new ones. The paper aims to discuss these issues. Design/methodology/approach – In this paper, a new time integration method is proposed mathematically and numerically, which is accordingly applied to single-degree-of-freedom (SDOF) and multi-degree-of-freedom (MDOF) systems. Finally, the results are compared to the existing methods such as Newmark’s method and closed form solution. Findings – It is concluded that, in the proposed method, the data variance of each set of structural responses such as displacement, velocity, or acceleration in different time steps is less than those in Newmark’s method, and the proposed method is more accurate and stable than Newmark’s method and is capable of analyzing the structure at fewer numbers of iteration or computation cycles, hence less time-consuming. Originality/value – A new mathematical and numerical time integration method is proposed for the computation of structural responses with higher accuracy and stability, lower data variance, and fewer numbers of iterations for computational cycles.

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P=0.014) and distant metastasis rates 23%, 64%, and 50% (P=0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n=14) and group 2 (microsatellite instable; n=19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n=36) and 39% in group 4 (NSMP; P<0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; P<0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment

Clinoenstatite coatings have high bonding strength, bioactive ion release, and osteoimmunomodulatory effects that enhance in vivo osseointegration

A number of coating materials have been developed over past two decades seeking to improve the osseointegration of orthopedic metal implants. Despite the many candidate materials trialed, their low rate of translation into clinical applications suggests there is room for improving the current strategies for their development. We therefore propose that the ideal coating material(s) should possess the following three properties: (i) high bonding strength, (ii) release of functional ions, and (iii) favourable osteoimmunomodulatory effects. To test this proposal, we developed clinoenstatite (CLT, MgSiO3), which as a coating material has high bonding strength, cytocompability and immunomodulatory effects that are favourable for in vivo osteogenesis. The bonding strength of CLT coatings was 50.1 ± 3.2 MPa, more than twice that of hydroxyapatite (HA) coatings, at 23.5 ± 3.5 MPa. CLT coatings released Mg and Si ions, and compared to HA coatings, induced an immunomodulation more conducive for osseointegration, demonstrated by downregurelation of pro-inflammatory cytokines, enhancement of osteogenesis, and inhibition of osteoclastogenesis. In vivo studies demonstrated that CLT coatings improved osseointegration with host bone, as shown by the enhanced biomechanical strength and increased de novo bone formation, when compared with HA coatings. These results support the notion that coating materials with the proposed properties can induce an in vivo environment better suited for osseointegration. These properties could, therefore, be fundamental when developing high-performance coating materials.

Advances in solid-catalytic and non-catalytic technologies for biodiesel production

The insecure supply of fossil fuel coerces the scientific society to keep a vision to boost investments in the renewable energy sector. Among the many renewable fuels currently available around the world, biodiesel offers an immediate impact in our energy. In fact, a huge interest in related research indicates a promising future for the biodiesel technology. Heterogeneous catalyzed production of biodiesel has emerged as a preferred route as it is environmentally benign needs no water washing and product separation is much easier. The number of well-defined catalyst complexes that are able to catalyze transesterification reactions efficiently has been significantly expanded in recent years. The activity of catalysts, specifically in application to solid acid/base catalyst in transesterification reaction depends on their structure, strength of basicity/acidity, surface area as well as the stability of catalyst. There are various process intensification technologies based on the use of alternate energy sources such as ultrasound and microwave. The latest advances in research and development related to biodiesel production is represented by non-catalytic supercritical method and focussed exclusively on these processes as forthcoming transesterification processes. The latest developments in this field featuring highly active catalyst complexes are outlined in this review. The knowledge of more extensive research on advances in biofuels will allow a deeper insight into the mechanism of these technologies toward meeting the critical energy challenges in future.

