Exploring the dynamics of flagellar dynein within the axoneme with Fluctuating Finite Element Analysis.

Flagellar dyneins are the molecular motors responsible for producing the propagating bending motions of cilia and flagella. They are located within a densely packed and highly organised super-macromolecular cytoskeletal structure known as the axoneme. Using the mesoscale simulation technique Fluctuating Finite Element Analysis (FFEA), which represents proteins as viscoelastic continuum objects subject to explicit thermal noise, we have quantified the constraints on the range of molecular conformations that can be explored by dynein-c within the crowded architecture of the axoneme. We subsequently assess the influence of crowding on the 3D exploration of microtubule-binding sites, and specifically on the axial step length. Our calculations combine experimental information on the shape, flexibility and environment of dynein-c from three distinct sources; negative stain electron microscopy, cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET). Our FFEA simulations show that the super-macromolecular organisation of multiple protein complexes into higher-order structures can have a significant influence on the effective flexibility of the individual molecular components, and may, therefore, play an important role in the physical mechanisms underlying their biological function.

Species distribution models have limited spatial transferability for invasive species.

The reliability of transferring species distribution models (SDMs) to new ranges and future climates has been widely debated. Biological invasions offer the unique opportunity to evaluate model transferability, as distribution data between species' native and introduced ranges are geographically independent of each other. Here, we performed the first global quantitative synthesis of the spatial transferability of SDMs for 235 invasive species and assessed the association of model transferability with the focal invader, model choice and parameterisation. We found that SDMs had limited spatial transferability overall. However, model transferability was higher for terrestrial endotherms, species introduced from or to the Southern Hemisphere, and species introduced more recently. Model transferability was also positively associated with the number of presences for model calibration and evaluation, respectively, but negatively with the number of predictors. These findings highlight the importance of considering the characteristics of the focal invader, environment and modelling in the application and assessment of SDMs.

Multi-model ensembles in climate science: Mathematical structures and expert judgements.

Projections of future climate change cannot rely on a single model. It has become common to rely on multiple simulations generated by Multi-Model Ensembles (MMEs), especially to quantify the uncertainty about what would constitute an adequate model structure. But, as Parker points out (2018), one of the remaining philosophically interesting questions is: "How can ensemble studies be designed so that they probe uncertainty in desired ways?" This paper offers two interpretations of what General Circulation Models (GCMs) are and how MMEs made of GCMs should be designed. In the first interpretation, models are combinations of modules and parameterisations; an MME is obtained by "plugging and playing" with interchangeable modules and parameterisations. In the second interpretation, models are aggregations of expert judgements that result from a history of epistemic decisions made by scientists about the choice of representations; an MME is a sampling of expert judgements from modelling teams. We argue that, while the two interpretations involve distinct domains from philosophy of science and social epistemology, they both could be used in a complementary manner in order to explore ways of designing better MMEs.

Influence of 3D Printing Direction in PLA Acoustic Guitars on Vibration Response.

The design of musical instruments is a discipline that is still carried out in an artisanal way, with limitations and high costs. With the additive manufacturing technique, it is possible to obtain results for the generation of not only electrical but also acoustic instruments. However, it is necessary to generate a procedure to evaluate the influence of the process on the final result of the acoustics obtained. This study focuses on investigating the relationship between the construction of acoustic guitars and their final sound. The reinforcement structures at the top of the instrument are analysed, as well as how this design affects the vibratory behaviour of the top in the first five vibratory modes. Specifically, this article presents a procedure for the design of customised acoustic guitars using additive manufacturing through parametrisation and a vibrational analysis of the designed tops using finite element (FEA) and experimental physical tests, in order to develop a methodology for the study of stringed instruments. As a result, an 11% increase in the high-frequency response was achieved with a printing direction of +45°, and a reduction in the high-frequency response with ±45°. In addition, at high frequencies, a relative error of 5% was achieved with respect to the simulation. This work fulfils an identified need to study the manufacture of acoustic guitars using polylactic acid (PLA), and to be able to offer the musician a customised instrument. This represents a breakthrough in the use of this manufacturing technology, extending its relationship with product design.

A Framework for Susceptibility Analysis of Brain Tumours Based on Uncertain Analytical Cum Algorithmic Modeling.

