dbBCO – Baza publikacji konsorcium

Baza publikacji konsorcium Biocentrum Ochota. Baza skupia wszystkie publikacje naukowe w których wykorzystana była infrastruktura informatyczna zbudowana w ramach konsorcium. Publikacje posiadają odpowiednie odnośniki, style oraz możliwość załadowania pełnej wersji tekstu tam gdzie licencja wydawcy na to pozwala.

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Kaczanowski, S., Siedlecki, P. & Zielenkiewicz, P. The High Throughput Sequence Annotation Service (HT-SAS) – the shortcut from sequence to true Medline words. BMC Bioinformatics 10, 148 (2009). (Download)

Abstract: Background Advances in high-throughput technologies available to modern biology have created an increasing flood of experimentally determined facts. Ordering, managing and describing these raw results is the first step which allows facts to become knowledge. Currently there are limited ways to automatically annotate such data, especially utilizing information deposited in published literature. Results To aid researchers in describing results from high-throughput experiments we developed HT-SAS, a web service for automatic annotation of proteins using general English words. For each protein a poll of Medline abstracts connected to homologous proteins is gathered using the UniProt-Medline link. Overrepresented words are detected using binomial statistics approximation. We tested our automatic approach with a protein test set from SGD to determine the accuracy and usefulness of our approach. We also applied the automatic annotation service to improve annotations of proteins from Plasmodium bergei expressed exclusively during the blood stage. Conclusion Using HT-SAS we created new, or enriched already established annotations for over 20% of proteins from Plasmodium bergei expressed in the blood stage, deposited in PlasmoDB. Our tests show this approach to information extraction provides highly specific keywords, often also when the number of abstracts is limited. Our service should be useful for manual curators, as a complement to manually curated information sources and for researchers working with protein datasets, especially from poorly characterized organisms.

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Wójcikowski, M., Zielenkiewicz, P. & Siedlecki, P. DiSCuS: An Open Platform for (Not Only) Virtual Screening Results Management. J. Chem. Inf. Model. 54, 347–354 (2014).

Abstract: DiSCuS, a ?Database System for Compound Selection?, has been developed. The primary goal of DiSCuS is to aid researchers in the steps subsequent to generating high-throughput virtual screening (HTVS) results, such as selection of compounds for further study, purchase, or synthesis. To do so, DiSCuS provides (1) a storage facility for ligand?receptor complexes (generated with external programs), (2) a number of tools for validating these complexes, such as scoring functions, potential energy contributions, and med-chem features with ligand similarity estimates, and (3) powerful searching and filtering options with logical operators. DiSCuS supports multiple receptor targets for a single ligand, so it can be used either to evaluate different variants of an active site or for selectivity studies. DiSCuS documentation, installation instructions, and source code can be found at http://discus.ibb.waw.pl.

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Gladki, A., Siedlecki, P., Kaczanowski, S. & Zielenkiewicz, P. e-LiSe—an online tool for finding needles in the ‘(Medline) haystack’. Bioinformatics 24, 1115–1117 (2008). (Download)

Abstract: Summary: Using literature databases one can find not only known and true relations between processes but also less studied, non-obvious associations. The main problem with discovering such type of relevant biological information is ‘selection’. The ability to distinguish between a true correlation (e.g. between different types of biological processes) and random chance that this correlation is statistically significant is crucial for any bio-medical research, literature mining being no exception. This problem is especially visible when searching for information which has not been studied and described in many publications. Therefore, a novel bio-linguistic statistical method is required, capable of ‘selecting’ true correlations, even when they are low-frequency associations. In this article, we present such statistical approach based on Z-score and implemented in a web-based application ‘e-LiSe’. Availability: The software is available at http://miron.ibb.waw.pl/elise/ Contact: piotr@ibb.waw.pl Supplementary information: Supplementary materials are available at http://miron.ibb.waw.pl/elise/supplementary/

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Wójcikowski, M., Zielenkiewicz, P. & Siedlecki, P. Open Drug Discovery Toolkit (ODDT) - a new open-source player in the drug discovery field. J. Cheminf. (2015).
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Szczepek, E., Czerwosz, L., Nowiński, K., Jurkiewicz, J. & Czernicki, Z. Evaluation of volumetric changes in differential diagnosis of brain atrophy and active hydrocephalus. Adv Exp Med Biol 840, 59–67 (2015).

Abstract: Despite a variety of diagnostic methods, differentiation of symptoms of normal pressure hydrocephalus from those of atrophic processes of the brain is still a difficult task. In the present study an attempt of non-invasive differential diagnosis of normal pressure hydrocephalus (NPH) and brain atrophy (BA) was presented using volumetric analysis of CT images of the head by means of VisNow proprietary software. The analysis was based on the number of voxels converted to the amount of cerebrospinal fluid (CSF) in the subarachnoid space, skull base casters, and the ventricular system. The results demonstrate that the mean volumes of CSF in these compartments in patients with NPH differed significantly from those in BA. Similarly, the mean volumes of CSF in the subarachnoid space and skull base casters in patients with BA differed significantly from those in NPH. Volumetric assessment presented in the paper by application of VisNow software seems useful in the evaluation of NPH and brain BA.

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Soko\lowska, B., Jóźwik, A., Niebroj-Dobosz, I. & Hausmanowa-Petrusewicz, I. A pattern recognition approach to Emery-Dreifuss muscular dystrophy (EDMD) study. Journal of Medical Informatics & Technologies Vol. 23, 165–172 (2014).
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Kryshtafovych, A., Milostan, M., Szajkowski, L., Daniluk, P. & Fidelis, K. CASP6 data processing and automatic evaluation at the protein structure prediction center. Proteins 61 Suppl 7, 19–23 (2005).

Abstract: We present a short overview of the system governing data processing and automatic evaluation of predictions in CASP6, implemented at the Livermore Protein Structure Prediction Center. The system incorporates interrelated facilities for registering participants, collecting prediction targets from crystallographers and NMR spectroscopists and making them available to the CASP6 participants, accepting predictions and providing their preliminary evaluation, and finally, storing and visualizing results. We have automatically evaluated predictions submitted to CASP6 using criteria and methods developed over the successive CASP experiments. Also, we have tested a new evaluation technique based on non-rigid-body type superpositions. Approximately the same number of predictions has been submitted to CASP6 as to all previous CASPs combined, making navigation through and understanding of the data particularly challenging. To facilitate this, we have substantially modernized all data handling procedures, including implementation of a dedicated relational database. An overview of our redesigned website is also presented (http://predictioncenter.org/casp6/).

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Gambin, A., Lasota, S. & Rutkowski, M. Analyzing stationary States of gene regulatory network using petri nets. Studies in health technology and informatics 162, 143–59 (2011).

Abstract: We introduce and formally define the notion of a stationary state for Petri nets. We also propose a fully automatic method for finding such states. The procedure makes use of the Presburger arithmetic to describe all the stationary states. Finally we apply this novel approach to find stationary states of a gene regulatory network describing the flower morphogenesis of A. thaliana. This shows that the proposed method can be successfully applied in the study of biological systems.

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Kolinski, M., Plazinska, A. & Jozwiak, K. Recent Progress in Understanding of Structure, Ligand Interactions and the Mechanism of Activation of the β2-Adrenergic Receptor. Current medicinal chemistry (2012).

Abstract: The understanding of b2-adrenergic receptor (b2AR) interactions with ligands as well as the mechanism of receptor activation changed radically from 2007, when the first crystallographic structure of the receptor was reported. Since then numerous crystallographic studies described interactions with all main classes of b2AR ligands and with G proteins, which provided a great insight into the molecular structure of the receptor. However, molecular mechanisms of receptor activations remain to be determined. Functional research supported the concept of ligand - directed signaling at b-adrenoceptors. Agonist can activate alternative signaling pathways with different capacities and trigger cellular effects. It indicates that agonists nominally belonging to the same class may bind to and/or stabilize different active conformations of the receptor which are selectively recognized by signaling proteins in the allosteric manner.

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Jóźwik, A., Soko\lowska, B., Niebroj-Dobosz, I. & Janik, P. Extraction of biomedical traits for patients with Amyotrophic Lateral Sclerosis using parallel and hierarchical classifiers. International Journal of Biometrics 3, 85–94 (2011).

Abstract: This paper concerns the analysis and interpretation of results obtained from biomedical experiments. The biomedical approach allows differentiating patients by testing their EPO concentration in serum and cerebrospinal fluids. The diagnostic tests can be applied in patient monitoring, or future therapeutic research. The paper presents the possibility of recognition of the clinical status of patients with Amyotrophic Lateral Sclerosis (ALS) by the use of parallel and hierarchical classifiers. The proposed method can be used in biometric identification of ALS patients. The results demonstrate that the pattern recognition methods may be helpful in evaluation of the clinical progress of ALS.

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Maciejewska, A. M., Jóźwik, A., Kuśmierek, J. T. & Soko\lowska, B. Application of the k-NN classifier for mutagenesis tests. Recognition of wild type and defective in DNA repair bacterial strains on the basis of adaptive response to alkylating agents. Biocybernetics and Biomedical Engineering 28, 45–50 (2008).

Abstract: The k-Nearest Neighbor classifier (k-NN) was applied to differentiate two bacterial strains, the wild type and its mug derivative. Bacterial cells were exposed to different concentrations of chloroacetaldehyde and studied under two different conditions, i.e. with and without induction of an adaptive response. We evaluated the influence of adaptation on the wt and mug strains by estimating the probability of misclassification to the class: no adaptation or adaptation. We have also checked differentiation between wt and mug, separately for adapted and non-adapted conditions. Our results confirm the usefulness of the k-NN classifier as a tool for statistical analysis of results of mutagenesis tests.

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Kmiecik, S., Jamroz, M. & Kolinski, M. Structure Prediction of the Second Extracellular Loop in G-Protein-Coupled Receptors. Biophys J 106, 2408–2416 (2014).

