Modelling early responses to neurodegenerative mutations in mice

Considering the many differences between mice and humans, it is perhaps surprising how well mice model late-onset human neurodegenerative disease. Models of Alzheimer's disease, frontotemporal dementia, Parkinson's disease and Huntington's disease show some striking similarities to the corresponding human pathologies in terms of axonal transport disruption, protein aggregation, synapse loss and some behavioural phenotypes. However, there are also major differences. To extrapolate from mouse models to human disease, we need to understand how these differences relate to intrinsic limitations of the mouse system and to the effects of transgene overexpression. In the present paper, we use examples from an amyloid-overexpression model and a mutant-tau-knockin model to illustrate what we learn from each type of approach and what the limitations are. Finally, we discuss the further contributions that knockin and similar approaches can make to understanding pathogenesis and how best to model disorders of aging in a short-lived mammal.     

ON FITTING EQUATIONS TO SENSORY DATA: A POINT OF VIEW, AND A PARADOX IN MODELING AND OPTIMIZING

When fitting equations to data relating ingredients or factor scores to subjective ratings, there are at least two methods to create the equations. One method, (linear) forces in linear terms and allows additional quadratic and interaction terms. The other method, (quadratic) forces in linear and quadratic terms, and then permits cross-terms to enter. The two methods produce contradictory results. The first (and expected) contradiction is that the quadratic model shows optimum levels in the middle range of the levels tested for some, but not all, ingredients. The second (and unexpected) contradiction is that the linear method (which usually does not incorporate many additional terms) generates better validation predictions for " hold-out" samples than does the quadratic method. The differences between the optimum generated by the linear model and the optimum generated by the quadratic model can be quite substantial in terms of expected liking, sensory profile, and image profile.     

Polymorphism at the α-glycerophosphate dehydrogenase locus in Drosophila melanogaster. I. Properties of adult allozymes

A biochemical comparison was made between alpha-glycerophosphate dehydrogenase allozymes from Drosophila melanogaster. Enzymes extracted from the three major genotypes were indistinguishable in terms of their pH optima and thermal stabilities. Distinctive differences were observed for three parameters; temperature dependence of specific activity, temperature dependence of K-m, and reaction rate constancy over a physiological temperature range. These results are discussed in terms of a model of balancing selection and the existence of spatial and temporal allele frequency clines in natural populations.     

Subject-specific musculoskeletal model of the lower limb in a lying and standing position

Accurate estimation of joint loads implies using subject-specific musculoskeletal models. Moreover, as the lines of action of the muscles are dictated by the soft tissues, which are in turn influenced by gravitational forces, we developed a method to build subject-specific models of the lower limb in a functional standing position. Bones and skin envelope were obtained in a standing position, whereas muscles and a set of bony landmarks were obtained from conventional magnetic resonance images in a lying position. These muscles were merged with the subject-specific skeletal model using a nonlinear transformation, taking into account soft tissue movements and gravitational effects. Seven asymptomatic lower limbs were modelled using this method, and results showed realistic deformations. Comparing the subject-specific skeletal model to a scaled reference model rendered differences in terms of muscle length up to 4% and in terms of moment arm for adductor muscles up to 30%. These preliminary findings enlightened the importance of subject-specific modelling in a functional position.     

Study on the molecular models commonly used in the simulation of dilute polymeric solutions in flow

Three molecular models, commonly used in the simulation of polymeric solutions and melts were employed to describe the rheological behaviour of dilute, elastic and constant viscosity solution formed by bead-and-bond chain molecules immersed into a soft-sphere solvent. The intermolecular interactions for the three models were calculated by the Lennard-Jones potential. The differences amongst the models proceeded from the intramolecular restrictions: the simplest one is a Freely-Joined-Chain (FJC) model with harmonic bond potentials, in the second model bonds are restricted by a finite extensible non-linear elastic (FENE) potential plus a repulsive WCA potential, and the third model is conformed by the United Atom (UA) approach which includes bond, flexion and torsion potentials. Both Couette and Poiseuille flows were simulated using Non-Equilibrium Molecular Dynamics. Deformation displayed by the three chain models; defined in terms of their radius of gyration was calculated and according to results it was found that for Couette flow, the three chains exhibit similar response to deformation. In Poiseulle flow, the FJC and FENE models behave similarly but the UA model presents a larger resistance to deformation. For both flow regimes, the forces involved to deform the chains were estimated in terms of the first normal stress differences. From these estimations it was found that the UA model depicted the stiffest chain, followed by the FENE model, and last the FJC model.     

