Using Dominances for Solving the Protein Family Identification Problem

Published in Workshop on Algorithms for Bioinformatics (WABI 2011)International audienceIdentification of protein families is a computational biology challenge that needs efficient and reliable methods. Here we introduce the concept of dominance and propose a novel combined approach based on Distance Alignment Search Tool (DAST), which contains an exact algorithm with bounds. Our experiments show that this method successfully finds the most similar proteins in a set without solving all instances.L'identification des familles protéique est un challenge de la biologie computationnelle qui nécessite des méthodes efficaces et robustes. Nous introduisons ici le concept de dominance entre instance de comparaison de structures protéiques, et proposons une nouvelle approche basée sur DAST (Distance Alignment Search Tool), un algorithme exact auquel nous rajoutons des bornes. Les résultats obtenus montrent que notre méthode résout correctement le problème de l'identification des familles protéique sans avoir besoin de résoudre toutes les instances de comparaison de structure

Similarités et divergences, globales et locales, entre structures protéiques

This thesis focusses on local and global similarities and divergences inside protein structures. First, structures are scored, with criteria of similarity and distance in order to provide a supervised classification. This structural domain classification inside existing hierarchical databases is possible by using dominances and learning. These methods allow to assign new domains with accuracy and exactly. Second we focusses on local similarities and proposed a method of protein comparison modelisation inside graphs. Graph traversal allows to find protein similar substructures. This method is based on compatibility between elements and criterion of distances. We can use it and detect events such that circular permutations, hinges and structural motif repeats. Finally we propose a new approach of accurate protein structure analysis that focused on divergences between similar structures.Cette thèse s'articule autour de la détection de similarités globales et locales dans les structures protéiques. Premièrement les structures sont comparées, mesurées en termes de distance métrique dans un but de classification supervisée. Cette classification des domaines structuraux au sein de classifications hiérarchiques se fait par le biais de dominances et d'apprentissages permettant d'assigner plus rapidement et de manière exacte de nouveaux domaines. Deuxièmement, nous proposons une méthode de manière de traduire un problème biologique dans les formalisme des graphes. Puis nous résolvons ce problème via le parcours de ces graphes pour extraire les différentes sous-structures similaires. Cette méthode repose sur des notions de compatibilités entre éléments des structures ainsi que des critères de distances entre éléments. Ces techniques sont capables de détecter des événements tels que des permutations circulaires, des charnières (flexibilité) et des répétitions de motifs structuraux. Finalement nous proposons une nouvelle approche dans l'analyse fine de structures afin de faciliter la recherche de régions divergentes entre structures 3D fortement similaires

Genetic management of Atlantic cod (Gadus morhua L.) hatchery populations.

Intensive aquaculture of Atlantic cod is fast developing in both Northern Europe and Canada. The last six years have seen major improvements in the larval rearing protocols and husbandry techniques for this species. Although breeding programmes are currently being developed by both governmental and private institutions in the main cod producing countries (i.e. Norway, Iceland and Canada), most hatcheries still rely on the mass spawning of their own broodstock. Mass spawning tanks are complex systems where fish are left to spawn naturally and fertilised eggs are collected with the overflowing water, with little or no control over the matings of the animals. Few published studies in other commercial marine species (i.e. turbot and sole) have attempted to analyse the output from such systems using microsatellite markers and several parentage analysis software programs. A review of these publications exposed a lack of consistency in the methods used to analyse such complex datasets. This problem was addressed by carrying out a detailed comparison of two analytical principals (i.e. assignment by strict exclusion and assignment by probabilities) and four parentage software programmes (i.e. FAP, VITASSIGN, CERVUS and PAPA), using the DNA profiles, at 5 loci, from 300 cod fry issued from the mass spawning of a large hatchery cod broodstock tank (consisting of 99 fish). This study revealed large discrepancies in the allocation outcomes between exclusion-based and probability-based assignments caused by the important rate of typing errors present in the dataset. Out of the four softwares tested, FAP (Taggart, 2007) was the most appropriate to use for handling such a dataset. It combined the most conservative method of assignment with the most informative output for the results displayed. In an attempt to study the breeding dynamics in a cod commercial hatchery, parental contributions to five groups of 300 fry (from five single days of spawning and from two commercial mass spawning cod tanks) were analysed, based on the genotyping data from eight loci. The parentage results from the exclusion-based analyses revealed that, on a single day, at least 25 to 30% of the total breeding population contributed to fertilised eggs that resulted in viable offspring at 50 and 83 days post-hatch. Family representations were highly skewed - with the marked dominance of a few males - and effective breeding populations were consistently low (approx. 5% of the total breeding population). Parental contribution to a group of 960 codlings - produced following intensive commercial practices (i.e. including successive size gradings and mixing of batches) and belonging to a single graded group - was also analysed, based on the genotyping data from eleven loci. The effective breeding population size of the juvenile batch (c. 14% of the total broodstock population) was two to three times greater than the effective size observed on a single day of mass spawning. The per-generation rate of inbreeding was however relatively high, for this batch alone, at 2.5%. Based on these results, suggestions were made to manage hatchery cod broodstock populations and implement genetic selection. Early maturation of farmed cod in sea cages (at two or three years old) is a major concern for ongrowers. Understanding the mechanism(s) behind sex determination in cod would probably help the development of a method to control sexual maturation. In an attempt to elucidate sex determination in cod, a protocol to induce gynogenesis was developed. Gynogenetic fish were successfully produced by irradiating cod milt with UV and applying a cold shock (at -6oC) to newly fertilised eggs. However, due to poor survival during larval rearing, only one gynogenetic fish survived long enough to be sexed; not enough to conclude anything on the sex determination mechanism(s) in cod