Abstract:

G-protein-coupled receptors (GPCRs) play key roles in living organisms. Therefore, it is important to determine their functional structures. The second extracellular loop (ECL2) is a functionally important region of GPCRs, which poses significant challenge for computational structure prediction methods. In this work, we evaluated CABS, a well-established protein modeling tool for predicting ECL2 structure in 13 GPCRs. The ECL2s (with between 13 and 34 residues) are predicted in an environment of other extracellular loops being fully flexible and the transmembrane domain fixed in its x-ray conformation. The modeling procedure used theoretical predictions of ECL2 secondary structure and experimental constraints on disulfide bridges. Our approach yielded ensembles of low-energy conformers and the most populated conformers that contained models close to the available x-ray structures. The level of similarity between the predicted models and x-ray structures is comparable to that of other state-of-the-art computational methods. Our results extend other studies by including newly crystallized GPCRs.

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Soko\lowska, B., Jóźwik, A. & Pokorski, M. A fuzzy-classifier system to distinguish respiratory patterns evolving after diaphragm paralysis in the cat. The Japanese journal of physiology 53, 301–7 (2003).

Abstract: We applied the fuzzy "k-nearest neighbor" (k-NN) classifier of the pattern recognition theory to fathom the abnormal way of breathing resulting from diaphragm paralysis and to distinguish the dominant component, tidal or frequency, of the breathing pattern on which ventilatory compensation relies in such a pathological state. We addressed this issue in the experimental model of diaphragm paralysis as a result of bilateral phrenicotomy in anesthetized, spontaneously breathing cats. Of several variables recorded, we selected two features, minute ventilation and arterial CO(2) tension, that were used for the k-NN analysis. The results demonstrate that the ability to maintain ventilation critically depended on the increase in frequency of breathing. Other breathing pattern strategies were ineffective. The k-NN evaluation with the two selected features discerned the prevailing pattern of breathing with sufficient probability. Such an evaluation may be a useful tool in predicting the development of compensatory strategies in disordered patterns of breathing.

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Roytberg, M. et al. On subset seeds for protein alignment. IEEE/ACM transactions on computational biology and bioinformatics / IEEE, ACM 6, 483–94 (2009).

Abstract: We apply the concept of subset seeds to similarity search in protein sequences. The main question studied is the design of efficient seed alphabets to construct seeds with optimal sensitivity/selectivity trade-offs. We propose several different design methods and use them to construct several alphabets. We then perform a comparative analysis of seeds built over those alphabets and compare them with the standard Blastp seeding method, as well as with the family of vector seeds. While the formalism of subset seeds is less expressive (but less costly to implement) than the cumulative principle used in Blastp and vector seeds, our seeds show a similar or even better performance than Blastp on Bernoulli models of proteins compatible with the common BLOSUM62 matrix. Finally, we perform a large-scale benchmarking of our seeds against several main databases of protein alignments. Here again, the results show a comparable or better performance of our seeds versus Blastp.

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Niebroj-Dobosz, I., Madej-Pilarczyk, A., Marchel, M., Soko\lowska, B. & Hausmanowa-Petrusewicz, I. Osteopontin–a fibrosis-related marker–in dilated cardiomyopathy in patients with Emery-Dreifuss muscular dystrophy. Scandinavian journal of clinical and laboratory investigation 71, 658–62 (2011).

Abstract: BACKGROUND: As osteopontin (OPN) may be assumed to have diagnostic/prognostic value in heart diseases, it is worth assessing whether it is also involved in the pathogenesis and can be applied in the diagnosis of the dilated cardiomyopathy (DCM) in Emery-Dreifuss muscular dystrophy (EDMD). METHODS: Serum levels of osteopontin were quantified by means of sandwich immunoassay in 25 EDMD patients (10 laminopathies AD-EDMD and 15 emerinopathies–X-EDMD), eight carriers of X-EDMD, nine disease controls (patients with dystrophinopathy) and 20 age-matched healthy controls. RESULTS: The levels of circulating OPN were elevated in all AD-EDMD and X-linked EDMD patients, as well as in X-EDMD carriers and patients suffering progressive muscular dystrophy. There was no correlation between the osteopontin level and different cardiac parameters, including left-ventricular end-diastolic diameter, left atrial diameter, the left ventricular ejection fraction and the CK-MB level. There was a slight negative correlation with the ages of the patients. CONCLUSIONS: The presented results indicate that assessments of circulating OPN levels may help to identify EDMD patients at risk of dilated cardiomyopathy and might be therefore included among the set of biomarkers referred to with a view to appropriate early cardiologic diagnosis and therapy being commenced with in time.

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Kryshtafovych, A., Krysko, O., Daniluk, P., Dmytriv, Z. & Fidelis, K. Protein structure prediction center in CASP8. Proteins 77 Suppl 9, 5–9 (2009).

Abstract: We present an outline of the Critical Assessment of Protein Structure Prediction (CASP) infrastructure implemented at the University of California, Davis, Protein Structure Prediction Center. The infrastructure supports selection and validation of prediction targets, collection of predictions, standard evaluation of submitted predictions, and presentation of results. The Center also supports information exchange relating to CASP experiments and structure prediction in general. Technical aspects of conducting the CASP8 experiment and relevant statistics are also provided.

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Latek, D. et al. Modeling of ligand binding to G protein coupled receptors: cannabinoid CB1, CB2 and adrenergic β 2 AR. Journal of molecular modeling 17, 2353–66 (2011).

Abstract: Cannabinoid and adrenergic receptors belong to the class A (similar to rhodopsin) G protein coupled receptors. Docking of agonists and antagonists to CB(1) and CB(2) cannabinoid receptors revealed the importance of a centrally located rotamer toggle switch and its possible participation in the mechanism of agonist/antagonist recognition. The switch is composed of two residues, F3.36 and W6.48, located on opposite transmembrane helices TM3 and TM6 in the central part of the membranous domain of cannabinoid receptors. The CB(1) and CB(2) receptor models were constructed based on the adenosine A(2A) receptor template. The two best scored conformations of each receptor were used for the docking procedure. In all poses (ligand-receptor conformations) characterized by the lowest ligand-receptor intermolecular energy and free energy of binding the ligand type matched the state of the rotamer toggle switch: antagonists maintained an inactive state of the switch, whereas agonists changed it. In case of agonists of β(2)AR, the (R,R) and (S,S) stereoisomers of fenoterol, the molecular dynamics simulations provided evidence of different binding modes while preserving the same average position of ligands in the binding site. The (S,S) isomer was much more labile in the binding site and only one stable hydrogen bond was created. Such dynamical binding modes may also be valid for ligands of cannabinoid receptors because of the hydrophobic nature of their ligand-receptor interactions. However, only very long molecular dynamics simulations could verify the validity of such binding modes and how they affect the process of activation.

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Szczepek, E. et al. Gait disturbances in Computer Dyno Graphy examination in patients with normal pressure hydrocephalus before and after surgery. Neurologia i neurochirurgia polska 42, 22–7 (2008).

Abstract: BACKGROUND AND PURPOSE: Gait disturbances resulting from the normal pressure hydrocephalus (NPH) syndrome significantly restrain locomotion, which in serious cases can lead to a total loss of the ability to move. Hence the need to create an objective method of evaluating gait disturbances described by values of gait parameters and changes of these parameters resulting from neurosurgical treatment. The aim of this project is to create an effective, non-invasive diagnostics method describing movement disorders in patients with NPH before and after surgery. MATERIAL AND METHODS: An evaluation of the effectiveness of gait analysis was carried out with Ultraflex, which uses the Computer Dyno Graphy (CDG) system to measure the distribution of forces of reaction on the ground during walking. The control group consisted of 17 healthy individuals (age range 50-65 years) and the treatment group included 17 patients with enlargement of the ventricular system (9 females and 8 males, mean age 58.6 years, range 50-65 years), 8 of whom were qualified for surgical treatment. Analyzed parameters: ground reaction force, single and double support, stance. RESULTS: Changes of parameters reflected gait improvement. CONCLUSIONS: The results obtained indicate that gait analysis using the CDG system might be a good method for assessing the effectiveness of NPH surgery.

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Kryshtafovych, A. et al. New tools and expanded data analysis capabilities at the Protein Structure Prediction Center. Proteins 69 Suppl 8, 19–26 (2007).

Abstract: We outline the main tasks performed by the Protein Structure Prediction Center in support of the CASP7 experiment and provide a brief review of the major measures used in the automatic evaluation of predictions. We describe in more detail the software developed to facilitate analysis of modeling success over and beyond the available templates and the adopted Java-based tool enabling visualization of multiple structural superpositions between target and several models/templates. We also give an overview of the CASP infrastructure provided by the Center and discuss the organization of the results web pages available through http://predictioncenter.org.

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Bhatia, P., Kolinski, M., Moaddel, R., Jozwiak, K. & Wainer, I. W. Determination and modelling of stereoselective interactions of ligands with drug transporters: a key dimension in the understanding of drug disposition. Xenobiotica; the fate of foreign compounds in biological systems 38, 656–75 (2008).

Abstract: 1. Stereochemistry is an important dimension in pharmacology and plays a role in every aspect of the pharmacological fate of chiral xenobiotics. This includes small molecule-drug transporter binding. 2. This paper reviews the reported stereoselectivities of substrate and inhibitor interactions with P-glycoprotein and the organic cation transporter obtained using standard functional and binding studies, as well as data obtained from online cellular membrane affinity chromatography studies. 3. The use of stereochemical data in quantitative structure-activity relationship (QSAR) and pharmacophore modelling is also addressed as is the effect of ignoring the fact that small molecule-drug transporter interactions take place in three-dimensional and asymmetric space.

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Sosnowski, T. R., Kolinski, M. & Gradoń, L. Interactions of benzo[a]pyrene and diesel exhaust particulate matter with the lung surfactant system. The Annals of occupational hygiene 55, 329–38 (2011).

