References of "Jurkowski, Wiktor 40021149"
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See detailAnalysis of ELP4, SRPX2, and interacting genes in typical and atypical rolandic epilepsy
Reinthaler, E.; Lal, D.; Jurkowski, Wiktor UL et al

in Epilepsia (2014), 55(8), 8993

Rolandic epilepsy (RE) and its atypical variants (atypical rolandic epilepsy, ARE) along the spectrum of epilepsy–aphasia disorders are characterized by a strong but largely unknown genetic basis. Two ... [more ▼]

Rolandic epilepsy (RE) and its atypical variants (atypical rolandic epilepsy, ARE) along the spectrum of epilepsy–aphasia disorders are characterized by a strong but largely unknown genetic basis. Two genes with a putative (ELP4) or a proven (SRPX2) function in neuronal migration were postulated to confer susceptibility to parts of the disease spectrum: the ELP4 gene to centrotemporal spikes and SRPX2 to ARE. To reexamine these findings, we investigated a cohort of 280 patients of European ancestry with RE/ARE for the etiological contribution of these genes and their close interaction partners. We performed next-generation sequencing and single-nucleotide polymorphism (SNP)–array based genotyping to screen for sequence and structural variants. In comparison to European controls we could not detect an enrichment of rare deleterious variants of ELP4, SRPX2, or their interaction partners in affected individuals. The previously described functional p.N327S variant in the X chromosomal SRPX2 gene was detected in two affected individuals (0.81%) and also in controls (0.26%), with some preponderance of male patients. We did not detect an association of SNPs in the ELP4 gene with centrotemporal spikes as previously reported. In conclusion our data do not support a major role of ELP4 and SRPX2 in the etiology of RE/ARE. [less ▲]

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See detailIntegrating Pathways of Parkinson's Disease in a Molecular Interaction Map
Fujita, Kazuhiro A.; Ostaszewski, Marek UL; Matsuoka, Yukiko et al

in Molecular Neurobiology (2014)

Parkinson's disease (PD) is a major neurodegenerative chronic disease, most likely caused by a complex interplay of genetic and environmental factors. Information on various aspects of PD pathogenesis is ... [more ▼]

Parkinson's disease (PD) is a major neurodegenerative chronic disease, most likely caused by a complex interplay of genetic and environmental factors. Information on various aspects of PD pathogenesis is rapidly increasing and needs to be efficiently organized, so that the resulting data is available for exploration and analysis. Here we introduce a computationally tractable, comprehensive molecular interaction map of PD. This map integrates pathways implicated in PD pathogenesis such as synaptic and mitochondrial dysfunction, impaired protein degradation, alpha-synuclein pathobiology and neuroinflammation. We also present bioinformatics tools for the analysis, enrichment and annotation of the map, allowing the research community to open new avenues in PD research. The PD map is accessible at http://minerva.uni.lu/pd_map . [less ▲]

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See detailHippocampal extracellular matrix levels and stochasticity in synaptic protein expression increase with age and are associated with age-dependent cognitive decline.
Vegh, Marlene J.; Rausell, Antonio; Loos, Maarten et al

in Molecular & cellular proteomics : MCP (2014)

Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and ... [more ▼]

Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wildtype mice have hippocampus-dependent spatial memory impairments. To identify the molecular mechanisms that are relevant to these memory deficits we investigated the temporal profile of mouse hippocampal synaptic proteome changes at 20, 40, 50, 60, 70, 80, 90 and 100 weeks of age. Extracellular matrix proteins were the only group of proteins that showed a robust and progressive upregulation over time. This was confirmed by immunoblotting and histochemical analysis, indicating that the increased levels of hippocampal extracellular matrix may limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission. Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance at old age. [less ▲]

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See detailThe Parkinson's Disease Map: A Framework for Integration, Curation and Exploration of Disease-related Pathways
Ostaszewski, Marek UL; Fujita, Kazuhiro; Matsuoka, Yukiko et al

Poster (2013, March 09)

Objectives: The pathogenesis of Parkinson's Disease (PD) is multi-factorial and age-related, implicating various genetic and environmental factors. It becomes increasingly important to develop new ... [more ▼]

