The nature and rate of vocalisation by southern right whales (Eubalaena australis), and the evidence for individually distinctive calls

Southern right whale vocalisations recorded in Walker Bay, South Africa, between June and November 1999, were analysed to investigate the acoustic repertoire, the relationship between calling behaviour and whale presence, the proportions of vocal and silent whales, and of recorded calls from unseen whales, and the evidence for vocal individuality. This marks the first study of right whale vocalisation in South African waters. A simple matrix system with the axes acoustic contour and onset frequency described twelve call types. Analysis of call use over time indicated that some calls, as well as broadband gunshots, clustered strongly in bouts of differing lengths, and that their relative use varied over the season; the repertoire and its classification was compared with other accounts of right whale vocalisation [chapter one]. A generalised linear model explained the variation in the overall call rate in terms of the numbers of whales present, month and wind direction. The overall call rate, for each month and in all wind conditions, rose with increasing whale numbers to a plateau at between ten and fifteen whales, and then declined as whale numbers rose further, suggesting that the social motivation for vocalising was progressively reversed. An inverse linear relationship between call rate per whale and whale abundance was clearly demonstrated over the whole season, indicating that call rates were unreliable as an indicator of whale numbers [chapter two]. A dual-axis, three-element hydrophone array suspended at 5m from floating buoys was designed to assign whale vocalisations to calling whales. The array was calibrated with an overall mean error of 3°. Bearings to calling whales were calculated using correlelograms, and compared with the observed positions of whales. On average 31% of low up (upwardly inflected) calls and 11% of medium and high down (downwardly inflected) calls came from whales not sighted from the boat; up to just under half of the whales sighted from the boat were silent. This indicates the importance of integrating visual and acoustic data when estimating whale numbers [chapter three]. In characterising individuality in vocalisations, we used cluster analysis of acoustic properties of whale calls to derive the Euclidean distances (a measure of similarity) between each possible pair of calls within a continuous recording session. Calls clearly from different whales (distant call pairs) were more dissimilar than calls possibly from one whale (‘close’ call pairs), lending support to the hypothesis of vocal individuality. The similarity between ‘close’ up calls was greatest when the calls were within 0.5 minutes of each other, and declined progressively, up to a separation of 6.5 minutes, as the likelihood of both calls being from one whale declined, indicating individual bout-calling. Medium and high down (downwardly inflected) calls, associated with surface active groups (SAGs), and thought by other researchers to be produced by the focal female, were more similar within any given SAG than when compared across SAGs. This evidence strongly suggests that southern right whales produce individually distinctive vocalisations [chapter four].Thesis (PhD)--University of Pretoria, 2010.Zoology and Entomologyunrestricte

A graph-theoretic approach for classification and structure prediction of transmembrane β-barrel proteins

BACKGROUND: Non-synonymous coding SNPs (nsSNPs) that are associated to disease can also be related with alterations in protein stability. Computational methods are available to predict the effect of single amino acid substitutions (SASs) on protein stability based on a single folded structure. However, the native state of a protein is not unique and it is better represented by the ensemble of its conformers in dynamic equilibrium. The maintenance of the ensemble is essential for protein function. In this work we investigated how protein conformational diversity can affect the discrimination of neutral and disease related SASs based on protein stability estimations. For this purpose, we used 119 proteins with 803 associated SASs, 60% of which are disease related. Each protein was associated with its corresponding set of available conformers as found in the Protein Conformational Database (PCDB). Our dataset contains proteins with different extensions of conformational diversity summing up a total number of 1023 conformers. RESULTS: The existence of different conformers for a given protein introduces great variability in the estimation of the protein stability (\u394\u394G) after a single amino acid substitution (SAS) as computed with FoldX. Indeed, in 35% of our protein set at least one SAS can be described as stabilizing, destabilizing or neutral when a cutoff value of \ub12 kcal/mol is adopted for discriminating neutral from perturbing SASs. However, when the \u394\u394G variability among conformers is taken into account, the correlation among the perturbation of protein stability and the corresponding disease or neutral phenotype increases as compared with the same analysis on single protein structures. At the conformer level, we also found that the different conformers correlate in a different way to the corresponding phenotype. CONCLUSIONS: Our results suggest that the consideration of conformational diversity can improve the discrimination of neutral and disease related protein SASs based on the evaluation of the corresponding Gibbs free energy change

Acoustic behaviour of southern right whales in relation to numbers of whales present in Walker Bay, South Africa

Estimating numbers of whales present in an area from recorded call rates could be a useful conservation tool. We recorded southern right whale Eubalaena australis vocalisations and presence in Walker Bay on the south coast of South Africa. In all, 45 sessions with synchronous acoustic and visual data were analysed to determine call rates directly (overall call rate, OCR) and in relation to the number of whales sighted (call rate per whale, CPW) and number of groups sighted (call rate per group, CPG). The OCRs were examined in the presence of varying numbers of whales, using a log-linear model to investigate the dependence of the call rate on whale density. The number of whales present exerted a strong quadratic effect on the OCR, which peaked at around 15 whales and decreased to a low rate as whale presence approached a maximum, for all calls combined and for four of their constituent 13 call types: a quadratic trend was present to varying degrees among the remaining call types. Both quadratic and linear trends were absent when OCR was assessed against number of groups present, possibly because group size increased with increasing density of whales. A linear regression on the CPW and CPG suggested that there was a negative inverse relationship with the number of whales and groups present respectively. These findings are important in that, while they preclude the estimation of absolute numbers from call rates, they imply that, under the conditions prevailing in Walker Bay, southern right whales were aware of the presence, arrival and departure of other animals in their vicinity and adjusted their vocal behaviour accordingly.The National Research Foundation, the Worldwide Fund for Nature, South Africa (WWF SA), PetroSA (formerly Soekor), the Wildlife and Environment Society of South Africa and Spescom,.http://www.tandfonline.com/loi/tams20nf201