Mathematical models of diffusion-limited gas bubble dynamics in tissue

Mathematical models of bubble evolution in tissue have recentlybeen incorporated into risk functions for predicting the incidence ofdecompression sickness (DCS) in human subjects after diving and/or flying exposures. Bubble dynamics models suitable forthese applications assume the bubble to be either contained in anunstirred tissue (two-region model) or surrounded by a boundary layerwithin a well-stirred tissue (three-region model). The contrastingpremises regarding the bubble-tissue system lead to differentexpressions for bubble dynamics described in terms of ordinarydifferential equations. However, the expressions are shown to bestructurally similar with differences only in the definitions ofcertain parameters that can be transformed to make the modelsequivalent at large tissue volumes. It is also shown that thetwo-region model is applicable only to bubble evolution in tissues ofinfinite extent and cannot be readily applied to bubble evolution infinite tissue volumes to simulate how such evolution is influenced byinteractions among multiple bubbles in a given tissue. Two-regionmodels that are incorrectly applied in such cases yield results thatmay be reinterpreted in terms of their three-region model equivalents but only if the parameters in the two-region model transform into consistent values in the three-region model. When such transforms yieldinconsistent parameter values for the three-region model, results maybe qualitatively correct but are in substantial quantitative error.Obviation of these errors through appropriate use of the differentmodels may improve performance of probabilistic models of DCSoccurrence that express DCS risk in terms of simulated in vivo gas andbubble dynamics.     

Chelal growth in pseudoscorpions

There is a linear relationship between the successive positions of named trichobothria on the pedipalpal chelae during the course of post-embryonic development of five British pseudoscorpions belonging to the family Neobisiidae. Growth constants calculated from the trichobothrial data are higher than those calculated for the chelal axis. This discrepancy is resolved in terms of a model, based on growing and non-growing regions, which is a good approximation to the data. The extent of these regions is calculated for all stages and differences between the species are noted. The assumptions implicit in the model, its realism and its predictive value are discussed.     

Implications of absence of measurement invariance for detecting sex limitation and genotype by environment interaction.

Using univariate sum scores in genetic studies of twin data is common practice. This practice precludes an investigation of the measurement model relating the individual items to an underlying factor. Absence of measurement invariance across a grouping variable such as gender or environmental exposure refers to group differences with respect to the measurement model. It is shown that a decomposition of a sum score into genetic and environmental variance components leads to path coefficients of the additive genetic factor that are biased differentially across groups if individual items are non-invariant. The arising group differences in path coefficients are identical to what is known as "scalar sex limitation" when gender is the grouping variable, or as "gene by environment interaction" when environmental exposure is the grouping variable. In both cases the interpretation would be in terms of a group-specific effect size of the genetic factor. This interpretation may be incorrect if individual items are non-invariant.     

A model of fertility motivation, desires, and expectations early in women's reproductive careers

We propose a general model of the relationships connecting fertility motivations, desires, and expectations in which motivations are antecedent to desires, which in turn are antecedent to expectations. We describe differences in the model as it applies to women early in their reproductive careers, specifically, after marriage but before their 1st birth and after their 1st birth but before their 2nd. We test the model with data from 311 just-married and 318 just-mothered US women enrolled in a prospective psychology of reproduction study, using LISREL (analysis of linear structural relationships by the method of maximum likelihood) software to estimate structural equations for both groups. The general model fits the data well. There are 3 primary differences in the model with respect to the 2 groups of married women. How soon a woman expects her next child affects how many children she expects only among the just-married woman. The number of children expected by the woman is the only antecedent to how soon she expects her next child among the just-mothered women. Both positive and negative maternal motivation has effects among the just-married women, but only negative maternal motivation has effects among the just-mothered women. These and other differences are discussed in terms of psychological and situational developments occurring early in women's reproductive careers.     

A model of fertility motivation,desires, and expectations early in women's reproductive careers

Abstract

We propose a general model of the relationships connecting fertility motivations, desires, and expectations in which motivations are antecedent to desires, which in turn are antecedent to expectations. We describe differences in the model as it applies to women early in their reproductive careers, specifically, after marriage but before their first birth and after their first birth but before their second. We test the model with data from 311 just‐married and 318 just‐mothered women, using LISREL to estimate structural equations for both groups. The general model fits the data well. There are three primary differences in the model with respect to the two groups of married women. How soon a woman expects her next child affects how many children she expects only among the just‐married woman. The number of children expected by the woman is the only antecedent to how soon she expects her next child among the just‐mothered women. Both positive and negative maternal motivation has effects among the just‐married women, but only negative maternal motivation has effects among the just‐mothered women. These and other differences are discussed in terms of psychological and situational developments occurring early in women's reproductive careers.     