Combined NIR/MIR analysis: A novel method for the classification of complex substances such as Illicium verum Hook. F. and its adulterants

A novel combined near- and mid-infrared (NIR and MIR) spectroscopic method has been researched and developed for the analysis of complex substances such as the Traditional Chinese Medicine (TCM), Illicium verum Hook. F. (IVHF), and its noxious adulterant, Iuicium lanceolatum A.C. Smith (ILACS). Three types of spectral matrix were submitted for classification with the use of the linear discriminant analysis (LDA) method. The data were pretreated with either the successive projections algorithm (SPA) or the discrete wavelet transform (DWT) method. The SPA method performed somewhat better, principally because it required less spectral features for its pretreatment model. Thus, NIR or MIR matrix as well as the combined NIR/MIR one, were pretreated by the SPA method, and then analysed by LDA. This approach enabled the prediction and classification of the IVHF, ILACS and mixed samples. The MIR spectral data produced somewhat better classification rates than the NIR data. However, the best results were obtained from the combined NIR/MIR data matrix with 95–100% correct classifications for calibration, validation and prediction. Principal component analysis (PCA) of the three types of spectral data supported the results obtained with the LDA classification method.

Understanding solid-state transformations during dehydration: new insights using vibrational spectroscopy and multivariate modelling

Many active pharmaceutical ingredients (APIs) have both anhydrate and hydrate forms. Due to the different physicochemical properties of solid forms, the changes in solid-state may result in therapeutic, pharmaceutical, legal and commercial problems. In order to obtain good solid dosage form quality and performance, there is a constant need to understand and control these phase transitions during manufacturing and storage. Thus it is important to detect and also quantify the possible transitions between the different forms. In recent years, vibrational spectroscopy has become an increasingly popular tool to characterise the solid-state forms and their phase transitions. It offers several advantages over other characterisation techniques including an ability to obtain molecular level information, minimal sample preparation, and the possibility of monitoring changes non-destructively in-line. Dehydration is the phase transition of hydrates which is frequently encountered during the dosage form production and storage. The aim of the present thesis was to investigate the dehydration behaviour of diverse pharmaceutical hydrates by near infrared (NIR), Raman and terahertz pulsed spectroscopic (TPS) monitoring together with multivariate data analysis. The goal was to reveal new perspectives for investigation of the dehydration at the molecular level. Solid-state transformations were monitored during dehydration of diverse hydrates on hot-stage. The results obtained from qualitative experiments were used to develop a method and perform the quantification of the solid-state forms during process induced dehydration in a fluidised bed dryer. Both in situ and in-line process monitoring and quantification was performed. This thesis demonstrated the utility of vibrational spectroscopy techniques and multivariate modelling to monitor and investigate dehydration behaviour in situ and during fluidised bed drying. All three spectroscopic methods proved complementary in the study of dehydration. NIR spectroscopy models could quantify the solid-state forms in the binary system, but were unable to quantify all the forms in the quaternary system. Raman spectroscopy models on the other hand could quantify all four solid-state forms that appeared upon isothermal dehydration. The speed of spectroscopic methods makes them applicable for monitoring dehydration and the quantification of multiple forms was performed during phase transition. Thus the solid-state structure information at the molecular level was directly obtained. TPS detected the intermolecular phonon modes and Raman spectroscopy detected mostly the changes in intramolecular vibrations. Both techniques revealed information about the crystal structure changes. NIR spectroscopy, on the other hand was more sensitive to water content and hydrogen bonding environment of water molecules. This study provides a basis for real time process monitoring using vibrational spectroscopy during pharmaceutical manufacturing.

Nonlinear analysis for the pre- and post-yield behaviour of a composite structure with the refined plastic hinge approach

The computational technique of the full ranges of the second-order inelastic behaviour evaluation of steel-concrete composite structure is not always sought forgivingly, and therefore it hinders the development and application of the performance-based design approach for the composite structure. To this end, this paper addresses of the advanced computational technique of the higher-order element with the refined plastic hinges to capture the all-ranges behaviour of an entire steel-concrete composite structure. Moreover, this paper presents the efficient and economical cross-section analysis to evaluate the element section capacity of the non-uniform and arbitrary composite section subjected to the axial and bending interaction. Based on the same single algorithm, it can accurately and effectively evaluate nearly continuous interaction capacity curve from decompression to pure bending technically, which is the important capacity range but highly nonlinear. Hence, this cross-section analysis provides the simple but unique algorithm for the design approach. In summary, the present nonlinear computational technique can simulate both material and geometric nonlinearities of the composite structure in the accurate, efficient and reliable fashion, including partial shear connection and gradual yielding at pre-yield stage, plasticity and strain-hardening effect due to axial and bending interaction at post-yield stage, loading redistribution, second-order P-δ and P-Δ effect, and also the stiffness and strength deterioration. And because of its reliable and accurate behavioural evaluation, the present technique can be extended for the design of the high-strength composite structure and potentially for the fibre-reinforced concrete structure.