Abstract: One of the reasons for cellular changes in the lung tissue exposed to the diesel exhaust composed of soot particles with adsorbed volatile organic molecules is the reduction of the clearance rate in the pulmonary region of the respiratory system. The interaction of the fractal-like particles and organic substances with a surfactant monolayer limits its dynamic activity. The surface properties of Survanta, a purified extract of bovine lung surfactant (LS), which interacted with carbon particles (200 nm aggregates) and benzo[a]pyrene (BaP), molecules were measured with the oscillating bubble technique. The results showed a significant lowering of the dynamics of the surfactant monolayer compared to the control case (no exposure). Additional measurements of surface pressure during the monotonic compression of the air-water interface containing the major LS phospholipid, dipalmitoylphosphatidylcholine (DPPC), showed that the presence of BaP molecules in the system influenced its stability. The experimental results were supplemented with a theoretical molecular dynamics model of the interaction between BaP and DPPC molecules. The simulation results indicated the insertion of BaP molecules into the lipid layer, which explained the measured effects.

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Niebroj-Dobosz, I., Madej-Pilarczyk, A., Marchel, M., Soko\lowska, B. & Hausmanowa-Petrusewicz, I. Circulating tenascin-C levels in patients with dilated cardiomyopathy in the course of Emery-Dreifuss muscular dystrophy. Clinica chimica acta; international journal of clinical chemistry 412, 1533–8 (2011).

Abstract: BACKGROUND: Tenascin-C (TN-C), an extracellular matrix glycoprotein, is of diagnostic and prognostic value in different heart diseases. One such dilated cardiomyopathy (DCM) with conduction disturbances is one of the most serious manifestations in Emery-Dreifuss muscular dystrophy (EDMD). Herein we therefore detail work to evaluate the potential significance of circulating TN-C in patients with EDMD, speculating that it may define the cardiac dysfunction, especially in patients who may be cardiac asymptomatic, but still be at risk of sudden death. MATERIAL AND METHOD: Serum levels of TN-C were quantified by sandwich immunoassay ELISA in 25 EDMD patients (10 with laminopathy-AD-EDMD and 15 with emerinopathy-X-EDMD), 8 X-EDMD carriers, 9 disease controls (patients with dystrophinopathy), and 15 age-matched healthy controls. Fourteen of the EDMD patients had repeated TN-C examinations after 3 to 7 years. RESULTS: The levels of circulating TN-C were elevated in AD-EDMD and X-EDMD patients, as well as in some X-EDMD carriers, and patients with dystrophinopathy. The correlation between the TN-C level and left end-systolic ventricle diameter (LVDD) was significant in X-EDMD, while those with left atrium diameter (LAD) and the ejection fraction (EF) were not. In "follow-up" studies TN-C levels were not found to change over time in AD-EDMD, while rising in X-EDMD. CONCLUSIONS: The presented results indicate that assessments of circulating TN-C levels may help to identify EDMD patients at risk of dilated cardiomyopathy. TN-C might therefore be considered a candidate for a new biomarker, useful in detecting of cardiomyopathy and in further monitoring of the DCM therapy in patients with EDMD.

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Sobhanifar, S. et al. Structural investigation of the C-terminal catalytic fragment of presenilin 1. Proceedings of the National Academy of Sciences of the United States of America 107, 9644–9 (2010).

Abstract: The gamma-secretase complex has a decisive role in the development of Alzheimer’s disease, in that it cleaves a precursor to create the amyloid beta peptide whose aggregates form the senile plaques encountered in the brains of patients. Gamma-secretase is a member of the intramembrane-cleaving proteases which process their transmembrane substrates within the bilayer. Many of the mutations encountered in early onset familial Alzheimer’s disease are linked to presenilin 1, the catalytic component of gamma-secretase, whose active form requires its endoproteolytic cleavage into N-terminal and C-terminal fragments. Although there is general agreement regarding the topology of the N-terminal fragment, studies of the C-terminal fragment have yielded ambiguous and contradictory results that may be difficult to reconcile in the absence of structural information. Here we present the first structure of the C-terminal fragment of human presenilin 1, as obtained from NMR studies in SDS micelles. The structure reveals a topology where the membrane is likely traversed three times in accordance with the more generally accepted nine transmembrane domain model of presenilin 1, but contains unique structural features adapted to accommodate the unusual intramembrane catalysis. These include a putative half-membrane-spanning helix N-terminally harboring the catalytic aspartate, a severely kinked helical structure toward the C terminus as well as a soluble helix in the assumed-to-be unstructured N-terminal loop.

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Soko\lowska, B., Jóźwik, A., Niebroj-Dobosz, I., Janik, P. & Kwiecinski, H. Evaluation of matrix metalloproteinases in serum of patients with amyotrophic lateral sclerosis with pattern recognition methods. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 60 Suppl 5, 117–20 (2009).

Abstract: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, which are present in central and peripheral nervous system. They are considered to be involved in the pathogenesis of several neurological diseases, as multiple sclerosis, Alzheimer disease, and amyotrophic lateral sclerosis (ALS). The aim of the present study was to evaluate the application of the pattern recognition methods for the assessment of MMPs in serum of patients with ALS. Thirty patients with amyotrophic lateral sclerosis (ALS), in two subgroups: (i) with mild and (ii) severe progressing ALS, and 15 control healthy subjects were studied. The metalloproteinases MT-MMP-1, MMP-2, MMP-9 were examined. Additional variables (age of subjects and disease duration) were also analyzed by using a standard, parallel and hierarchical classifiers. Our results indicate that: (i) MMP-2 in serum may be an important marker for the evaluation of ALS progress; (ii) the set of two features MT-MMP-1, MMP-9 may be helpful in differentiation between ALS and healthy subjects; (iii) the error rates obtained for the pair-wise linear classifier were similar to those received for the classifiers (standard, parallel, and hierarchical) based on k-NN rule. We conclude that the pattern recognition methods may be useful for the evaluation of significance MMPs as markers in neurodegenerative diseases, such as ALS.

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Soko\lowska, B. & Pokorski, M. Ventilatory augmentation by acute intermittent hypoxia in the rabbit. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 57 Suppl 4, 341–7 (2006).

Abstract: This study seeks to determine the effects on respiratory function of acute intermittent hypoxia. The experiments were performed on anesthetized, spontaneously breathing rabbits. The experimental protocol consisted of 5 one-minute episodes of hypoxia (14% O(2) in N(2)) interspersed with three-minute normoxic recovery periods. Ventilatory variables, minute ventilation (MV) and its tidal and frequency components, were derived from the continuously recorded airflow signal. We found that MV progressively increased with each next hypoxic-normoxic cycle; the increases were driven by both ventilatory components. Ventilatory augmentation concerned both the stimulus (hypoxic) and recovery (normoxic) periods, but it was significantly greater in the former. The augmented ventilation was sustained for up to 30 min after the last hypoxic run, which suggests the appearance of ventilatory long-term facilitation. The results demonstrate that acute intermittent hypoxia consisting of a few hypoxic-normoxic cycles is capable of inducing appreciable ventilatory changes. Such changes reflect plasticity of the respiratory motor output developing on a short-term basis during ongoing cycles of hypoxia, which, in the present study, correlated with the number of hypoxic cycle. Ventilatory augmentation in response to acute cyclic hypoxic episodes may give insights into the mechanisms of respiratory improvement by intermittent hypoxic training, increasingly used in both sports physiology and medicinal approaches.

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Soko\lowska, B., Rekawek, A. & Jóźwik, A. Respiratory responses to acute intermittent hypoxia and hypercapnia in awake rats. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 59 Suppl 6, 659–67 (2008).

Abstract: This article deals with the recognition of early changes in the breathing pattern, in response to acute intermittent stimuli in awake rats. Two different types of stimuli were given: 9% hypoxia in N(2) and 10% hypercapnia in O(2). Animals were exposed to 3 consecutive cycles consisting of 3-min stimulus period separated by 8-min normoxic recovery intervals. Features of the breathing pattern, such as respiratory frequency, tidal volume, minute ventilation, inspiration and expiration times, peak inspiratory and expiratory flows, were measured by whole body plethysmography. The data were analyzed with the use of pattern recognition methods. We conclude that the overall respiratory changes were rather slight. However, computerized analysis using a k-nearest neighbor decision rule (k-NN) allowed for a good recognition of the respiratory responses to the stimuli. The misclassification rate (E(r)) varied from 5 to 10%. After feature selection, E(r) decreased below 1%. The k-NN classifier differentiated correctly also the type of intermittent stimulus. Our experimental results demonstrate usefulness of pattern recognition algorithms in studying respiratory effects in biological models.

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Niebroj-Dobosz, I., Soko\lowska, B., Madej-Pilarczyk, A., Marchel, M. & Hausmanowa-Petrusewicz, I. Tissue inhibitors of matrix metalloproteinases in serum are cardiac biomarkers in Emery-Dreifuss muscular dystrophy. Kardiol Pol (2015). doi:10.5603/KP.a2014.0243

Abstract: BACKGROUND: Tissue inhibitors of matrix metalloproteinases (TIMPs) are known to be involved in cardiovascular diseases. Hitherto, they have not been examined in dilated cardiomyopathy (DCM) in course of Emery-Dreifuss muscular dystrophy (EDMD).AIM: The aim of this study was to define TIMPs in serum as they might help in defining cardiac dysfunction at early cardiological stages of this disease and detect preclinical stages of cardiomyopathy.METHODS: Twenty five EDMD patients connected with lamin A/C (AD-EDMD) or emerin (X-EDMD) deficiency and 20 healthy age-matched controls were examined. The serum levels of the tissue inhibitors TIMP-1, -2, -3 were quantified using the ELISA sandwich immunoassay procedure with appropriate antibodies. RESULTS: Serum levels of TIMP-1 were normal in autosomal AD-EDMD, or increased in the majority of X-linked EDMD. The level of TIMP-2 was decreased in 25%/21% of AD-EDMD/X-EDMD cases. TIMP-3 serum level was significantly reduced in all the examined patients. Receiver operating curves (ROC) indicated that in terms of sensitivity and specificity characteristics the performance of TIMP-3, (less that of TIMP-2), makes them the best markers of cardiac involvement among the examined TIMPs.CONCLUSIONS: Evidence is provided that the levels of TIMP-3, in some cases also TIMP-2, are decreased in Emery-Dreifuss muscular dystrophy. The decrease might be associated with an adverse effect on MMPs and remodeling of the myocardial matrix. The specific decrease of TIMP-3 indicates that this biomarker might help in early detection of cardiac involvement in EDMD. Up-regulation of TIMP-1 in the majority of patient with X-EDMD indicates on increased ECM turnover, early onset of tissue remodeling and may contribute to arrhythmia, frequently occurring in this form of the disease.