A Universal Method for Analysing Copolymer Growth

Polymers consisting of more than one type of monomer, known as copolymers, are vital to both living and synthetic systems. Copolymerisation has been studied theoretically in a number of contexts, often by considering a Markov process in which monomers are added or removed from the growing tip of a long copolymer. To date, the analysis of the most general models of this class has necessitated simulation. We present a general method for analysing such processes without resorting to simulation. Our method can be applied to models with an arbitrary network of sub-steps prior to addition or removal of a monomer, including non-equilibrium kinetic proofreading cycles. Moreover, the approach allows for a dependency of addition and removal reactions on the neighbouring site in the copolymer, and thermodynamically self-consistent models in which all steps are assumed to be microscopically reversible. Using our approach, thermodynamic quantities such as chemical work; kinetic quantities such as time taken to grow; and statistical quantities such as the distribution of monomer types in the growing copolymer can be derived either analytically or numerically directly from the model definition.Comment: 24 pages, 11 figure

How to turn the Fast-Track into a Fast-Track: Process integration for evaluation of the quality of Digital Health Applications (DiGAs) on the example of the German Fast-Track Process

In this paper, we address the research question of which integration points in the \textit{German Fast-Track process} are particularly well suited for the integration of evaluation platforms for digital health applications. For this purpose, possible integration points are first identified and then analyzed with the help of a utility analysis with regard to the posed research question. Finally, a recommendation for action is made based on the results of the conducted utility analysis

Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening

Aims: G protein-coupled receptor (GPCR) kinases (GRKs) are mainly involved in the desensitization of GPCRs. Among them, GRK2 has been described to be upregulated in many pathological conditions and its crucial role in cardiac hypertrophy, hypertension, and heart failure promoted the search for pharmacological inhibitors of its activity. There have been several reports of potent and selective inhibitors of GRK2, most of them directed to the kinase domain of the protein. However, the homologous to the regulator of G protein signaling (RH) domain of GRK2 has also been shown to regulate GPCRs signaling. Herein, we searched for potential inhibitors of receptor desensitization mediated by RH domain of GRK2. Materials and methods: We performed a docking-based virtual screening utilizing the crystal structure of GRK2 to search for potential inhibitors of the interaction between GRK2 and Gαq protein. To evaluate the biological activity of compounds we measured, calcium response of histamine H1 receptor (H1R) using Fura-2AM dye and H1R internalization by saturation binding experiments in A549 cells. GRK2(45–178)GFP translocation was determined in HeLa cells through confocal fluorescence imaging. Key findings: We identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to plasma membrane. Also candidates presented adequate lipophilia and cytotoxicity profile. Significance: We obtained compounds with the ability of reducing RH mediated actions of GRK2 that can be useful as a starting point in the development of novel drug candidates aimed to treat pathologies were GRK2 plays a key role.Fil: Echeverría, Emiliana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Velez Rueda, Ana Julia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cabrera, Maia Diana Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; ArgentinaFil: Juritz, Ezequiel. Universidad Nacional de Quilmes; Argentina. Universidad Andrés Bello; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Burghi, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Fabian, Lucas Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Davio, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernandez, Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentin

Pocketome: an encyclopedia of small-molecule binding sites in 4D

The importance of binding site plasticity in protein–ligand interactions is well-recognized, and so are the difficulties in predicting the nature and the degree of this plasticity by computational means. To assist in understanding the flexible protein–ligand interactions, we constructed the Pocketome, an encyclopedia of about one thousand experimentally solved conformational ensembles of druggable binding sites in proteins, grouped by location and consistent chain/cofactor composition. The multiplicity of pockets within the ensembles adds an extra, fourth dimension to the Pocketome entry data. Within each ensemble, the pockets were carefully classified by the degree of their pairwise similarity and compatibility with different ligands. The core of the Pocketome is derived regularly and automatically from the current releases of the Protein Data Bank and the Uniprot Knowledgebase; this core is complemented by entries built from manually provided seed ligand locations. The Pocketome website (www.pocketome.org) allows searching for the sites of interest, analysis of conformational clusters, important residues, binding compatibility matrices and interactive visualization of the ensembles using the ActiveICM web browser plugin. The Pocketome collection can be used to build multi-conformational docking and 3D activity models as well as to design cross-docking and virtual ligand screening benchmarks

PCDB: a database of protein conformational diversity

PCDB (http://www.pcdb.unq.edu.ar) is a database of protein conformational diversity. For each protein, the database contains the redundant compilation of all the corresponding crystallographic structures obtained under different conditions. These structures could be considered as different instances of protein dynamism. As a measure of the conformational diversity we use the maximum RMSD obtained comparing the structures deposited for each domain. The redundant structures were extracted following CATH structural classification and cross linked with additional information. In this way it is possible to relate a given amount of conformational diversity with different levels of information, such as protein function, presence of ligands and mutations, structural classification, active site information and organism taxonomy among others. Currently the database contains 7989 domains with a total of 36581 structures from 4171 different proteins. The maximum RMSD registered is 26.7 Å and the average of different structures per domain is 4.5