Exact algorithms for pairwise protein structure alignment

Klau, G.W. [Promotor

SWOSU Research and Scholarly Activity Fair 2017

Welcome to the Twenty-Fourth SWOSU Research and Scholarly Activity Fair! On display today are 158 poster presentations and 11 oral presentations, involving 314 student researchers, writers, presenters, and artists, and 47 faculty sponsors encompassing scholarly activity from the SWOSU Departments of Art, Communication, and Theatre; Biological Sciences; Business & Computer Science; Chemistry and Physics; Engineering Technology; Language & Literature; Music; Pharmaceutical Sciences; Psychology; and Social Sciences; and SWOSU School of Nursing and Allied Health Sciences. In addition, there are poster presentations from the Western Technology Center Biomedical Academy, Francis Tuttle Technology Center, El Reno Public Schools, and BlueSTEM AgriLearning Center

Mathematical modeling of phasic calcium dynamics in HaCaT cells

openBackground: Connexin (Cx) channels are ubiquitous, providing pathways for movement of molecules between cells and for release of molecular effectors into the extracellular environment (plasma membrane hemichannels (HCs)). To maintain an adequate permeability barrier, HCs are tightly regulated by normal extracellular calcium ion (Ca2+) to be closed under most conditions. Cx mutations that disrupt HC regulation by Ca2+ cause human pathologies, due to aberrantly open HCs. These pathological conditions including cardiac infarct, stroke, deafness, cataracts, epilepsy, Alzheimer’s disease, and skin diseases. Therefore, Cx HCs have emerged as a valid therapeutic target. Cx HCs activity has been explored indirectly by the release of adenosine triphosphate (ATP) and other metabolite, as well as by electrophysiological methods and/or using HC-permeable dye uptake measurements. Recently, all-optical assay based on fluorometric measurements of Ca2+ uptake with a Ca2+-selective genetically encoded indicator (GCaMP6s), that permits the optical tracking of cytosolic Ca2+ concentration changes with high sensitivity, was presented, the assay in stable pools of HaCaT cells overexpressing Cxs of interest, under control of a tetracycline (Tet) responsive element (TRE) promoter (Tet-on), for the characterization of new monoclonal antibodies targeting the extracellular domain of the HCs. Aim: Developing a mathematical model of Ca2+ dynamics with the aim of simulating the complex responses measured experimentally by fluorescence microscopy in HaCaT cells challenged by a sudden increase of the extracellular Ca2+ concentration. Moreover, the model aims to explain the observed damping effects caused by increasing concentrations of different HC blockers, including monoclonal antibodies targeted at the HC extracellular domain. Method: Open source ImageJ software as well as Vimmaging (a custom-made software developed under the MATLAB environment) were used to derive Ca2+ uptake traces in HaCaT-Cx26- GCaMP6s cell cultured bathed in extracellular medium and exposed to CaCl2 bolus concentrations to reach final extracellular Ca2+ concentrations of 2mM, 1mM, 560M, 260M, and 100M. A set of previously derived differential equations that successfully modeled epidermal Ca2+ dynamics in vivo was adapted to the peculiar toolset of ion channels and transporters expressed in HaCaT cells to generate an original model variant account quantitatively for the insurgence of a biphasic elevation of intracellular Ca2+ when the extracellular Ca2+ concentration overcomes a critical threshold. Conclusion: Our mathematical simulation of Ca2+ dynamic has revealed that the first elevation phase of Ca2+ observed experimentally is due to the release of Ca2+ from endoplasmic reticulum to cytosol, whereas the second peak is the result of influx of Ca2+ from extracellular milieu to cytosol through HC.Background: Connexin (Cx) channels are ubiquitous, providing pathways for movement of molecules between cells and for release of molecular effectors into the extracellular environment (plasma membrane hemichannels (HCs)). To maintain an adequate permeability barrier, HCs are tightly regulated by normal extracellular calcium ion (Ca2+) to be closed under most conditions. Cx mutations that disrupt HC regulation by Ca2+ cause human pathologies, due to aberrantly open HCs. These pathological conditions including cardiac infarct, stroke, deafness, cataracts, epilepsy, Alzheimer’s disease, and skin diseases. Therefore, Cx HCs have emerged as a valid therapeutic target. Cx HCs activity has been explored indirectly by the release of adenosine triphosphate (ATP) and other metabolite, as well as by electrophysiological methods and/or using HC-permeable dye uptake measurements. Recently, all-optical assay based on fluorometric measurements of Ca2+ uptake with a Ca2+-selective genetically encoded indicator (GCaMP6s), that permits the optical tracking of cytosolic Ca2+ concentration changes with high sensitivity, was presented, the assay in stable pools of HaCaT cells overexpressing Cxs of interest, under control of a tetracycline (Tet) responsive element (TRE) promoter (Tet-on), for the characterization of new monoclonal antibodies targeting the extracellular domain of the HCs. Aim: Developing a mathematical model of Ca2+ dynamics with the aim of simulating the complex responses measured experimentally by fluorescence microscopy in HaCaT cells challenged by a sudden increase of the extracellular Ca2+ concentration. Moreover, the model aims to explain the observed damping effects caused by increasing concentrations of different HC blockers, including monoclonal antibodies targeted at the HC extracellular domain. Method: Open source ImageJ software as well as Vimmaging (a custom-made software developed under the MATLAB environment) were used to derive Ca2+ uptake traces in HaCaT-Cx26- GCaMP6s cell cultured bathed in extracellular medium and exposed to CaCl2 bolus concentrations to reach final extracellular Ca2+ concentrations of 2mM, 1mM, 560M, 260M, and 100M. A set of previously derived differential equations that successfully modeled epidermal Ca2+ dynamics in vivo was adapted to the peculiar toolset of ion channels and transporters expressed in HaCaT cells to generate an original model variant account quantitatively for the insurgence of a biphasic elevation of intracellular Ca2+ when the extracellular Ca2+ concentration overcomes a critical threshold. Conclusion: Our mathematical simulation of Ca2+ dynamic has revealed that the first elevation phase of Ca2+ observed experimentally is due to the release of Ca2+ from endoplasmic reticulum to cytosol, whereas the second peak is the result of influx of Ca2+ from extracellular milieu to cytosol through HC