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\Luksza, M., Kluge, B., Ostrowski, J., Karczmarski, J. & Gambin, A. Two-stage model-based clustering for liquid chromatography mass spectrometry data analysis. Statistical applications in genetics and molecular biology 8, Article 15 (2009).

Abstract: Proteomic mass spectrometry is gaining an increasing role in diagnostics and in studies on protein complexes and biological systems. This experimental technology is producing high-throughput data which is inherently noisy and may contain various errors. Mathematical processing can help in removing them.In this paper we focus on the peak alignment problem in LC-MS spectra. As an alternative to heuristic approaches to the problem, we propose a mathematically sound method which exploits a model-based clustering. In this framework experiment errors are modeled as deviations from real values and mass spectra are regarded as finite Gaussian mixtures. The advantage of such an approach is that it provides convenient techniques for adjusting parameters and selecting solutions of best quality. The method can be parameterized by assuming various constraints. In this paper we investigate and compare different classes of models. We analyze the results in terms of statistically significant biomarkers that can be identified after the alignment of spectra. The study was conducted on a dataset of plasma samples of colorectal cancer patients and healthy donors.

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Sinkiewicz-Darol, E. et al. The LITAF/SIMPLE I92V sequence variant results in an earlier age of onset of CMT1A/HNPP diseases. Neurogenetics 16, 27–32 (2015).

Abstract: Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) represent the most common heritable neuromuscular disorders. Molecular diagnostics of CMT1A/HNPP diseases confirm clinical diagnosis, but their value is limited to the clinical course and prognosis. However, no biomarkers of CMT1A/HNPP have been identified. We decided to explore if the LITAF/SIMPLE gene shared a functional link to the PMP22 gene, whose duplication or deletion results in CMT1A and HNPP, respectively. By studying a large cohort of CMT1A/HNPP-affected patients, we found that the LITAF I92V sequence variant predisposes patients to an earlier age of onset of both the CMT1A and HNPP diseases. Using cell transfection experiments, we showed that the LITAF I92V sequence variant partially mislocalizes to the mitochondria in contrast to wild-type LITAF which localizes to the late endosome/lysosomes and is associated with a tendency for PMP22 to accumulate in the cells. Overall, this study shows that the I92V LITAF sequence variant would be a good candidate for a biomarker in the case of the CMT1A/HNPP disorders.

1.
Soko\lowska, B., Jóźwik, A., Niebroj-Dobosz, I. & Janik, P. The pair-wise linear classifier and the k-NN rule In application to ALS progression differentiation. Journal of Medical Informatics & Technologies Vol. 20, 79–83 (2012).
1.
Soko\lowska, B. & Jóźwik, A. A pattern recognition method to distinguish gradual unilateral diaphragm paralysis in the cat. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 54 Suppl 1, 42–7 (2003).

Abstract: This work deals with the application of a pattern recognition method to distinguish the degree of diaphragm paralysis after gradual unilateral sections of phrenic nerve rootlets in anesthetized, spontaneously breathing cats. The data set consisted of the features that characterize breathing pattern and of phrenic nerve amplitude. The method called for stratification of 6-dimensional vectors into three classes: intact, partial, and complete unilateral phrenicotomy, which offers the possibility to construe the classification rule on the basis of the information contained in a set of feature vectors with the known class-membership. This method deals with the use of a distance function as a measure of similarity between two feature points. The results show that the degree of diaphragm paralysis could be recognized with the probability higher than 90%. Distinguishing the severity of diaphragmatic dysfunction and the compensatory strategies of the respiratory system, knowing only a handful of basic values describing breathing pattern, might have a practical meaning in respiratory emergencies.

1.
Filipek, S. et al. A concept for G protein activation by G protein-coupled receptor dimers: the transducin/rhodopsin interface. Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology 3, 628–38 (2004).

Abstract: G protein-coupled receptors (GPCRs) are ubiquitous and essential in modulating virtually all physiological processes. These receptors share a similar structural design consisting of the seven-transmembrane alpha-helical segments. The active conformations of the receptors are stabilized by an agonist and couple to structurally highly conserved heterotrimeric G proteins. One of the most important unanswered questions is how GPCRs couple to their cognate G proteins. Phototransduction represents an excellent model system for understanding G protein signaling, owing to the high expression of rhodopsin in rod photoreceptors and the multidisciplinary experimental approaches used to study this GPCR. Here, we describe how a G protein (transducin) docks on to an oligomeric GPCR (rhodopsin), revealing structural details of this critical interface in the signal transduction process. This conceptual model takes into account recent structural information on the receptor and G protein, as well as oligomeric states of GPCRs.

1.
Niebroj-Dobosz, I., Soko\lowska, B., Madej-Pilarczyk, A., Marchel, M. & Hausmanowa-Petrusewicz, I. Cardiovascular risk markers in dilated cardiomyopathy in Emery-Dreifuss muscular dystrophy (EDMD). Int J Cardiol 173, 324–5 (2014).

Abstract: Cardiovascular risk biomarkers help to define cardiac dysfunction, assist pharmacological therapy and select patients qualifying for cardiac device implantation and/or heart transplant. Some biomarkers are of value in detecting dilated cardiomyopathy (DCM) in Emery–Dreifuss muscular dystrophy (EDMD), a genetically transmitted deficiency of emerin (EDMD1) or lamin A/C (EDMD2). Clinical symptoms of EDMD manifest as skeletal muscle atrophy, joint contractures and dilated cardiomyopathy (DCM). The latter often remains clinically silent for a prolonged period, but finally might lead to sudden death.

1.
Zekanowski, C. et al. Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Experimental neurology 200, 82–8 (2006).

Abstract: Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes are associated with early-onset familial Alzheimer’s disease (EOAD). There are several reports describing mutations in PSEN1 in cases with frontotemporal dementia (FTD). We identified two novel mutations in the PSEN1 gene: L226F and L424H. The first mutation was detected in a patient with a clinical diagnosis of FTD and a post-mortem diagnosis of AD. The second mutation is connected with a clinical phenotype of variant AD with strong FTD signs. In silico modeling revealed that the mutations, as well as mutations used for comparison (F177L and L424R), change the local structure, stability and/or properties of the transmembrane regions of the presenilin 1 protein (PS1). In contrast, a silent non-synonymous substitution F175S is eclipsed by external residues and has no influence on PS1 interfacial surface. We suggest that in silico analysis of PS1 substitutions can be used to characterize novel PSEN1 mutations, to discriminate between silent polymorphisms and a potential disease-causing mutation. We also propose that PSEN1 mutations should be considered in FTD patients with no MAPT mutations.

1.
Soko\lowska, B. & Jóźwik, A. Distinguishing the strength of hypoxic stimulus in intermittent hypoxia. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 58 Suppl 5, 657–63 (2007).

Abstract: The intermittent hypoxia (IH) phenomenon is a subject of intensive examinations. In this study we examined whether it could be possible to distinguish the strength of the hypoxic stimulus given in IH cycles on the basis of observed changes in the breathing pattern. We investigated the ventilatory responses to five hypoxic-normoxic cycles (1 min hypoxia/3 min normoxia) in rabbits. Two different hypoxic stimuli were given: gas mixtures of 14% and 11% O2 in N2, each one in a separate run of IH. Ventilatory features: frequency (f), tidal volume (VT) and minute ventilation (VE) were analyzed using the algorithms of the pattern recognition theory. The probability of wrong classification was used as a criterion for the recognition quality evaluation. This probability can be estimated experimentally by calculating the percentage of misclassifications, i.e., an error rate (Er). When the features were analyzed alone, the VT offered the lowest misclassification rate of 19.3% and 10.3% in the stimulus and normoxic periods, respectively. However, using the single features measured during the stimulus and recovery phases allowed to decrease the error rate more than 2-fold, achieving 4.3% for VT. The best results were obtained for both phases associated with single cycles of IH. Suitable feature selection procedures enabled reducing the global misclassification rate to 0.7%. In conclusion, the pattern recognition approach may potentially be useful for controlling the stimulus strength in intermittent hypoxic training.

1.
Austermann, J. et al. Generation and characterization of a novel, permanently active S100P mutant. Biochimica et biophysica acta 1793, 1078–85 (2009).

Abstract: S100 proteins function as Ca2+ signal transducers by regulating cellular targets in their Ca2+ bound conformation. S100P is a member of the S100 protein family that can activate the membrane and F-actin binding protein ezrin in a Ca2+ dependent manner at least in vitro. Here we generated a novel tool to elucidate directly the S100P-ezrin interaction in vivo. This was achieved by constructing a S100P derivative that contained mutations in the two EF hand loops predicted to lock the protein in a permanently active state. The resulting S100P mutant, termed here S100P pa, could be purified as a soluble protein and showed biochemical properties displayed by wild-type S100P only in the presence of Ca2+. Importantly, S100P pa bound to the N-terminal domain of ezrin in the absence of Ca2+ showing an affinity only slightly reduced as compared to that of Ca2+-bound WT S100P. In line with this permanent complex formation, S100P pa colocalized with ezrin to plasma membrane protrusions of epithelial cells even in the absence of intracellular Ca2+ transients. Thus, S100P pa is a novel type of S100 protein mutant locked in a permanently active state that shows an unregulated complex formation with its cellular target ezrin.

1.
Björkholm, P. et al. Using multi-data hidden Markov models trained on local neighborhoods of protein structure to predict residue-residue contacts. Bioinformatics (Oxford, England) 25, 1264–70 (2009).