Objectives: The pathogenesis of Parkinson's Disease (PD) is multi-factorial and age-related, implicating various genetic and environmental factors. It becomes increasingly important to develop new approaches to organize and explore the exploding knowledge of this field. Methods: The published knowledge on pathways implicated in PD, such as synaptic and mitochondrial dysfunction, alpha-synuclein pathobiology, failure of protein degradation systems and neuroinflammation has been organized and represented using CellDesigner. This repository has been linked to a framework of bioinformatics tools including text mining, database annotation, large-scale data integration and network analysis. The interface for online curation of the repository has been established using Payao tool. Results: We present the PD map, a computer-based knowledge repository, which includes molecular mechanisms of PD in a visually structured and standardized way. A bioinformatics framework that facilitates in-depth knowledge exploration, extraction and curation supports the map. We discuss the insights gained from PD map-driven text mining of a corpus of over 50 thousands full text PD-related papers, integration and visualization of gene expression in post mortem brain tissue of PD patients with the map, as well as results of network analysis. Conclusions: The knowledge repository of disease-related mechanisms provides a global insight into relationships between different pathways and allows considering a given pathology in a broad context. Enrichment with available text and bioinformatics databases as well as integration of experimental data supports better understanding of complex mechanisms of PD and formulation of novel research hypotheses. [less ▲]

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See detailLigand binding properties of human galanin receptors
Jurkowski, Wiktor UL; Yarzdi, Samira; Elofsson, Arne

in Molecular Mebrance Biology (2013), 30(2), 206-216

The galanin receptor family comprises of three members, GalR1, GalR2 and GalR3, all belonging to the G-protein-couple receptor superfamily. All three receptors bind the peptide hormone galanin, but show ... [more ▼]

The galanin receptor family comprises of three members, GalR1, GalR2 and GalR3, all belonging to the G-protein-couple receptor superfamily. All three receptors bind the peptide hormone galanin, but show distinctly different binding properties to other molecules and effects on intracellular signaling. To gain insight on the molecular basis of receptor subtype specificity, we have generated a three-dimensional model for each of the galanin receptors based on its homologs in the same family. We found significant differences in the organization of the binding pockets among the three types of receptors, which might be the key for specific molecular recognition of ligands. Through docking of fragments of the galanin peptide and a number of ligands, we investigated the involvement of transmembrane and loop residues in ligand interaction. [less ▲]

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See detailThe C-terminal cavity of the Na,K-ATPase analyzed by docking and electrophysiology
Paulsen, P. A.; Jurkowski, Wiktor UL; Apostolov, R. et al

in Molecular Membrane Biology (2013), 30(2), 195-205

The Na,K-ATPase is essential to all animals, since it maintains the electrochemical gradients that energize the plasma membrane. Naturally occurring inhibitors of the pump from plants have been used ... [more ▼]

The Na,K-ATPase is essential to all animals, since it maintains the electrochemical gradients that energize the plasma membrane. Naturally occurring inhibitors of the pump from plants have been used pharmaceutically in cardiac treatment for centuries. The inhibitors block the pump by binding on its extracellular side and thereby locking it. To explore the possibilities for designing an alternative way of targeting the pump function, we have examined the structural requirements for binding to a pocket that accommodates the two C-terminal residues, YY, in the crystal structures of the pump. To cover the sample space of two residues, we first performed docking studies with the 400 possible dipeptides. For validation of the in silico predictions, pumps with 13 dipeptide sequences replacing the C-terminal YY were expressed in Xenopus laevis oocytes and examined with electrophysiology. Our data show a significant correlation between the docking scores from two different methods and the experimentally determined sodium affinities, which strengthens the previous hypothesis that sodium binding is coupled to docking of the C-terminus. From the dipeptides that dock the best and better than wild-type YY, it may therefore be possible to develop specific drugs targeting a previously unexplored binding pocket in the sodium pump. [less ▲]

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See detailNetwork analysis for systems biology
Chaiboonchoe, A.; Jurkowski, Wiktor UL; Pellet, J. et al

in Prokop, Aleš; Csukás (Eds.) Springer book in Systems Biology, Vol.1: Systems Biology:, Integrative Biology and Simulation Tools (2013)

Network analysis is an essential component of systems biology approaches toward understanding the molecular and cellular interactions underlying biological systems functionalities and their perturbations ... [more ▼]