Susceptibility analysis is an intelligent technique that not only assists decision makers in assessing the suspected severity of any sort of brain tumour in a patient but also helps them diagnose and cure these tumours. This technique has been proven more useful in those developing countries where the available health-based and funding-based resources are limited. By employing set-based operations of an arithmetical model, namely fuzzy parameterised complex intuitionistic fuzzy hypersoft set (FPCIFHSS), this study seeks to develop a robust multi-attribute decision support mechanism for appraising patients' susceptibility to brain tumours. The FPCIFHSS is regarded as more reliable and generalised for handling information-based uncertainties because its complex components and fuzzy parameterisation are designed to deal with the periodic nature of the data and dubious parameters (sub-parameters), respectively. In the proposed FPCIFHSS-susceptibility model, some suitable types of brain tumours are approximated with respect to the most relevant symptoms (parameters) based on the expert opinions of decision makers in terms of complex intuitionistic fuzzy numbers (CIFNs). After determining the fuzzy parameterised values of multi-argument-based tuples and converting the CIFNs into fuzzy values, the scores for such types of tumours are computed based on a core matrix which relates them with fuzzy parameterised multi-argument-based tuples. The sub-intervals within [0, 1] denote the susceptibility degrees of patients corresponding to these types of brain tumours. The susceptibility of patients is examined by observing the membership of score values in the sub-intervals.

Modelling environmentally mediated spread of livestock-associated methicillin-resistant Staphylococcus aureus in a pig herd.

Infectious disease models are a useful tool to support within-herd disease control strategies. This study presents a stochastic compartment model with environmentally mediated transmission to represent the spread of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in a farrow-to-finish pig herd. The aims of the study were to (1) construct a model of the spread of LA-MRSA that included spread of LA-MRSA through the environment; (2) parameterise the model to fit previously published observational data in order to obtain realistic LA-MRSA transmission rates; (3) and to investigate how changes in the mixing of animals in the farrowing and finishing units may affect the prevalence of LA-MRSA in a herd. The results showed that indirect transmission allowed LA-MRSA to persist in the herd without the assumption of persistently shedding individuals. Reducing the mixing of pigs upon entry to the finishing unit was also shown to lower the LA-MRSA prevalence in the unit if the initial LA-MRSA level in the unit was low, but at high prevalence, no effect of mixing was identified. In the farrowing unit, changing the proportion of piglets that were cross-fostered did not affect the within-herd LA-MRSA prevalence. The study demonstrates that there are several important knowledge gaps regarding the shedding and transmission of LA-MRSA in different animal age groups and further experimental studies are needed. This work also provides a new, robust and flexible model framework for the investigation of control and mitigation strategies for LA-MRSA and other infections in a pig herd.

A protocol to build soil descriptions for APSIM simulations.

Soil processes have a major impact on agroecosystems, controlling water and nutrient cycling, regulating plant growth and losses to the wider environment. Process-based agroecosystem simulation models generally encompass detailed descriptions of the soil, including a wide number of parameters that can be daunting to users with a limited soil science background. In this work we review and present an abridged description of the models used to simulate soil processes in the APSIM (Agricultural Production Systems sIMulator) framework. Such a resource is needed because this information is currently spread over multiple publications and some elements have become outdated. We list and briefly describe the parameters, and establish a protocol with guidelines, for building a soil description for APSIM. This protocol will promote consistency, enhancing the quality of the science done employing APSIM, and provide an easier pathway for new users. This compilation should also be of relevance to users of other models that require detailed soil information.•This paper presents a brief description of the models for simulating soil processes in the APSIM model.•The method stablishes guidelines to define the parameters for building a soil description for APSIM.

Mathematical and computational models for bone tissue engineering in bioreactor systems.

Research into cellular engineered bone grafts offers a promising solution to problems associated with the currently used auto- and allografts. Bioreactor systems can facilitate the development of functional cellular bone grafts by augmenting mass transport through media convection and shear flow-induced mechanical stimulation. Developing successful and reproducible protocols for growing bone tissue in vitro is dependent on tuning the bioreactor operating conditions to the specific cell type and graft design. This process, largely reliant on a trial-and-error approach, is challenging, time-consuming and expensive. Modelling can streamline the process by providing further insight into the effect of the bioreactor environment on the cell culture, and by identifying a beneficial range of operational settings to stimulate tissue production. Models can explore the impact of changing flow speeds, scaffold properties, and nutrient and growth factor concentrations. Aiming to act as an introductory reference for bone tissue engineers looking to direct their experimental work, this article presents a comprehensive framework of mathematical models on various aspects of bioreactor bone cultures and overviews modelling case studies from literature.