Abstract: MOTIVATION: Correct prediction of residue-residue contacts in proteins that lack good templates with known structure would take ab initio protein structure prediction a large step forward. The lack of correct contacts, and in particular long-range contacts, is considered the main reason why these methods often fail. RESULTS: We propose a novel hidden Markov model (HMM)-based method for predicting residue-residue contacts from protein sequences using as training data homologous sequences, predicted secondary structure and a library of local neighborhoods (local descriptors of protein structure). The library consists of recurring structural entities incorporating short-, medium- and long-range interactions and is general enough to reassemble the cores of nearly all proteins in the PDB. The method is tested on an external test set of 606 domains with no significant sequence similarity to the training set as well as 151 domains with SCOP folds not present in the training set. Considering the top 0.2 x L predictions (L = sequence length), our HMMs obtained an accuracy of 22.8% for long-range interactions in new fold targets, and an average accuracy of 28.6% for long-, medium- and short-range contacts. This is a significant performance increase over currently available methods when comparing against results published in the literature. AVAILABILITY: http://predictioncenter.org/Services/FragHMMent/.

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Thavasi, V. et al. Study on the feasibility of bacteriorhodopsin as bio-photosensitizer in excitonic solar cell: a first report. Journal of nanoscience and nanotechnology 9, 1679–87 (2009).

Abstract: Bacteriorhodopsin (bR) is a membrane protein found in the archae Halobacterium salinarum. Here, we studied wild type bR and especially the triple mutant bR, 3Glu [E9Q/E194Q/E204Q], in combination with wide gap semiconductor TiO2 for their suitability as efficient light harvester in solar cell. Our differential scanning calorimetry data show thermal robustness of bR wild type and 3Glu mutant, which make them good candidates as photosensitizer in solar cells. Molecular modeling indicates that binding of bR to the exposed oxygen atoms of anatase TiO2 is favorable for electron transfer and directed by local, small distance interactions. A solar cell, based on bR wild type and bR triple mutant immobilized on nanocrystalline TiO2 film was successfully constructed. The photocurrent density-photo voltage (J-V) characteristics of bio-sensitized solar cell (BSSC), based on the wild type bR and 3Glu mutant adsorbed on nanocrystalline TiO2 film electrode were measured. The results show that the 3Glu mutant displays better photoelectric performance compared to the wild type bR, giving a short-circuit photocurrent density (J(sc)) of 0.09 mA/cm2 and the open-circuit photovoltage (V(oc)) 0.35 V, under an illumination intensity of 40 mW/cm2.

1.
Soko\lowska, B. & Jóźwik, A. PATTERN RECOGNITION APPROACH FOR ANALYSIS OF METABOLIC RESPONSE TO INTERMITTENT HYPOXIA. (2010).
1.
Czerwosz, L., Szczepek, E., Soko\lowska, B., Jurkiewicz, J. & Czernicki, Z. Posturography in Differential Diagnosis of Normal Pressure Hydrocephalus and Brain Atrophy. Advances in experimental medicine and biology 755, 311–324 (2013).

Abstract: Differentiation between normal pressure hydrocephalus (NPH) and brain atrophy is difficult in clinical practice. The purpose of this paper was to apply two advanced statistical, pattern recognition methods: discriminant analysis (DA) and k-nearest neighbour (K-NN) for the classification of NPH and atrophy patients to approach computer aided differential diagnosis. The classification is based on a few measures of the center of foot pressure (COP) movements (radius, area, and length). The posturography method gives a measure of current postural stability by a quantitative evaluation of postural sways. Measurements have been performed in the standing upright position in two conditions: with eyes open (EO) and closed (EC). The study comprises 18 patients (mean age 64 ±13 years) diagnosed as normal pressure hydrocephalus and qualifying for shunt implantation. The patients were evaluated by static posturography twice: before and after surgery. The NPH patients were compared with 36 atrophy patients (mean age 64±13 years) and 47 healthy persons (mean age 60 ±7 years). There were two basic dissimilarities in the NPH patients before surgery in comparison with the other groups: very large sways and their independence from vision. Over 90% of the NPH cases both before and after surgery were correctly classified. There also were over 90% of correctly classified patients if we compared the before surgery NPH and atrophy patients. Further posturographic measurements and data collection are needed to verify these results.

1.
Niebroj-Dobosz, I., Janik, P., Soko\lowska, B. & Kwiecinski, H. Matrix metalloproteinases and their tissue inhibitors in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis. European journal of neurology : the official journal of the European Federation of Neurological Societies 17, 226–31 (2010).

Abstract: BACKGROUND AND PURPOSE: Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We investigated the expression of MMPs and tissue inhibitors of matrix metalloproteinases (TIMPs) in serum and cerebrospinal fluid (CSF) correlating the results with age, disease duration and the clinical course. METHODS: The material consisted of 30 ALS patients and 15 age-matched healthy controls. ELISA method to determine the expression of MT-MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 in serum and CSF was used. MMP-2 and MMP-9 by zymography was also tested. RESULTS: In serum MT-MMP-1, MMP-2, MMP-9 and TIMP-1 expression was increased, especially in mild ALS cases. TIMP-2 values were normal. In CSF MT-MMP-1, MMP-2 and TIMP-1 level was either increased or normal, that of MMP-9 was decreased. TIMP-2 did not change. No correlation of MMPs and TIMP-1 expression in serum and CSF and the age of the patients was found. A correlation was observed between MMPs and TIMPs and disease duration. CONCLUSIONS: Increased level of MMPs and TIMP-1 of ALS patients may reflect the degeneration process of motor neurons and skeletal muscles and/or is associated with tissues remodeling. The low level of MMP-9 in CSF may result from impaired balance between MMP-9 and TIMP-1 and/or its increased intrathecal degradation and physical clearance. Although the role of changed MMPs/TIMPs level in the pathogenesis of ALS is not clear their analysis in serum may be used as prognostic factor and a potential marker for monitoring treatment effects.

1.
Rybinski, M., Lula, M., Banasik, P., Lasota, S. & Gambin, A. Tav4SB: integrating tools for analysis of kinetic models of biological systems. BMC systems biology 6, 25 (2012).

Abstract: ABSTRACT: BACKGROUND: Progress in the modeling of biological systems strongly relies on the availability of specialized computer-aided tools. To that end, the Taverna Workbench eases integration of software tools for life science research and provides a common workflow-based framework for computational experiments in Biology. RESULTS: The Taverna services for Systems Biology (Tav4SB) project provides a set of new Web service operations, which extend the functionality of the Taverna Workbench in a domain of systems biology. Tav4SB operations allow you to perform numerical simulations or model checking of, respectively, deterministic or stochastic semantics of biological models. On top of this functionality, Tav4SB enables the construction of high-level experiments. As an illustration of possibilities offered by our project we apply the multi-parameter sensitivity analysis. To visualize the results of model analysis a flexible plotting operation is provided as well. Tav4SB operations are executed in a simple grid environment, integrating heterogeneous software such as Mathematica, PRISM and SBML ODE Solver. The user guide, contact information, full documentation of available Web service operations, workflows and other additional resources can be found at the Tav4SB project’s Web page: http://bioputer.mimuw.edu.pl/tav4sb/. CONCLUSIONS: The Tav4SB Web service provides a set of integrated tools in the domain for which Web-based applications are still not as widely available as for other areas of computational biology. Moreover, we extend the dedicated hardware base for computationally expensive task of simulating cellular models. Finally, we promote the standardization of models and experiments as well as accessibility and usability of remote services.

1.
Gambin, A., Szczurek, E., Dutkowski, J., Bakun, M. & Dadlez, M. Classification of peptide mass fingerprint data by novel no-regret boosting method. Computers in biology and medicine 39, 460–73 (2009).

Abstract: We have developed an integrated tool for statistical analysis of large-scale LC-MS profiles of complex protein mixtures comprising a set of procedures for data processing, selection of biomarkers used in early diagnostic and classification of patients based on their peptide mass fingerprints. Here, a novel boosting technique is proposed, which is embedded in our framework for MS data analysis. Our boosting scheme is based on Hannan-consistent game playing strategies. We analyze boosting from a game-theoretic perspective and define a new class of boosting algorithms called H-boosting methods. In the experimental part of this work we apply the new classifier together with classical and state-of-the-art algorithms to classify ovarian cancer and cystic fibrosis patients based on peptide mass spectra. The methods developed here provide automatic, general, and efficient means for processing of large scale LC-MS datasets. Good classification results suggest that our approach is able to uncover valuable information to support medical diagnosis.

1.
Niebroj-Dobosz, I., Madej-Pilarczyk, A., Marchel, M., Soko\lowska, B. & Hausmanowa-Petrusewicz, I. Matrix metalloproteinases in serum of Emery-Dreifuss muscular dystrophy patients. Acta biochimica Polonica 56, 717–22 (2009).

Abstract: In the pathogenesis of dilated cardiomyopathy (DCM) in Emery-Dreifuss muscular dystrophy (EDMD) matrix metalloproteinases (MMPs) are supposed to be involved and may have diagnostic/prognostic value. Serum levels of MT1-MMP, MMP-2 and MMP-9 were quantified by ELISA and zymography in 22 EDMD patients and 15 age-matched controls. In the autosomal-dominant EDMD MMP-2 and MT1-MMP were increased in all cases, and MMP-9 was increased in two of the eight examined patients. In the X-linked EDMD MMP-2 expression was increased in all the cases, MMP-9 level was elevated in 3 of the 14 cases, and MT1-MMP was decreased in eight of these patients. There was no evident correlation between the MMPs level and the different cardiac parameters including left-ventricular end-diastolic diameter, left atrial diameter and left ventricular ejection fraction in either form of EDMD. The presented results indicate that a changed level of matrix metalloproteinases, especially that of MMP-2 in serum, may be of value for detection of cardiac involvement in EDMD patients, especially in those patients with no evident subjective cardiac symptoms. Further follow-up studies of MMPs are needed to check if their determination is of value for monitoring of the progression of atrial/ventricular dilatation. MMPs determinations may also be useful for monitoring DCM treatment by synthetic MMPs inhibitors.

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Kolinski, M. & Filipek, S. Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations. Journal of molecular modeling 16, 1567–76 (2010).