Network analysis is an essential component of systems biology approaches toward understanding the molecular and cellular interactions underlying biological systems functionalities and their perturbations in disease. Regulatory and signalling pathways, which involve DNA, RNA proteins and metabolites as key elements, coordinate most aspects of cellular functioning. Cellular processes, which are dependent on the structure and dynamics of gene regulatory networks, can be studied by employing a network representation of molecular interactions. In this chapter we describe several types of networks and how combination of different analytic approaches can be used to study diseases. We provide a list of selected tools for visualization and network analysis. We introduce protein-protein interaction networks, gene regulatory networks, signalling networks and metabolic networks. We then define concepts underlying network representation of cellular processes and molecular interactions. We finally discuss how the level of accuracy in inferring functional relationships influences the choice of methods applied for the analysis of a particular network type. [less ▲]

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See detailOn different aspects of network analysis in systems biology
Chaiboonchoe, Amphun; Jurkowski, Wiktor UL; Pellet, Johann et al

in Systems Biology (2013), 1

Network analysis is an essential component of systems biology approaches toward understanding the molecular and cellular interactions underlying biological systems functionalities and their perturbations ... [more ▼]

Network analysis is an essential component of systems biology approaches toward understanding the molecular and cellular interactions underlying biological systems functionalities and their perturbations in disease. Regulatory and signalling pathways involve DNA, RNA, proteins and metabolites as key elements to coordinate most aspects of cellular functioning. Cellular processes depend on the structure and dynamics of gene regulatory networks and can be studied by employing a network representation of molecular interactions. This chapter describes several types of biological networks, how combination of different analytic approaches can be used to study diseases, and provides a list of selected tools for network visualization and analysis. It also introduces protein-protein interaction networks, gene regulatory networks, signalling networks and metabolic networks to illustrate concepts underlying network representation of cellular processes and molecular interactions. It finally discusses how the level of accuracy in inferring functional relationships influences the choice of methods applied for the analysis of a particular biological network type. © Springer Science+Business Media Dordrecht 2013. All rights are reserved. [less ▲]

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See detailThe early-stage intermediate
Jurkowski, Wiktor UL; Baster, Z.; Dulak, D. et al

in Roterman-Konieczna, I. (Ed.) Protein Fold Silico Protein Fold Versus Protein Struct Predict (2012)

The multistep polypeptide chain folding model presented in this chapter involves several intermediates, the first of which is called the early-stage (ES) intermediate. This intermediate is assumed to be ... [more ▼]

The multistep polypeptide chain folding model presented in this chapter involves several intermediates, the first of which is called the early-stage (ES) intermediate. This intermediate is assumed to be defined solely on the basis of the backbone conformation and does not take side chains into account. The geometric principles that guide the backbone alignment process and its quantitative influence on the structural arrangement of the folded chain can be expressed by means of a contingency table, linking known structural motifs to specific polypeptide sequences. The basic unit of this algorithm is the tetrapeptide, and the corresponding ES conformational subspace is assumed to consist of seven types of motifs. This limited subspace represents a subset of the full conformational space (i.e., the Ramachandran plot). The volumetric structure of the ES intermediate corresponds to the output of the early folding stage and, simultaneously, provides input for further stages of the folding process. [less ▲]

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See detailStructural information involved in the interpretation of the stepwise protein folding process
Alejster, P.; Jurkowski, Wiktor UL; Roterman-Konieczna, I.

in Protein folding in silico : protein folding versus protein structure prediction (2012)

Calculating the quantity of information present in each step of the protein folding process suggests that the multistep approach requires less information than the one-step model. Quantitative analysis ... [more ▼]

Calculating the quantity of information present in each step of the protein folding process suggests that the multistep approach requires less information than the one-step model. Quantitative analysis reveals that the amino acids present in the polypeptide chain do not carry enough information to accurately predict the values of the angles Φ and Ψ in folded proteins. This conclusion results from comparing the amount of information carried by amino acids with the quantity of information necessary to determine Φ and Ψ, taking the complete Ramachandran map as the conformational space. It is shown that the two-step model (comprising two stages, the ES and LS) requires less information, owing to the fact that the final predictions of the angles Φ and Ψ can be based on a preexisting ES structure. Analysis based on information theory points to particular zones of the Ramachandran map that appear to play an important role in the context of protein structure prediction. [less ▲]