Patient-specific parameterised cam geometry in finite element models of femoroacetabular impingement of the hip.

BACKGROUND: Impingement resulting in soft tissue damage has been observed in hips with abnormal morphologies. Geometric parameterisation can be used to automatically generate a range of bone geometries for use in computational models, including femurs with cam deformity on the femoral neck. METHODS: This study verified patient-specific parametric finite element models of 20 patients with cam deformity (10 female, 10 male) through comparison to their patient-specific segmentation-based equivalents. The parameterisation system was then used to generate further models with parametrically defined geometry to investigate morphological changes in both the femur and acetabulum and their effects on impingement. FINDINGS: Similar findings were observed between segmentation-based and parametric models when assessing soft tissue strains under impingement conditions, resulting from high flexion and internal rotations. Parametric models with cam morphology demonstrated that clinically used alpha angles should not be relied on for estimating impingement severity since planar views do not capture the full three-dimensional geometry of the joint. Furthermore, the parametric approach allowed study of labral shape changes, indicating higher strains can result from bony overcoverage. INTERPRETATION: The position of cams, as well as their size, can affect the level of soft tissue strain occurring in the hip. This highlights the importance of reporting the full details of three-dimensional geometry used when developing computational models of the hip joint and suggests that it could be beneficial to stratify the patient population when considering treatment options, since certain morphologies may be at greater risk of elevated soft tissue strain.

Generation of AMBER force field parameters for zinc centres of M1 and M17 family aminopeptidases.

The M1 and M17 aminopeptidases are metallo-exopeptidases that rely on the presence of divalent cations, usually zinc, in their active site for proteolytic activity. They are from separate protease superfamilies, however, members often have overlapping substrate specificity. Inhibitors of one or both enzymes can be used to modulate hypertension, reduce proliferation of certain types of cancers and control malaria parasites. Current inhibitors act to chelate the zinc ions in the active site, locking the enzymes in an inactive transition state. We were interested in using a computational approach to understand the structure and dynamics of the M1 and M17 aminopeptidases, however, the presence of the essential metal ions in the proteases presents a challenge to classical molecular dynamics (MD) simulation. The zinc amber force field does not contain applicable descriptions of the zinc coordination environment present in either of these two protease families. To provide tools for the study of these two enzymes, we have used the metal centre parameter builder to generate new hybrid bonded/nonbonded force field (FF) parameters to correctly describe the active site architecture for each enzyme. The new parameters were evaluated by fitting the normal mode frequencies of molecular mechanics to the quantum mechanics frequencies and validated by performing short MD simulations. The new FF parameters now enable more accurate and reliable MD simulations for any member of the M1 or M17 aminopeptidase superfamilies.

Three-dimensional assessment of impingement risk in geometrically parameterised hips compared with clinical measures.

Abnormal bony morphology is a factor implicated in hip joint soft tissue damage and an increased lifetime risk of osteoarthritis. Standard 2-dimensional radiographic measurements for diagnosis of hip deformities, such as cam deformities on the femoral neck, do not capture the full joint geometry and are not indicative of symptomatic damage. In this study, a 3-dimensional geometric parameterisation system was developed to capture key variations in the femur and acetabulum of subjects with clinically diagnosed cam deformity. The parameterisation was performed for computed tomography scans of 20 patients (10 female and 10 male). Novel quantitative measures of cam deformity were taken and used to assess differences in morphological deformities between males and females. The parametric surfaces matched the more detailed, segmented hip bone geometry with low fitting error. The quantitative severity measures captured both the size and the position of cams and distinguished between cam and control femurs. The precision of the measures was sufficient to identify differences between subjects that could not be seen with the sole use of 2-dimensional imaging. In particular, cams were found to be more superiorly located in males than in females. As well as providing a means to distinguish between subjects more clearly, the new geometric hip parameterisation facilitates the flexible and rapid generation of a range of realistic hip geometries including cams. When combined with material property models, these stratified cam shapes can be used for further assessment of the effect of the geometric variation under impingement conditions.

Coarse-grained bond and angle distributions from atomistic simulations: On the systematic parameterisation of lipid models.