Abstract: Among the structurally similar guanidinonaltrindole (GNTI) compounds, 5’-GNTI is an antagonist while 6’-GNTI is an agonist of the kappaOR opioid receptor. To explore how a subtle alteration of the ligand structure influences the receptor activity, we investigated two concurrent processes: the final steps of ligand binding at the receptor binding site and the initial steps of receptor activation. To trace these early activation steps, the membranous part of the receptor was built on an inactive receptor template while the extracellular loops were built using the ab initio CABS method. We used the simulated annealing procedure for ligand docking and all-atom molecular dynamics simulations to determine the immediate changes in the structure of the ligand-receptor complex. The binding of an agonist, in contrast to an antagonist, induced the breakage of the "3-7 lock" between helices TM3 and TM7. We also observed an action of the extended rotamer toggle switch which suggests that those two switches are interdependent.

1.
Sosnowski, T. R., Kolinski, M. & Gradoń, L. Alteration of surface properties of dipalmitoyl phosphatidylcholine by benzo[a]pyrene: a model of pulmonary effects of diesel exhaust inhalation. J Biomed Nanotechnol 8, 818–25 (2012).

Abstract: Effects of benzo[a]pyrene (BaP) on the surface properties of dipalmitoyl phosphatidylcholine (DPPC) being the basic component of pulmonary surfactant and lipid membranes were studied experimentally and analyzed by molecular dynamics simulations. Isotherms and surface compressibility of mixed BaP/DPPC monolayers on water were determined using Langmuir-Wilhelmy film balance. It was demonstrated that BaP induced concentration-dependent deviations from the initial surface activity of the phospholipid film and a noticeable decrease of its fluidity. Results obtained by molecular dynamics simulations allow to explain the observed effects indicating a migration of BaP molecules towards hydrophobic part of the interfacial layer of DPPC and the concentration-dependent restriction of flexibility of the hydrocarbon chains of phospholipid molecules. The results of the study may be related to the physicochemical disturbance of the pulmonary surfactant system after breathing with air contaminated by diesel exhaust components. It is speculated that such phenomena may have an input to undesired health effects.

1.
Rybinski, M. & Gambin, A. Model-based selection of the robust JAK-STAT activation mechanism. Journal of theoretical biology (2012). doi:10.1016/j.jtbi.2012.04.031

Abstract: JAK-STAT pathway family is a principal signaling mechanism in eukaryotic cells. Evolutionary conserved roles of this mechanism include control over fundamental processes such as cell growth or apoptosis. Deregulation of the JAK-STAT signaling is frequently associated with cancerogenesis. JAK-STAT pathways become hyper-activated in many human tumors. Therefore, components of these pathways are an attractive target for drugs, which design requires as adequate models as possible. Although, in principle, JAK-STAT signaling is relatively simple, the ambiguities in a receptor activation prevent a clear explanation of the underlying molecular mechanism. Here, we compare four variants of a computational model of the JAK1/2-STAT1 signaling pathway. These variants capture known, basic discrepancies in the mechanism of activation of a cytokine receptor, in the context of all key components of the pathway. We carry out a comparative analysis using mass action kinetics. The investigated differences are so marginal that all models satisfy a goodness of fit criteria to the extent that the state of the art Bayesian model selection (BMS) method fails to significantly promote one model. Therefore, we comparatively investigate changes in a robustness of the JAK1/2-STAT1 pathway variants using the global sensitivity analysis method (GSA), complemented with the identifiability analysis (IA). Both BMS and GSA are used to analyze the models for the varying parameter values. We found out that, both BMS and GSA, narrowed down to the receptor activation component, slightly promote the least complex model. Further, insightful, comprehensive GSA, motivated by the concept of robustness, allowed us to show that the precise order of reactions of a ligand binding and a receptor dimerization is not as important as the on-membrane pre-assembly of the dimers in the absence of ligand. The main value of this work is an evaluation of the usefulness of different model selection methods in a frequently encountered, but not much discussed case of a model of a considerable size, which has several variants differing at peripheries. In such situation, all considered variants can reach nearly perfect agreement with respect to their numerical simulations results and, most often, the sufficient experimental data to test against is not available. We argue that in such an adverse setting, the GSA and IA, although not directly corresponding to the model selection problem, can be more informative than the representative, generalizability-based approaches to this task. An additional insight into how the responsibility for the network dynamics spreads among model parameters, enables more conscious, expert-mediated choice of the preferred model.

1.
Soko\lowska, B. & Jóźwik, A. Statistical evaluation of ventilatory patterns in response to intermittent hypoxia in the rabbit. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 56 Suppl 4, 203–7 (2005).

Abstract: In the present study we investigated whether classical or non-classical statistical methods might be useful in the diagnosis of early changes evoked by intermittent hypoxia (IH) in an experimental model. The experiments were carried out in anesthetized, spontaneously breathing rabbits. IH consisted of 5 cycles of breathing 14% O(2) in N(2) for 1 min interspersed with 3 min normoxic intervals. The following ventilatory variables were evaluated: frequency breathing, tidal volume, and minute ventilation. The results indicate that IH had a progressively stimulatory effect on the baseline ventilation and on the hypoxic ventilatory responses. Further, the algorithms of the pattern recognition theory might be a suitable tool for the recognition of early ventilatory effects of recurrent hypoxic events in the IH model. The recognition of IH states may be useful in clinical and sports medicine.

1.
Janowska, B. et al. Nucleotide excision repair and recombination are engaged in repair of trans-4-hydroxy-2-nonenal adducts to DNA bases in Escherichia coli. International journal of biological sciences 5, 611–20 (2009).

Abstract: One of the major products of lipid peroxidation is trans-4-hydroxy-2-nonenal (HNE). HNE forms highly mutagenic and genotoxic adducts to all DNA bases. Using M13 phage lacZ system, we studied the mutagenesis and repair of HNE treated phage DNA in E. coli wild-type or uvrA, recA, and mutL mutants. These studies revealed that: (i) nucleotide excision and recombination, but not mismatch repair, are engaged in repair of HNE adducts when present in phage DNA replicating in E. coli strains; (ii) in the single uvrA mutant, phage survival was drastically decreased while mutation frequency increased, and recombination events constituted 48% of all mutations; (iii) in the single recA mutant, the survival and mutation frequency of HNE-modified M13 phage was slightly elevated in comparison to that in the wild-type bacteria. The majority of mutations in recA(-) strain were G:C –> T:A transversions, occurring within the sequence which in recA(+) strains underwent RecA-mediated recombination, and the entire sequence was deleted; (iv) in the double uvrA recA mutant, phage survival was the same as in the wild-type although the mutation frequency was higher than in the wild-type and recA single mutant, but lower than in the single uvrA mutant. The majority of mutations found in the latter strain were base substitutions, with G:C –> A:T transitions prevailing. These transitions could have resulted from high reactivity of HNE with G and C, and induction of SOS-independent mutations.

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Ishikawa, T. et al. Activities of Topoisomerase I in Its Complex with SRSF1. Biochemistry (2012). doi:10.1021/bi300043t

Abstract: Human DNA topoisomerase I (topo I) catalyzes DNA relaxation and phosphorylates SRSF1. Whereas the structure of topo I complexed with DNA has been resolved, the structure of topo I in the complex with SRSF1 and structural determinants of topo I activities in this complex are not known. The main obstacle to resolving the structure is a contribution of unfolded domains of topo I and SRSF1 in formation of the complex. To overcome this difficulty, we employed a three-step strategy: identifying the interaction regions, modeling the complex, and validating the model with biochemical methods. The binding sites in both topo I and SRSF1 are localized in the structured regions as well as in the unfolded domains. One observes cooperation between the binding sites in topo I but not in SRSF1. Our results indicate two features of the unfolded RS domain of SRSF1 containing phosphorylated residues that are critical for the kinase activity of topo I: its spatial arrangement relative to topo I and the organization of its sequence. The efficiency of phosphorylation of SRSF1 depends on the length and flexibility of the spacer between the two RRM domains that uniquely determine an arrangement of the RS domain relative to topo I. The spacer also influences inhibition of DNA nicking, a prerequisite for DNA relaxation. To be phosphorylated, the RS domain has to include a short sequence recognized by topo I. A lack of this sequence in the mutants of SRSF1 or its spatial inaccessibility in SRSF9 makes them inadequate as topo I/kinase substrates.

1.
Cieplak, M., Filipek, S., Janovjak, H. & Krzyśko, K. A. Pulling single bacteriorhodopsin out of a membrane: Comparison of simulation and experiment. Biochimica et biophysica acta 1758, 537–44 (2006).

Abstract: Mechanical unfolding of single bacteriorhodopsins from a membrane bilayer is studied using molecular dynamics simulations. The initial conformation of the lipid membrane is determined through all-atom simulations and then its coarse-grained representation is used in the studies of stretching. A Go-like model with a realistic contact map and with Lennard-Jones contact interactions is applied to model the protein-membrane system. The model qualitatively reproduces the experimentally observed differences between force-extension patterns obtained on bacteriorhodopsin at different temperatures and predicts a lack of symmetry in the choice of the terminus to pull by. It also illustrates the decisive role of the interactions of the protein with the membrane in determining the force pattern and thus the stability of transmembrane proteins.

1.
Niebroj-Dobosz, I., Marchel, M., Madej-Pilarczyk, A., Soko\lowska, B. & Hausmanowa-Petrusewicz, I. Circulating autoantibodies to troponin I in Emery-Dreifuss muscular dystrophy. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases 27, 1–6 (2008).

Abstract: The pathogenesis of dilated cardiomyopathy in Emery- Dreifuss muscular dystrophy (EDMD) is still unknown. Autoimmune mechanisms have recently been taken into account. The aim of this investigation was to determine whether the level of circulating antibodies to heart proteins which were previously detected, correlates with disease progression. Troponin I was chosen as the target. Ten patients with EDMD and 10 age-matched normal controls were tested. An enzyme linked immunoassay (ELISA) technique was used to determine the possible relation between the level of anti-troponin I antibodies at diagnosis and at followup. Autoantibodies against troponin I were detected in all EDMD patients. At diagnosis the level was higher in the X-linked EDMD form (X-EDMD), as compared to the autosomal dominant form (AD-EDMD). At follow-up the elevated level of the autoantibodies persisted in all the EDMD cases. However, in the AD-EDMD form, the level was found to be significantly rising with disease progression, in the X-EDMD form, on the other hand, it was declining. No clear-cut relationship between the level of the circulating antibodies and cardiac symptomatology was present. Detection of anti-troponin I antibodies may provide a non-invasive marker of early stages of dilated cardiomyopathy in EDMD.

