Identifying sequence regions undergoing conformational change via predicted continuum secondary structure

Motivation: Conformational flexibility is essential to the function of many proteins, e.g. catalytic activity. To assist efforts in determining and exploring the functional properties of a protein, it is desirable to automatically identify regions that are prone to undergo conformational changes. It was recently shown that a probabilistic predictor of continuum secondary structure is more accurate than categorical predictors for structurally ambivalent sequence regions, suggesting that such models are suited to characterize protein flexibility. Results: We develop a computational method for identifying regions that are prone to conformational change directly from the amino acid sequence. The method uses the entropy of the probabilistic output of an 8-class continuum secondary structure predictor. Results for 171 unique amino acid sequences with well-characterized variable structure (identified in the 'Macromolecular movements database') indicate that the method is highly sensitive at identifying flexible protein regions, but false positives remain a problem. The method can be used to explore conformational flexibility of proteins (including hypothetical or synthetic ones) whose structure is yet to be determined experimentally.

Prediction of protein continuum secondary structure with probabilistic models based on NMR solved structures

Background: The structure of proteins may change as a result of the inherent flexibility of some protein regions. We develop and explore probabilistic machine learning methods for predicting a continuum secondary structure, i.e. assigning probabilities to the conformational states of a residue. We train our methods using data derived from high-quality NMR models. Results: Several probabilistic models not only successfully estimate the continuum secondary structure, but also provide a categorical output on par with models directly trained on categorical data. Importantly, models trained on the continuum secondary structure are also better than their categorical counterparts at identifying the conformational state for structurally ambivalent residues. Conclusion: Cascaded probabilistic neural networks trained on the continuum secondary structure exhibit better accuracy in structurally ambivalent regions of proteins, while sustaining an overall classification accuracy on par with standard, categorical prediction methods.

Structural change in macroeconomic time series: A complex systems perspective

We demonstrate that the process of generating smooth transitions Call be viewed as a natural result of the filtering operations implied in the generation of discrete-time series observations from the sampling of data from an underlying continuous time process that has undergone a process of structural change. In order to focus discussion, we utilize the problem of estimating the location of abrupt shifts in some simple time series models. This approach will permit its to address salient issues relating to distortions induced by the inherent aggregation associated with discrete-time sampling of continuous time processes experiencing structural change, We also address the issue of how time irreversible structures may be generated within the smooth transition processes. (c) 2005 Elsevier Inc. All rights reserved.

Optimal crossover designs for logistic regression models in pharmacodynamics

Pharmacodynamics (PD) is the study of the biochemical and physiological effects of drugs. The construction of optimal designs for dose-ranging trials with multiple periods is considered in this paper, where the outcome of the trial (the effect of the drug) is considered to be a binary response: the success or failure of a drug to bring about a particular change in the subject after a given amount of time. The carryover effect of each dose from one period to the next is assumed to be proportional to the direct effect. It is shown for a logistic regression model that the efficiency of optimal parallel (single-period) or crossover (two-period) design is substantially greater than a balanced design. The optimal designs are also shown to be robust to misspecification of the value of the parameters. Finally, the parallel and crossover designs are combined to provide the experimenter with greater flexibility.

Stirring in 3-d spherical models of convection in the Earth's mantle

On a global scale basalts from mid-ocean ridges are strikingly more homogeneous than basalts from intraplate volcanism. The observed geochemical heterogeneity argues strongly for the existence of distinct reservoirs in the Earth's mantle. It is an unresolved problem of Geodynamics as to how these findings can be reconciled with large-scale convection. We review observational constraints, and investigate stirring properties of numerical models of mantle convection. Conditions in the early Earth may have supported layered convection with rapid stirring in the upper layers. Material that has been altered near the surface is transported downwards by small-scale convection. Thereby a layer of homogeneous depleted material develops above pristine mantle. As the mantle cools over Earth history, the effects leading to layering become reduced and models show the large-scale convection favoured for the Earth today. Laterally averaged, the upper mantle below the lithosphere is least affected by material that has experienced near-surface differentiation. The geochemical signature obtained during the previous episode of small-scale convection may be preserved there for the longest time. Additionally, stirring is less effective in the high viscosity layer of the central lower mantle [1, 2], supporting the survival of medium-scale heterogeneities there. These models are the first, using 3-d spherical geometry and mostly Earth-like parameters, to address the suggested change of convective style. Although the models are still far from reproducing our planet, we find that proposal might be helpful towards reconciling geochemical and geophysical constraints.

Trust and psychological strain experienced by employees during organisational change

Most modern models of personality are hierarchical, perhaps as a result of their development by means of exploratory factor analysis. Based on new ideas about the structure of personality and how it divides into biologically based and sociocognitively based components (as proposed by Carver, Cloninger, EUiot and Thrash, and ReveUe), I develop a series of rules that show how scales of personality may be linked from those that are most distal to those which are most proximal. I use SEM to confirm the proposed structure in scales of the Temperament Character Inventory (TCI) and the Eysenck Personality Profiler. Good fit is achieved and all proposed paths are significant. The model is then used to predict work performance, deviance and job satisfacdon.