Community extinction patterns in coloured environments

Understanding community responses to environmental variation is a fundamental aspect of ecological research, with direct ecological, conservation and economic implications. Here, we examined the role of the magnitude, correlation and autocorrelation structures of environmental variation on species' extinction risk (ER), and the probability of actual extinction events in model competitive communities. Both ER and probability increased with increasing positive autocorrelation when species responded independently to the environment, yet both decreased with a strong correlation between species-specific responses. These results are framed in terms of the synchrony between--and magnitude of variation within--species population sizes and are explained in terms of differences in noise amplification under different conditions. The simulation results are robust to changes in the strength of interspecific density dependence, and whether noise affects density-independent or density-dependent population processes. Similar patterns arose under different ranges of noise severity when these different model assumptions were examined. We compared our results with those from an analytically derived solution, which failed to capture many features of the simulation results.     

Species pool size and invasibility of island communities: a null model of sampling effects

The success of alien species on oceanic islands is considered to be one of the classic observed patterns in ecology. Explanations for this pattern are based on lower species richness on islands and the lower resistance of species‐poor communities to invaders, but this argument needs re‐examination. The important difference between islands and mainland is in the size of species pools, not in local species richness; invasibility of islands should therefore be addressed in terms of differences in species pools. Here I examine whether differences in species pools can affect invasibility in a lottery model with pools of identical native and exotic species. While in a neutral model with all species identical, invasibility does not depend on the species pool, a model with non‐zero variation in population growth rates predicts higher invasibility of communities of smaller pools. This is because of species sampling; drawing species from larger pools increases the probability that an assemblage will include fast growing species. Such assemblages are more likely to exclude random invaders. This constitutes a mechanism through which smaller species pools (such as those of isolated islands) can directly underlie differences in invasibility.     

Dynamics from a predator-prey-quarry-resource-scavenger model

Allochthonous resources can be found in many foodwebs and can influence both the structure and stability of an ecosystem. In order to better understand the role of how allochthonous resources are transferred as quarry from one predator-prey system to another, we propose a predator-prey-quarry-resource-scavenger (PPQRS) model, which is an extension of an existing model for quarry-resource-scavenger (a predator-prey-subsidy (PPS) model). Instead of taking the allochthonous resource input rate as a constant, as has been done in previous theoretical work, we explicitly incorporated the underlying predator-prey relation responsible for the input of quarry. The most profound differences between PPS and PPQRS system are found when the predator-prey system has limit cycles, resulting in a periodic rather than constant influx of quarry (the allochthonous resource) into the scavenger-resource interactions. This suggests that the way in which allochthonous resources are input into a predator-prey system can have a strong influence over the population dynamics. In order to understand the role of seasonality, we incorporated non-autonomous terms and showed that these terms can either stabilize or destabilize the dynamics, depending on the parameter regime. We also considered the influence of spatial motion (via diffusion) by constructing a continuum partial differential equation (PDE) model over space. We determine when such spatial dynamics essentially give the same information as the ordinary differential equation (ODE) system, versus other cases where there are strong spatial differences (such as spatial pattern formation) in the populations. In situations where increasing the carrying capacity in the ODE model drives the amplitude of the oscillations up, we found that a large carrying capacity in the PDE model results in a very small variation in average population size, showing that spatial diffusion is stabilizing for the PPQRS model.     

Expression, purification, kinetic, and structural characterization of an alpha-class carbonic anhydrase from Aedes aegypti (AaCA1)

Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that catalyze the interconversion of carbon dioxide and bicarbonate. The alpha-class CAs are found predominantly in vertebrates, but they are also expressed in insects like mosquitoes. Recently, an alpha-CA from the midgut of Aedes aegypti larvae (AaCA1) was identified, cloned, and subsequently shown to share high sequence homologous to human CA I (HCA I). This paper presents the bacterial expression, purification, and kinetic characterization of the soluble CA domain of AaCA1. The data show AaCA1 is a highly active CA that displays inhibition by methazolamide and ethoxzolamide with nM affinity. Additionally, a homology model of AaCA1, based on the crystal structure of HCA I, is presented and the overall structure, active site, and surface charge properties are compared to those of HCA I and II. Measurements of catalysis show that AaCA1 is more like HCA II in terms of proton transfer, but more similar to HCA I in terms of conversion of carbon dioxide to bicarbonate, and these differences are rationalized in terms of structure. These results also indicate that amino acid differences in the active site of AaCA1 compared to human CAs could be used to design specific CA inhibitors for the management of mosquito populations.     