1.
Kluge, B., Gambin, A. & Niemiro, W. Modeling exopeptidase activity from LC-MS data. Journal of computational biology : a journal of computational molecular cell biology 16, 395–406 (2009).

Abstract: Recent studies demonstrate that the peptides in the serum of cancer patients that are generated (ex vivo) as a result of tumor protease activity can be used for the detection and classification of cancer. In this paper, we propose the first formal approach to modeling exopeptidase activity from liquid chromatography-mass spectrometry (LC-MS) samples. We design a statistical model of peptidome degradation and a Metropolis-Hastings algorithm for Bayesian inference of model parameters. The model is successfully validated on a real LC-MS dataset. Our findings support the hypotheses about disease-specific exopeptidase activity, which can lead to new diagnostic approach in clinical proteomics.

1.
Zimnicka, M. et al. Structural Elucidation of Specific Non-covalent Association of Folic Acid with Native Cyclodextrins using an IM-MS and Theoretical Approach. Anal Chem (2014). doi:10.1021/ac4039042

Abstract:

The combination of ion mobility mass spectrometry studies and theoretical calculations including docking studies permitted a detailed structural description of non-covalent complexes of folic acid (FA) and native cyclodextrins (α-CD, β-CD and γ-CD). The mode of non-covalent association depended on the cavity size of the cyclodextrin. The structure of FA/α-CD represented the exclusion complex in which the aminobenzoic moiety and the aromatic pteridine ring of folic acid remain outside the cyclodextrin cavity, while the glutamate residue is anchored in the interior of the α-cyclodextrin. A rotaxane-type structure was proposed for the FA/β-CD complex with the aminobenzoic part of FA being trapped in the central cavity of β-CD. The glutamate residue and the aromatic pteridine ring interact with the primary and secondary rim hydroxyl residues, respectively, enhancing complex stability. Two possible structures of FA/γ-CD were suggested, the first one being analogous to the FA/β-CD complex and the second one being more stable - in which the aromatic pteridine ring penetrates into the CD cavity while the glutamate residue with the aminobenzoic part of FA are exposed to the cone exterior of CD at its wider edge. Further insight into the association behavior of the folic acid towards cyclodextrins evaluated by thermodynamic calculations indicates that the process is highly exothermic. The complex stability increased in the order FA/α-CD < FA/β-CD < FA/γ-CD. This order is consistent with the previously determined relative gas-phase stability established based on the dissociation efficiency curves of the FA/CD complexes.

1.
Park, P. S.-H. et al. Stabilizing effect of Zn2+ in native bovine rhodopsin. The Journal of biological chemistry 282, 11377–85 (2007).

Abstract: Single-molecule force spectroscopy (SMFS) is a powerful tool to dissect molecular interactions that govern the stability and function of proteins. We applied SMFS to understand the effect of Zn2+ on the molecular interactions underlying the structure of rhodopsin. Force-distance curves obtained from SMFS assays revealed the strength and location of molecular interactions that stabilize structural segments within this receptor. The inclusion of ZnCl2 in SMFS assay buffer increased the stability of most structural segments. This effect was not mimicked by CaCl2, CdCl2, or CoCl2. Thus, Zn2+ stabilizes the structure of rhodopsin in a specific manner.

1.
Czerwosz, L. et al. Recognition of gait disturbances in patients with normal pressure hydrocephalus using a computer dynography system. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 59 Suppl 6, 201–7 (2008).

Abstract: Gait and body balance disturbances are important clinical problems in patients with normal pressure hydrocephalus (NPH). They affect patients’ locomotion and lead to a higher risk of falls. The gait pattern may be described as durations of the single and double support and of a stance phase. The aim of the present study was to apply the pattern recognition methods for the evaluation of gait disturbances in patients with NPH before and after neurosurgical treatment (shunt implantation). The results indicate that the parameters measured with a Computer DynoGraphy (CDG) system may effectively differentiate changes of gait in patients with NPH.

1.
Soko\lowska, B., Maciejewska, A. M., Jóźwik, A. & Kuśmierek, J. T. ESTIMATION OF SIGNIFICANCE OF ALKB AND ALKA PROTEINS IN DNA REPAIR IN ESCHERICHIA COLI MODEL. (2011).
1.
Ahmed, A. A. et al. A genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancer. Cancer chemotherapy and pharmacology 68, 1033–44 (2011).

Abstract: PURPOSE: To investigate the mechanistic basis of the anti-tumor effect of the compound ITB-301. METHODS: Chemical modifications of genistein have been introduced to improve its solubility and efficacy. The anti-tumor effects were tested in ovarian cancer cells using proliferation assays, cell cycle analysis, immunofluorescence, and microscopy. RESULTS: In this work, we show that a unique glycoside of genistein, ITB-301, inhibits the proliferation of SKOv3 ovarian cancer cells. We found that the 50% growth inhibitory concentration of ITB-301 in SKOv3 cells was 0.5 μM. Similar results were obtained in breast cancer, ovarian cancer, and acute myelogenous leukemia cell lines. ITB-301 induced significant time- and dose-dependent microtubule depolymerization. This depolymerization resulted in mitotic arrest and inhibited proliferation in all ovarian cancer cell lines examined including SKOv3, ES2, HeyA8, and HeyA8-MDR cells. The cytotoxic effect of ITB-301 was dependent on its induction of mitotic arrest as siRNA-mediated depletion of BUBR1 significantly reduced the cytotoxic effects of ITB-301, even at a concentration of 10 μM. Importantly, efflux-mediated drug resistance did not alter the cytotoxic effect of ITB-301 in two independent cancer cell models of drug resistance. CONCLUSION: These results identify ITB-301 as a novel anti-tubulin agent that could be used in cancers that are multidrug resistant. We propose a structural model for the binding of ITB-301 to α- and β-tubulin dimers on the basis of molecular docking simulations. This model provides a rationale for future work aimed at designing of more potent analogs.

1.
Grzebelus, D. et al. Population dynamics of miniature inverted-repeat transposable elements (MITEs) in Medicago truncatula. Gene 448, 214–20 (2009).

Abstract: Miniature inverted-repeat transposable elements (MITEs) are small and high copy number transposons, related to and mobilized by some class II autonomous elements. New MITE families can be identified by computer-based mining of sequenced genomes. We describe four MITE families related to MtPH transposons mined de novo in the genome of Medicago truncatula, together with one previously described family MITRAV. Different levels of their intra-family sequence diversity and insertion polymorphism indicate that they were active at different evolutionary periods. MetMIT1 and MITRAV families were uniform in sequence and produced highly polymorphic insertion sites in 26 ecotypes representing a M. truncatula core collection. A subset of insertions was present only in the reference genome of A17 ’Jemalong’, suggesting that the two families might have been active in the course of domestication. In contrast, all investigated insertions of the MetMIT2 family were fixed, showing that it was not active after M. truncatula speciation. MetMIT1 elements were divided into three clusters, i.e. (I) relatively heterogenous copies fixed in the genome of M. truncatula, (II) uniform but also mostly fixed, and (III) uniform and polymorphic among the investigated accessions. It might reflect the evolutionary history of the MetMIT1 family, showing multiple bursts of activity. A number of MetMIT1 and MITRAV insertions were present within 1 kb upstream or downstream the ORF. A high proportion of insertions proximal to coding regions was unique to A17 ’Jemalong’.

1.
Soko\lowska, B. & Jóźwik, A. Ventilatory response to hypoxia in experimental pathology of the diaphragm. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 55 Suppl 3, 121–6 (2004).

Abstract: In this study, we examined the usefulness of arterial blood gas variables, as changed by the hypoxic stimulus, in discerning various experimentally-induced conditions of diaphragm weakness in anesthetized cats. We defined three experimental situations (models): (i) intact muscle, statistical Class I, (ii) four degrees of muscle dysfunction (after sequential diaphragm denervation), Classes II-V, and (iii) entirely paralyzed muscle, Class VI. Responses to a hypoxic stimulus in the above-mentioned conditions were evaluated by using the methods of the pattern recognition theory. We found that before the hypoxic stimulus, with partial but of different severity denervation of the diaphragm, the k-nearest neighbor classifier (k-NN) assigned 100% of the classified cases to Class II (one phrenic nerve rootlet cut). In contrast, during hypoxia only 67% of cases were assigned to Class II, the remaining being spread throughout other classes of muscle weakness. When one limits the procedure to the extreme classes: Class I (intact diaphragm) and Class VI (totally denervated diaphragm), the k-NN picks out 33% and 50% cases of bilateral diaphragm paralysis before and during hypoxia, respectively. We conclude that any remaining innervations of the diaphragm ensure the functionally optimal level of lung ventilation that may waver when hypoxia develops.

1.
Czerwosz, L., Szczepek, E., Soko\lowska, B., Jurkiewicz, J. & Czernicki, Z. in Hydrocephalus (2012).
1.
Jozwiak, K., Krzyśko, K. A., Bojarski, L., Gacia, M. & Filipek, S. Molecular models of the interface between anterior pharynx-defective protein 1 (APH-1) and presenilin involving GxxxG motifs. ChemMedChem 3, 627–34 (2008).

Abstract: Gamma-secretase is an integral membrane protease, which is a complex of four membrane proteins. Improper functioning of gamma-secretase was found to be critical in the pathogenesis of Alzheimer’s disease. Despite numerous efforts, the structure of the protease as well as its proteolytic mechanism remains poorly understood. In this work we constructed a model of interactions between two proteins forming gamma-secretase: APH-1 and presenilin. This interface is based on a highly conserved GxxxGxxxG motif in the APH-1 protein. It can form a tight contact with a small-residue AxxxAxxxG motif in presenilin. Here, four binding modes based on similar structures involving GxxxG motifs in glycophorin and aquaporin were proposed and verified. The resulting best model employs antiparallel orientations of interacting helices and is in agreement with the currently accepted topology of both proteins. This model can be used for further structural characterization of gamma-secretase and its components.