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See detailFuzzy oil drop model to interpret the structure of antifreeze proteins and their mutants
Banach, Mateusz; Prymula, Katarzyna; Jurkowski, Wiktor UL et al

in Journal of Molecular Modeling (2012), 18(1), 229-237

Mutations in proteins introduce structural changes and influence biological activity: the specific effects depend on the location of the mutation. The simple method proposed in the present paper is based ... [more ▼]

Mutations in proteins introduce structural changes and influence biological activity: the specific effects depend on the location of the mutation. The simple method proposed in the present paper is based on a two-step model of in silico protein folding. The structure of the first intermediate is assumed to be determined solely by backbone conformation. The structure of the second one is assumed to be determined by the presence of a hydrophobic center. The comparable structural analysis of the set of mutants is performed to identify the mutant-induced structural changes. The changes of the hydrophobic core organization measured by the divergence entropy allows quantitative comparison estimating the relative structural changes upon mutation. The set of antifreeze proteins, which appeared to represent the hydrophobic core structure accordant with "fuzzy oil drop" model was selected for analysis. [less ▲]

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See detailGene regulatory network analysis supports inflammation as a key neurodegeneration process in prion disease.
Crespo, Isaac UL; Rump, Kirsten UL; Jurkowski, Wiktor UL et al

in BMC Systems Biology (2012), 6(132),

The activation of immune cells in the brain is believed to be one of the earliest events in prion disease development, where misfolded PrionSc protein deposits are thought to act as irritants leading to a ... [more ▼]

The activation of immune cells in the brain is believed to be one of the earliest events in prion disease development, where misfolded PrionSc protein deposits are thought to act as irritants leading to a series of events that culminate in neuronal cell dysfunction and death. The role of these events in prion disease though is still a matter of debate. To elucidate the mechanisms leading from abnormal protein deposition to neuronal injury, we have performed a detailed network analysis of genes differentially expressed in several mouse prion models [less ▲]

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See detailIntermediates in the protein folding process: a computational model
Roterman, Irena; Konieczny, Leszek; Banach, Mateusz et al

in International Journal of Molecular Sciences (2011), 12(8), 4850-60

The paper presents a model for simulating the protein folding process in silico. The two-step model (which consists of the early stage-ES and the late stage-LS) is verified using two proteins, one of ... [more ▼]

The paper presents a model for simulating the protein folding process in silico. The two-step model (which consists of the early stage-ES and the late stage-LS) is verified using two proteins, one of which is treated (according to experimental observations) as the early stage and the second as an example of the LS step. The early stage is based solely on backbone structural preferences, while the LS model takes into account the water environment, treated as an external hydrophobic force field and represented by a 3D Gauss function. The characteristics of 1ZTR (the ES intermediate, as compared with 1ENH, which is the LS intermediate) confirm the link between the gradual disappearance of ES characteristics in LS structural forms and the simultaneous emergence of LS properties in the 1ENH protein. Positive verification of ES and LS characteristics in these two proteins (1ZTR and 1ENH respectively) suggest potential applicability of the presented model to in silico protein folding simulations. [less ▲]

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See detailPPARγ population shift produces disease-related changes in molecular networks associated with metabolic syndrome
Jurkowski, Wiktor UL; Roomp, Kirsten UL; Crespo, Isaac UL et al

in Cell Death & Disease (2011), 2(8), 192

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding ... [more ▼]

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding domain at serine 273 has been shown to change the expression of a large number of genes implicated in obesity. The difference in gene expression seen when comparing wild-type phosphorylated with mutant non-phosphorylated PPARγ may have important consequences for the cellular molecular network, the state of which can be shifted from the healthy to a stable diseased state. We found that a group of differentially expressed genes are involved in bi-stable switches and form a core network, the state of which changes with disease progression. These findings support the idea that bi-stable switches may be a mechanism for locking the core gene network into a diseased state and for efficiently propagating perturbations to more distant regions of the network. A structural analysis of the PPARγ-RXRα dimer complex supports the hypothesis of a major structural change between the two states, and this may represent an important mechanism leading to the differential expression observed in the core network. [less ▲]

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See detailTwo-intermediate model to characterize the structure of fast-folding proteins
Roterman, I.; Konieczny, L.; Jurkowski, Wiktor UL et al

in Journal of Theoretical Biology (2011), 283(1), 60-70

This paper introduces a new model that enables researchers to conduct protein folding simulations. A two-step in silico process is used in the course of structural analysis of a set of fast-folding ... [more ▼]