A single cell based model for cell divisions with spontaneous topology changes

The development of multicellular organisms is accompanied by the formation of tis- sues of precise shapes, sizes and topologies. Remarkable similarities between tissue topologies, in particular proliferating epithelial topologies, in various species suggest that the mechanisms that govern the formation of tissues are conserved among species. To understand these mechanisms various models have been developed. In this thesis, we present a novel mechanical model for cell divisions and tissue for- mation. The model accounts for cell mechanics and cell-cell adhesion. In our model, each cell is treated individually, thus the changes in cell’s shape and its local rearrange- ments occur naturally as a response to the evolving cellular environment and cell-cell interactions. We introduce the processes of cell growth and divisions and numerically simulate tissue proliferation. As tissue grows starting from few cells, we follow the dynamics of the tissue growth and cell packing topologies. The outcomes are com- pared with experimental observations in Drosophila wing growth. Our model accounts for the exponential decay of the mitotic index and reproduces commonly observed cell packing topologies in proliferating epithelia. Next, we consider two biologically relevant division schemes, namely, division through asymmetric division plane and division by Hertwig’s rule. We study the im- pact of division planes on tissue growth and show that the division plane may affect cell packing topologies. Development of the tissue is accompanied by cellular rearrange- ments. We vary the extent of cellular rearrangements and analyse their effects on tissue topology. We find that when cells are allowed to move freely, more organized packing topologies emerge

BROADENING THE PERSPECTIVE OF ECONOMIC EVALUATION IN HEALTH CARE – A CASE STUDY IN DEMENTIA CARE IN THE UK

My thesis is an investigation of the methods to implement a broader societal perspective in economic evaluation. I proposed two potential approaches that could be used to implement a societal perspective in economic evaluation: An extended cost-per-QALY approach and a CCA-MCDA approach. The investigation was conducted in a case study of dementia care. The case study concerned the evaluation of 4 mutually exclusive options for primary care to early detect people with dementia. I reviewed previous economic evaluation studies in dementia and developed a new cost-effectiveness model for this evaluation. The model provided estimates for costs including health care, government-funded social care, privately funded social care and informal care. Benefits were measured in terms of patient QALYs and carer QALYs. Using the model’s estimates as the initial basis, I applied the principles of the extended cost-per-QALY approach and the CCA-MCDA to implement a broader societal perspective in the economic evaluation in the case study

Advancing Knowledge on Cyanobacterial Blooms in Freshwaters

Cyanobacterial blooms are a water quality problem that is widely acknowledged to have detrimental ecological and economic effects in drinking and recreational water supplies and fisheries. There is increasing evidence that cyanobacterial blooms have increased globally and are likely to expand in water resources as a result of climate change. Of most concern are cyanotoxins, along with the mechanisms that induce their release and determine their fate in the aquatic environment. These secondary metabolites pose a potential hazard to human health and agricultural and aquaculture products that are intended for animal and human consumption; therefore, strict and reliable control of cyanotoxins is crucial for assessing risk. In this direction, a deeper understanding of the mechanisms that determine cyanobacterial bloom structure and toxin production has become the target of management practices. This Special Issue, entitled “Advancing Knowledge on Cyanobacterial Blooms in Freshwaters”, aims to bring together recent multi- and interdisciplinary research, from the field to the laboratory and back again, driven by working hypotheses based on any aspect of mitigating cyanobacterial blooms, from ecological theory to applied research