Multidimensional Scaling Reveals the Main Evolutionary Pathways of Class A G-Protein-Coupled Receptors

Class A G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors in the human genome. Understanding the mechanisms which drove the evolution of such a large family would help understand the specificity of each GPCR sub-family with applications to drug design. To gain evolutionary information on class A GPCRs, we explored their sequence space by metric multidimensional scaling analysis (MDS). Three-dimensional mapping of human sequences shows a non-uniform distribution of GPCRs, organized in clusters that lay along four privileged directions. To interpret these directions, we projected supplementary sequences from different species onto the human space used as a reference. With this technique, we can easily monitor the evolutionary drift of several GPCR sub-families from cnidarians to humans. Results support a model of radiative evolution of class A GPCRs from a central node formed by peptide receptors. The privileged directions obtained from the MDS analysis are interpretable in terms of three main evolutionary pathways related to specific sequence determinants. The first pathway was initiated by a deletion in transmembrane helix 2 (TM2) and led to three sub-families by divergent evolution. The second pathway corresponds to the differentiation of the amine receptors. The third pathway corresponds to parallel evolution of several sub-families in relation with a covarion process involving proline residues in TM2 and TM5. As exemplified with GPCRs, the MDS projection technique is an important tool to compare orthologous sequence sets and to help decipher the mutational events that drove the evolution of protein families

Solving Euclidean Distance Matrix Completion Problems Via Semidefinite Programming

Given a partial symmetric matrix A with only certain elements specified, the Euclidean distance matrix completion problem (EDMCP) is to find the unspecified elements of A that make A a Euclidean distance matrix (EDM). In this paper, we follow the successful approach in [20] and solve the EDMCP by generalizing the completion problem to allow for approximate completions. In particular, we introduce a primal-dual interiorpoint algorithm that solves an equivalent (quadratic objective function) semidefinite programming problem (SDP). Numerical results are included which illustrate the efficiency and robustness of our approach. Our randomly generated problems consistently resulted in low dimensional solutions when no completion existed

Multidimensional asessment of awareness in early-stage dementia: a cluster-analytic approach

Background/Aims: Research on awareness in dementia has yielded variable and inconsistent associations between awareness and other factors. This study examined awareness using a multidimensional approach and applied cluster analytic techniques to identify associations between the level of awareness and other variables. Methods: Participants were 101 individuals with early-stage dementia (PwD) and their carers. Explicit awareness was assessed at 3 levels: performance monitoring in relation to memory, evaluative judgement in relation to memory, everyday activities and socio-emotional functioning, and metacognitive reflection in relation to the experience and impact of the condition. Implicit awareness was assessed with an emotional Stroop task. Results: Different measures of explicit awareness scores were related only to a limited extent. Cluster analysis yielded 3 groups with differing degrees of explicit awareness.These groups showed no differences in implicit awareness.Lower explicit awareness was associated with greater age, lower MMSE scores, poorer recall and naming scores,lower anxiety and greater carer stress. Conclusion: Multidi-mensional assessment offers a more robust approach toclassifying PwD according to level of awareness and hence to examining correlates and predictors of awareness

Optimization Using Surrogate Objectives on a Helicopter Test Example

This paper presents results for a 31 variable helicopter rotor design example. Results are given for several numerical methods. This is a brief description of a portion of the Boeing/IBM/Rice University collaboration whose purpose is to develop effective numerical methods for managing the use of approximation concepts or response surface methodology in design optimization

Memory awareness profiles differentiate mild cognitive impairment from early-stage dementia: evidence from assessments of performance monitoring and evaluative judgement

Background: Measures of memory awareness based on evaluative judgement and performance monitoring are often regarded as equivalent, but the Levels of Awareness framework suggests they reflect different awareness phenomena. Examination of memory awareness among groups with differing degrees of impairment provides a test of this proposition. Method: Ninety-nine people with dementia (PwD), 30 people with mild cognitive impairment (PwMCI), and their relatives completed isomorphic performance monitoring and evaluative judgement measures of memory awareness and were followed up at 12 and (PwD only) 20 months. In addition to the resulting awareness indices, comparative accuracy scores were calculated using the relatives’ data to establish whether any inaccuracy was specific to self-ratings. Results: When making evaluative judgements about their memory in general, both PwD and PwMCI tended to overestimate their own functioning relative to informant ratings made by relatives. When monitoring performance on memory tests, PwD again overestimated performance relative to test scores, but PwMCI were much more accurate. Comparative accuracy scores indicated that, unlike PwD, PwMCI do not show a specific inaccuracy in self-related appraisals. Conclusions: The results support the proposition that awareness indices at the levels of evaluative judgement and performance monitoring should be regarded as reflecting distinct awareness phenomena

Visualising concordance

Concordance coefficients, Graphical methods, Ranks, Parallel coordinates, Polar coordinates, Bubble plot, Pin-cushion plot,