Monitoring of Fungal Growth and Degradation of Wood

Valko- ja ruskolahosienet tunnetaan luonnossa tehokkaimpina puun ja karikkeen lignoselluloosan lahottajina. Valkolahosienet pystyvät hajottamaan kaikkia puun osia: ligniiniä, selluloosaa ja hemiselluloosaa. Selektiivisesti ligniiniä hajottavat sienet lahottavat puusta suhteessa enemmän vaikeasti hajoavaa ligniiniä kuin selluloosaa tai hemiselluloosaa, jolloin jäljelle jää valkoista ja miltei puhdasta selluloosaa. Bioteknisissä sovelluksissa juuri selektiviiviset valkolahottajat ovat kiinnostavia. Niiden avulla voidaan puuhaketta esikäsitellä esimerkiksi paperinvalmistuksessa haitallisen ligniinin poistamiseksi. Ruskolahosienet ovat huomattavia puun, puutavaran ja puisten rakenteiden lahottajia, kuten tässä työssä käytetty Gloeophyllum trabeum (saunasieni ) ja Poria (Postia) placenta (istukkakääpä). Ruskolahosienet hajottavat puusta hemiselluloosan lisäksi selluloosaa, jolloin jää jäljelle ruskea ja jauhomaiseksi mureneva ligniini. Ruskolahosienet muovaavat ligniiniä jonkin verran. Kahden ruskolahosienen G. trabeumin ja P. placentan lisäksi tutkittiin valkolahosieniä, joista Ceriporiopsis subvermispora (karstakääpä) ja harvinainen Physisporinus rivulosus -sieni (talikääpä) hajottavat ligniiniä erittäin selektiivisesti. Phanerochaete chrysosporium on kaikkialla paljon tutkittu sieni, ja Phlebia radiata valkolahosientä (rusorypykkä) on tutkittu paljon mikrobiologian osastolla. Lisäksi tutkittiin Phlebia tremellosa -sienten (hytyrypykkä) ligninolyyttisten entsyymien tuottoa ja 14C-leimatun synteettisen ligniinin (DHP) hajotusta. P. radiata ja P. tremellosa -sienten on todettu aiemmin hajottavan ligniiniä selektiivisesti. Työssä selvitettiin miten sienten kasvua voi mitata, miten vertailukelpoisia eri mittaamismenetelmillä saadut tulokset ovat ja ilmenevätkö sienten aktiivisimmat kasvuvaiheet samaan aikaan eri menetelmillä mitattuna. Tärkeimmät tulokset olivat seuraavat havainnot: (i) P. radiata ja P. tremellosa -sienikannat tuottivat ligniini- ja mangaaniperoksidaasientsyymejä (LiP ja MnP) sekä lakkaasia, ja sienistä puhdistettiin 2-3 LiP- ja P. radiatasta yksi MnP-entsyymi; (ii) P. tremellosa -sienet hajottivat leimattua synteettistä ligniiniä (DHP) yhtä hyvin kuin paljon tutkitut P. chrysosporium ja P. radiata -sienet; (iii) puu, sienen luonnollinen kasvualusta, lisäsi valkolaho- ja ruskolahosienten demetoksylaatiota [O14CH3]-leimatusta ligniinin malliyhdisteestä 14CO2:ksi ilman puuta olleeseen alustaan verrattuna; (iv) demetoksylaatio (14CO2:n tuotto) oli normaalissa ilma-atmosfäärissä useimmiten parempi happeen verrattuna; (v) hapessa paras 14CO2:n tuotto saatiin puupalakasvatuksissa, joihin oli lisätty ravinnetyppeä tai typen lisäksi glukoosia sekä valkolaho- että ruskolahosienillä; (vi) ilmassa 14CO2:n tuotto oli puulla voimakkainta valkolahosienillä ilman lisäravinteita, kun taas G. trabeum -sienellä se oli yhtä hyvä eri alustoissa; (vii) biomassan muodostuminen rihmastojen ergosterolipitoisuuksista mitattuna oli ruskolahosienillä parempi kuin valkolahosienillä; (viii) ja biomassojen huippupitoisuudet olivat 6:lla sienellä eri suuruisia ja niiden maksimimäärien ajankohdat vaihtelivat viiden viikon kasvatusten kuluessa. Mikrobiologian osastolla Viikissä eristetty ja paljon tutkittu P. radiata -valkolahosieni oli mukana kaikissa tehdyissä kokeissa. Sienen LiP-aktiivisuus ja 14CO2:n tuotto 14C-rengas-leimatusta synteettisestä ligniinistä (DHP) korreloivat erittäin hyvin. Biomassan muodostuminen ergosterolilla määritettynä tuki hyvin entsyymiaktiivisuusmittauksilla ja isotooppikasvatuksilla saatuja tuloksia.