The Function and Consequences of Alternative Fresh Produce Supply Chain Models

Around the world, consumers and retailers of fresh produce are becoming more and more discerning about factors such as food safety and traceability, health, convenience and the sustainability of production systems, and in doing so they are changing the way in which fresh produce supply chains are configured and managed. When consumers demand fresh, safe, convenient, value-for-money produce, retailers in an increasingly competitive environment are attracted to those business models most capable of meeting these demands profitably. Traditional models are proving less and less able to deliver competitive advantage in such an environment. As a result, opportunistic, adversarial, price-based approaches to doing business between chain members are being replaced by approaches that are more strategic, collaborative and value-based. The shaping force behind this change is the need for producers, wholesalers, category managers, retailers and consumers to have more certainty about the performance of the supply chains upon which they rely. Certainty is generated through the supply chain's ability to create, deliver and share value. How to build supply chains that create, deliver and share value is arguably the single biggest challenge to the competitiveness of fresh produce firms, and therefore to the industries to which they belong.

All in Good Time: Exploring Change in Neanderthal Behavioural Complexity

Since their discovery 150 years ago, Neanderthals have been considered incapable of behavioural change and innovation. Traditional synchronic approaches to the study of Neanderthal behaviour have perpetuated this view and shaped our understanding of their lifeways and eventual extinction. In this thesis I implement an innovative diachronic approach to the analysis of Neanderthal faunal extraction, technology and symbolic behaviour as contained in the archaeological record of the critical period between 80,000 and 30,000 years BP. The thesis demonstrates patterns of change in Neanderthal behaviour which are at odds with traditional perspectives and which are consistent with an interpretation of increasing behavioural complexity over time, an idea that has been suggested but never thoroughly explored in Neanderthal archaeology. Demonstrating an increase in behavioural complexity in Neanderthals provides much needed new data with which to fuel the debate over the behavioural capacities of Neanderthals and the first appearance of Modern Human Behaviour in Europe. It supports the notion that Neanderthal populations were active agents of behavioural innovation prior to the arrival of Anatomically Modern Humans in Europe and, ultimately, that they produced an early Upper Palaeolithic cultural assemblage (the Châtelperronian) independent of modern humans. Overall, this thesis provides an initial step towards the development of a quantitative approach to measuring behavioural complexity which provides fresh insights into the cognitive and behavioural capabilities of Neanderthals.

Exploring Change in Neanderthal Behavioural Complexity: An Innovative Approach to the Study of Neanderthal Behaviour

Diachronic approaches provide potential for a more sophisticated framework within which to examine change in Neanderthal behavioural complexity using archaeological proxies such as symbolic artefacts, faunal assemblages and technology. Analysis of the temporal appearance and distribution of such artefacts and assemblages provide the basis for identifying changes in Neanderthal behavioural complexity in terms of symbolism, faunal extraction and technology respectively. Although changes in technology and faunal extraction were examined in the wider study, only the results of the symbolic study are presented below to illustrate the potential of the approach.

Population subdivision in marine environments: the contributions of biogeography, geographic distance, and discontinuous habitat to genetic differentiation in a blennioid

The relative importance of factors that may promote genetic differentiation in marine organisms is largely unknown. Here, contributions to population structure from biogeography, habitat distribution, and isolation by distance were investigated in Axoclinus nigricaudus, a small subtidal rock reef fish, throughout its range in the Gulf of California. A 408 basepair fragment of the mitochondrial control region was sequenced from 105 individuals. Variation was significantly partitioned between many pairs of populations. Phylogenetic analyses, hierarchical analyses of variance, and general linear models substantiated a major break between two putative biogeographic regions. This genetic discontinuity coincides with an abrupt change in ecological characteristics (including temperature and salinity) but does not coincide with known oceanographic circulation patterns. Geographic distance and the nature of habitat separating populations (continuous habitat along a shoreline, discontinuous habitat along a shoreline, and open water) also contributed to population structure in general linear model analyses. To verify that local populations are genetically stable over time, one population was resampled on four occasions over eighteen months; it showed no evidence of a temporal component to diversity. These results indicate that having a planktonic life stage does not preclude geographically partitioned genetic variation over relatively small geographic distances in marine environments. Moreover, levels of genetic differentiation among populations of Axoclinus nigricaudus cannot be explained by a single factor, but are due to the combined influences of a biogeographic boundary, habitat, and geographic distance.

Management Approaches to Merger Evoked Cultural Change and Acculturation Outcomes

In a study of merger-evoked cultural change in three organizations, quantitative and qualitative data were collected from individuals at all employment levels in both merger partners within each organization. Results were that most individuals perceived that the merger had impacted significantly on them personally. There was, however, a perceived lack of congruence between the organizational cultures of merging partners, resulting in cultural clashes and significant changes to the organizations' organizational cultures. More specifically, outcomes for both individuals and the subsequent acculturation following the mergers were related to the approach adopted to manage the merger process: incremental, immediate, or indifferent.