This paper introduces a new model that enables researchers to conduct protein folding simulations. A two-step in silico process is used in the course of structural analysis of a set of fast-folding proteins. The model assumes an early stage (ES) that depends solely on the backbone conformation, as described by its geometrical properties--specifically, by the V-angle between two sequential peptide bond planes (which determines the radius of curvature, also called R-radius, according to a second-degree polynomial form). The agreement between the structure under consideration and the assumed model is measured in terms of the magnitude of dispersion of both parameters with respect to idealized values. The second step, called late-stage folding (LS), is based on the "fuzzy oil drop" model, which involves an external hydrophobic force field described by a three-dimensional Gauss function. The degree of conformance between the structure under consideration and its idealized model is expressed quantitatively by means of the Kullback-Leibler entropy, which is a measure of disparity between the observed and expected hydrophobicity distributions. A set of proteins, representative of the fast-folding group [less ▲]

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See detailThe complement regulator CD46 is bactericidal to Helicobacter pylori and blocks urease activity
Basmarke-Wehelie, Rahma; Sjolinder, Hong; Jurkowski, Wiktor UL et al

in Gastroenterology (2011), 141(3), 918-28

BACKGROUND & AIMS: CD46 is a C3b/C4b binding complement regulator and a receptor for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes ... [more ▼]

BACKGROUND & AIMS: CD46 is a C3b/C4b binding complement regulator and a receptor for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer. METHODS: Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses. RESULTS: H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity-associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked the urease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice. CONCLUSIONS: CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection. [less ▲]

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See detailDetermining receptor-ligand interaction of human galanin receptor type 3
Runesson, Johan; Sollenberg, Ulla E.; Jurkowski, Wiktor UL et al

in Neurochemistry International (2010), 57(7), 804-11

Galanin is a neuropeptide found throughout the central and peripheral nervous systems of a wide range of species, ranging from human and mouse to frog and tuna. Galanin mediates its physiological roles ... [more ▼]

Galanin is a neuropeptide found throughout the central and peripheral nervous systems of a wide range of species, ranging from human and mouse to frog and tuna. Galanin mediates its physiological roles through three receptors (GalR1-3), all members of the G-protein coupled receptor family. In mapping these roles, receptor subtype selective ligands are crucial tools. To facilitate the ligand design, data on receptor structure and interaction points are of great importance. The current study investigates the mechanism by which galanin interacts with GalR3. Mutated receptors were tested with competitive binding analysis in vitro. Our studies identify six mutagenic constructs that lost receptor affinity completely, despite being expressed at the cell surface. Mutations of the Tyr103(3.33) in transmembrane helix (TM) III, His251(6.51) in TM VI, Arg273(7.35) or His277(7.39) in TM VII, Phe263(6.63) or Tyr270(7.32) in the extracellular loop III all result in complete reduction of ligand binding. In addition, docking studies of an in silico model of GalR3 propose that four of the identified residues interact with pharmacophores situated within the galanin(2-6) sequence. This study provides novel insights into the interaction between ligands and GalR3 and highlights the requirement for correct design of targeting ligands. [less ▲]

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See detailPrediction of functional sites based on the fuzzy oil drop model
Brylinski, Michal; Prymula, Katarzyna; Jurkowski, Wiktor UL et al

in PLoS Computational Biology (2007), 3(5), 1-2

A description of many biological processes requires knowledge of the 3-D structure of proteins and, in particular, the defined active site responsible for biological function. Many proteins, the genes of ... [more ▼]

A description of many biological processes requires knowledge of the 3-D structure of proteins and, in particular, the defined active site responsible for biological function. Many proteins, the genes of which have been identified as the result of human genome sequencing, and which were synthesized experimentally, await identification of their biological activity. Currently used methods do not always yield satisfactory results, and new algorithms need to be developed to recognize the localization of active sites in proteins. This paper describes a computational model that can be used to identify potential areas that are able to interact with other molecules (ligands, substrates, inhibitors, etc.). The model for active site recognition is based on the analysis of hydrophobicity distribution in protein molecules. It is shown, based on the analyses of proteins with known biological activity and of proteins of unknown function, that the region of significantly irregular hydrophobicity distribution in proteins appears to be function related. [less ▲]

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