Scientists in Control: a progressive approach to preparing work ready graduates in QC, EQA and method evaluation

Introduction QC, EQA and method evaluation are integral to delivery of quality patient results. To ensure QUT graduates have a solid grounding in these key areas of practice, a theory-to-practice approach is used to progressively develop and consolidate these skills. Methods Using a BCG assay for serum albumin, each student undertakes an eight week project analysing two levels of QC alongside ‘patient’ samples. Results are assessed using both single rules and Multirules. Concomitantly with the QC analyses, an EQA project is undertaken; students analyse two EQA samples, twice in the semester. Results are submitted using cloud software and data for the full ‘peer group’ returned to students in spreadsheets and incomplete Youden plots. Youden plots are completed with target values and calculated ALP values and analysed for ‘lab’ and method performance. The method has a low-level positive bias, which leads to the need to investigate an alternative method. Building directly on the EQA of the first project and using the scenario of a lab that services renal patients, students undertake a method validation comparing BCP and BCG assays in another eight-week project. Precision and patient comparison studies allow students to assess whether the BCP method addresses the proportional bias of the BCG method and overall is a ‘better’ alternative method for analysing serum albumin, accounting for pragmatic factors, such as cost, as well as performance characteristics. Results Students develop understanding of the purpose and importance of QC and EQA in delivering quality results, the need to optimise testing to deliver quality results and importantly, a working knowledge of the analyses that go into ensuring this quality. In parallel to developing these key workplace competencies, students become confident, competent practitioners, able to pipette accurately and precisely and organise themselves in a busy, time pressured work environment.

Evaluating and validating abundance monitoring methods in the absence of populations of known size: review and application to a passive tracking index

Rarely is it possible to obtain absolute numbers in free-ranging populations and although various direct and indirect methods are used to estimate abundance, few are validated against populations of known size. In this paper, we apply grounding, calibration and verification methods, used to validate mathematical models, to methods of estimating relative abundance. To illustrate how this might be done, we consider and evaluate the widely applied passive tracking index (PTI) methodology. Using published data, we examine the rationality of PTI methodology, how conceptually animal activity and abundance are related and how alternative methods are subject to similar biases or produce similar abundance estimates and trends. We then attune the method against populations representing a range of densities likely to be encountered in the field. Finally, we compare PTI trends against a prediction that adjacent populations of the same species will have similar abundance values and trends in activity. We show that while PTI abundance estimates are subject to environmental and behavioural stochasticity peculiar to each species, the PTI method and associated variance estimate showed high probability of detection, high precision of abundance values and, generally, low variability between surveys, and suggest that the PTI method applied using this procedure and for these species provides a sensitive and credible index of abundance. This same or similar validation approach can and should be applied to alternative relative abundance methods in order to demonstrate their credibility and justify their use.