The relationship between DNA value and chromosome volume in the coleopteran genus Dermestes

DNA values and chromosome volumes were determined for six species of the coleopteran genus Dermestes which have very similar karyotypes. Large differences in DNA value occur which give no indication of a geometric series. DNA value is approximately proportional to chromosome volume, indicating that the DNA differences lie in the chromosomes. Evidence from the variation in volume of the sex chromosomes, along with the DNA values, cannot be interpreted in terms of a chromosome model with a variable number of strands. DNA values are often at variance with the taxonomic grouping of species within the genus.     

Do experimental units of different scale affect the biological performance of European sea bass Dicentrarchus labrax larvae?

The effects of different tank volumes (2000, 500 and 40 l) on European sea bass Dicentrarchus labrax larval rearing, relating to growth, survival, quality and stress variables, were investigated. A dynamic energy budget (DEB) model was used to analyse the results. The hydrodynamics of the tanks exhibited differences, with the water currents in the 2000 l tanks to be almost one order of magnitude stronger than those in the 40 l ones. Important differences in fish growth were observed between small and large tank‐rearing volumes, with the smallest tank resulting in the slowest growth. Based on the DEB model analysis, growth differences were related to feeding rates, with growth in the smaller tank limited by food availability. Differences in survival rates were not statistically significant among the tank‐rearing volumes. The quality evaluation of the fry (in terms of swimbladder, jaw and skeletal abnormalities) showed differences, with the smallest tank having the highest percentage of deformed individuals. This could be attributed to both the feeding variances and the hydrodynamics in the tanks. No differences were observed in terms of whole‐body cortisol at the two developmental stages; flexion, and when the larvae body was fully covered by melanophores; when analysis was performed. This indicates that the allostatic load exerted on fish of different groups was similar and inside the fish‐coping abilities range, in terms of the cortisol response axis. The selection of the experimental scale is of importance, especially when the results are to be transferred and applied on an industrial scale.     

Learning and imitation as a function of social status in macaque monkeys (Macaca nemestrina)

Learning and imitation were examined in animals selected from two groups of sixteen pigtail monkeys. There were significant differences in performance on a cued-alternation task as a function of both social status within the stable group, and prior exposure to a social model. High status animals responded more frequently, but were less successful in acquiring appropriate response delay. Exposure to the model improved response latencies and acquisition of response delay for all subjects. However, model exposure did not improve alternation performance. Results are discussed in terms of prior social experience of the subjects, general learning strategies, and differential sensitivity to multiple reinforcement contingencies. Findings are related to ethological concepts of imitation, and field reports on primate social learning.     

Hierarchical Bayes estimation of hunting success rates with spatial correlations

A Bayesian hierarchical generalized linear model is used to estimate hunting success rates at the subarea level for postseason harvest surveys. The model includes fixed week effects, random geographic effects, and spatial correlations between neighboring subareas. The computation is done by Gibbs sampling and adaptive rejection sampling techniques. The method is illustrated using data from the Missouri Turkey Hunting Survey in the spring of 1996. Bayesian model selection methods are used to demonstrate that there are significant week differences and spatial correlations of hunting success rates among counties. The Bayesian estimates are also shown to be quite robust in terms of changes of hyperparameters.     

A mechanistic model for quasistatic pulmonary pressure-volume curves for inflation

A mechanistic model of the respiratory system is proposed to understand differences in quasistatic pressure-volume (p-V) curves of the inflation process in terms of the alveolar recruitment and the elastic distension of the wall tissues. In the model, a total respiratory system consists of a large number of elements, each of which is a subsystem of a cylindrical chamber fitted with a piston attached to a spring. The alveolar recruitment is simulated by allowing a distribution of the critical pressure at which an element opens; while the wall distension is represented by the piston displacement. Relations are derived between parameters in the error-function p-V model equation and properties of the mechanistic model The parameters of the model-based p-V equation are determined for clinical data sets of patients with acute respiratory distress syndrome.     

Determination of peptide conformation via vibrational coupling: Application to diastereoisomeric alanyl dipeptides

Solution-phase Raman spectra of diastereomeric alanyl dipeptides, D -Ala-L -Ala and L -Ala-L -Ala, and various mono- and dideuterated isotopomers in H₂O and D₂O, are reported. Spectral differences between the diastereomeric forms are interpreted, using the Raman analog of the coupled oscillator model, in terms of geometric differences between certain vibrations in the diastereomeric forms. Application of the coupled-oscillator formalism allows the determination of a dihedral angle between the coupling vibrations. The results are compared with vibrational coupling employed by other workers in the determination of the vibrational spectra of peptides.