Coarse-grained (CG) models are popular alternatives to atomistic (AT) force fields as they enable simulations of larger systems at longer timescales. The bottom-up approach is a systematic parameterisation strategy whereby data from AT simulations are used to determine the CG parameters. This is particular straightforward with the bond and angle parameters as a direct Boltzmann inversion can be used. Still, a reference AT force field has to be chosen. In this study, I compare three common AT force fields (Stockholm lipids, Berger and Gromos) and investigate the sampling of bond and angle distributions in two CG models (Martini and Elba). As a test case, I choose a bilayer of POPC lipids. The AT simulations give distributions that agree to a large extent, especially in the fatty acid tails. However, the AT simulations sample distributions that differ from the distributions observed in CG simulations with respect to both location and width. The bond and angle distributions from the AT simulations are then used to re-parameterise the CG force fields. For the Martini model, this significantly alters the physical behaviour of the membrane, which likely is an effect of the mapping. However, for the Elba model the re-parameterised force field gives a membrane that is in some respects closer to the experimental membrane. Implications for CG parameterisation are discussed.

Geometric parameterisation of pelvic bone and cartilage in contact analysis of the natural hip: an initial study.

Parameterised finite element models of the human hip have the potential to allow controlled analysis of the effect of individual geometric features on the contact mechanics of the joint. However, the challenge lies in defining a set of parameters which sufficiently capture the joint geometry in order to distinguish between individuals. In this study, a simple set of parameters to describe the geometries of acetabulum and cartilage in the hip were extracted from two segmentation-based models, which were then used to generate the parameterised finite element models for the two subjects. The contact pressure and contact area at the articular surface predicted from the parameterised finite element models were compared with the results from the segmentation-based models. The differences in the predicted results between the parameterised models and segmentation-based models were found to be within 11% across seven activities simulated. In addition, the parameterised models were able to replicate features of the contact pressure/area fluctuations over the loading cycle that differed between the two subjects. These results provide confidence that the parameterised approach could be used to generate representative finite element models of the human hip for contact analysis. Such a method has the potential to be used to systematically evaluate geometric features that can be captured from simple clinical measurements and provide a cost- and time-effective approach for stratification of the acetabular geometries in the patient population.

Temporal associations between low body condition, lameness and milk yield in a UK dairy herd.

Previous work has hypothesised that cows in low body condition become lame. We tested this in a prospective longitudinal study. Body condition score (BCS), causes of lameness and milk yield were collected from a 600-cow herd over 44-months. Mixed effect binomial models and a continuous outcome model were used to investigate the associations between lameness, BCS and milk yield. In total, 14,320 risk periods were obtained from 1137 cows. There were 1510 lameness treatments: the most common causes of lameness were sole ulcer (SU) (39%), sole haemorrhage (SH) (13%), digital dermatitis (DD) (10%) and white line disease (WLD) (8%). These varied by year and year quarter. Body condition was scored at 60-day intervals. BCS ranged from 1 to 5 with a mean of 2.5, scores were higher in very early lactation but varied widely throughout lactation; approximately 45% of scores were <2.5. The key finding was that BCS<2.5 was associated with an increased risk of treatment for lameness in the following 0-2 months and >2-4 months for all causes of lameness and also specifically for SU/WLD lameness. BCS<2.5 was associated with an increased risk of treatment for SH in the following 0-2 months but not >2-4 months. There was no such association with DD. All lameness, SU/WLD, SH and DD were significantly more likely to occur in cows that had been lame previously, but the effect of BCS was present even when all repeat cases of lameness were excluded from the analysis. Milk yield was significantly higher and fell in the month before treatment in cows lame with SU/WLD but it was not significantly higher for cows that were treated for DD compared with non-lame cows. These findings support the hypothesis that low BCS contributes to the development of horn related claw lameness but not infectious claw diseases in dairy cows. One link between low BCS and lameness is a thin digital cushion which has been proposed as a trigger for claw horn disease. Cows with BCS 2 produced more milk than cows with BCS 2.5, however, this was only approximately 100 kg difference in yield over a 305-day lactation. Given the increased risk of lameness in cows with BCS 2, the direct costs of lameness and the small variability in milk yield by BCS, preventing cows from falling to BCS<2.5 would improve cow welfare and be economically beneficial.