1.
Czerwosz, L. et al. Analysis of postural sway in patients with normal pressure hydrocephalus: effects of shunt implantation. European journal of medical research 14 Suppl 4, 53–8 (2009).

Abstract: Poor postural balance is one of the major risk factors for falling in normal pressure hydrocephalus (NPH). Postural instability in the clinic is commonly assessed based upon force platform posturography. In this study we focused on the identification of changes in sway characteristics while standing quiet in patients with NPH before and after shunt implantation. Postural sway area and sway radius were analyzed in a group of 9 patients and 46 controls of both genders. Subject’s spontaneous sway was recorded while standing quiet on a force platform for 30-60 s, with eyes open and then closed. Both analyzed sway descriptors identified between-group differences and also an effect of shunt implantation in the NPH group. Sway radius and sway area in patients exhibited very high values compared with those in the control group. Importantly, the effect of eyesight in patients was not observed before shunt implantation and reappeared after the surgical treatment. The study documents that static force platform posturography may be a reliable measure of postural control improvement due to shunt surgery.

1.
Maciejewska, A. M., Soko\lowska, B., Nowicki, A. & Kuśmierek, J. T. The role of AlkB protein in repair of 1,N6$-ethenoadenine in Escherichia coli cells. Mutagenesis 26, 401–6 (2011).

Abstract: Etheno (ε) DNA adducts, including 1,N(6)-ethenoadenine (εA), are formed by various bifunctional agents of exogenous and endogenous origin. The AT→TA transversion, the most frequent mutation provoked by the presence of εA in DNA, is very common in critical codons of the TP53 and RAS genes in tumours induced by exposure to carcinogenic vinyl compounds. Here, using a method that allows examination of the mutagenic potency of a metabolite of vinyl chloride, chloroacetaldehyde (CAA), but eliminates its cytotoxicity, we studied the participation of alkA, alkB and mug gene products in the repair of εA in Escherichia coli cells. The test system used comprised the pIF105 plasmid bearing the lactose operon of CC105 origin, which allowed monitoring of Lac(+) revertants that arose by AT→TA substitutions due to the modification of adenine by CAA. The plasmid was CAA-modified in vitro and replicated in E.coli of various genetic backgrounds (wt, alkA, alkB, mug, alkAalkB, alkAmug and alkBmug). To modify the levels of the AlkA and AlkB proteins, mutagenesis was studied in E.coli cells induced or not in adaptive response to alkylating agents. Considering the levels of CAA-induced Lac(+) revertants in strains harbouring the CAA-modified pIF105 plasmid and induced or not in adaptive response, we conclude that the AlkB dioxygenase plays a major role in decreasing the level of AT→TA mutations, thus in the repair of εA in E.coli cells. The observed differences of mutation frequencies in the various mutant strains assayed indicate that Mug glycosylase is also engaged in the repair of εA, whereas the role the AlkA glycosylase in this repair is negligible.

1.
Daniluk, P. & Lesyng, B. A novel method to compare protein structures using local descriptors. BMC bioinformatics 12, 344 (2011).

Abstract: BACKGROUND: Protein structure comparison is one of the most widely performed tasks in bioinformatics. However, currently used methods have problems with the so-called "difficult similarities", including considerable shifts and distortions of structure, sequential swaps and circular permutations. There is a demand for efficient and automated systems capable of overcoming these difficulties, which may lead to the discovery of previously unknown structural relationships. RESULTS: We present a novel method for protein structure comparison based on the formalism of local descriptors of protein structure - DEscriptor Defined Alignment (DEDAL). Local similarities identified by pairs of similar descriptors are extended into global structural alignments. We demonstrate the method’s capability by aligning structures in difficult benchmark sets: curated alignments in the SISYPHUS database, as well as SISY and RIPC sets, including non-sequential and non-rigid-body alignments. On the most difficult RIPC set of sequence alignment pairs the method achieves an accuracy of 77% (the second best method tested achieves 60% accuracy). CONCLUSIONS: DEDAL is fast enough to be used in whole proteome applications, and by lowering the threshold of detectable structure similarity it may shed additional light on molecular evolution processes. It is well suited to improving automatic classification of structure domains, helping analyze protein fold space, or to improving protein classification schemes. DEDAL is available online at http://bioexploratorium.pl/EP/DEDAL.

1.
Janik, P., Kwiecinski, H., Soko\lowska, B. & Niebroj-Dobosz, I. Erythropoietin concentration in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Journal of neural transmission (Vienna, Austria : 1996) 117, 343–7 (2010).

Abstract: Erythropoietin (EPO) acts as a neuroprotective factor and is upregulated after neuronal injury. It has been reported that in cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients, the EPO concentration is decreased. In this study, EPO levels in serum and CSF of 30 patients with ALS and in 15 controls, using an ELISA technique, were estimated. EPO level in serum was decreased, especially in patients with bulbar onset ALS. A trend toward a progressive EPO decline with the duration of the disease in the mild + moderate ALS cases was observed. In severe cases, a tendency towards a positive correlation of EPO and duration of the disease was present. Serum EPO values were age related only in mild + moderate ALS in patients below 40 years of age. In CSF, the EPO levels were significantly decreased. Lower EPO values in the bulbar onset ALS when compared with the spinal onset ALS were present. The EPO decrease did not correlate with the severity and duration of the disease. Age relation of the EPO level only in the mild + moderate ALS cases more than 40 years was present. Lack of differences in EPO levels between patients with ALS of rapid and slow progression indicates that EPO concentration cannot be used as a prognostic factor. Nevertheless, the decreased serum and CSF EPO concentration and the known EPO neuroprotective action may indicate that EPO administration can be a new promising therapeutic approach in ALS.

1.
Lazarova, T. et al. The Effect of Triple Glutamic Mutations E9Q/E194Q/E204Q on the Structural Stability of Bacteriorhodopsin. FEBS J (2013). doi:10.1111/febs.12694

Abstract: Here we report on the structural features of the triple mutant E9Q/E194Q/E204Q (3Glu) of bacteriorhodopsin (bR) by combining experimental and molecular dynamics (MD) approaches. In 3Glu mutant, Glu9, Glu194 and Glu204 residues located at the extracellular side of the protein were mutated all together to glutamines. UV-Vis and DSC experiments served as diagnostic tools for monitoring the resistance against thermal stress of the active site and the tertiary structures of the 3Glu. The analyses of the UV-Vis thermal difference spectra demonstrate that the spectral forms at room temperature and the thermal unfolding path differ in the WT and the 3Glu. Even these spectral differences, the thermal unfolding of the active site occurs at rather similar melting temperatures in both proteins. A noteworthy consequence of the mutations is the altered 2D packing revealed by the lack of the pre-transition peak in DSC traces of 3Glu mutant, previously detected in WT and the corresponding single mutants. The infrared spectroscopy data agree with the loss of paracrystalinity illustrating a substantial conversion of αII to αI helical conformation in the 3Glu mutant. MD simulations show higher dynamics flexibility of most of EC regions of 3Glu, which may account for somewhat lower tertiary structural stability of the mutated protein. Finally, the hydrogen bond analysis reveals that the mutated Glu194 and Glu204 residues create about 50% less hydrogen bonds with water molecules compared to WT bR. These results exemplify the role of the water hydrogen-bonding network for structural integrity and conformational flexibility of bR. This article is protected by copyright. All rights reserved.

1.
Strömbergsson, H. et al. Interaction model based on local protein substructures generalizes to the entire structural enzyme-ligand space. Journal of chemical information and modeling 48, 2278–88 (2008).

Abstract: Chemogenomics is a new strategy in in silico drug discovery, where the ultimate goal is to understand molecular recognition for all molecules interacting with all proteins in the proteome. To study such cross interactions, methods that can generalize over proteins that vary greatly in sequence, structure, and function are needed. We present a general quantitative approach to protein-ligand binding affinity prediction that spans the entire structural enzyme-ligand space. The model was trained on a data set composed of all available enzymes cocrystallized with druglike ligands, taken from four publicly available interaction databases, for which a crystal structure is available. Each enzyme was characterized by a set of local descriptors of protein structure that describe the binding site of the cocrystallized ligand. The ligands in the training set were described by traditional QSAR descriptors. To evaluate the model, a comprehensive test set consisting of enzyme structures and ligands was manually curated. The test set contained enzyme-ligand complexes for which no crystal structures were available, and thus the binding modes were unknown. The test set enzymes were therefore characterized by matching their entire structures to the local descriptor library constructed from the training set. Both the training and the test set contained enzyme-ligand complexes from all major enzyme classes, and the enzymes spanned a large range of sequences and folds. The experimental binding affinities (p K i) ranged from 0.5 to 11.9 (0.7-11.0 in the test set). The induced model predicted the binding affinities of the external test set enzyme-ligand complexes with an r (2) of 0.53 and an RMSEP of 1.5. This demonstrates that the use of local descriptors makes it possible to create rough predictive models that can generalize over a wide range of protein targets.

1.
Plazinska, A., Kolinski, M., Wainer, I. W. & Jozwiak, K. Molecular interactions between fenoterol stereoisomers and derivatives and the β2-adrenergic receptor binding site studied by docking and molecular dynamics simulations. J Mol Model (2013). doi:10.1007/s00894-013-1981-y

Abstract: The β2 adrenergic receptor (β2-AR) has become a model system for studying the ligand recognition process and mechanism of the G protein coupled receptors activation. In the present study stereoisomers of fenoterol and some of its derivatives (N = 94 molecules) were used as molecular probes to identify differences in stereo-recognition interactions between β2-AR and structurally similar agonists. The present study aimed at determining the 3D molecular models of the fenoterol derivative-β2-AR complexes. Molecular models of β2-AR have been developed by using the crystal structure of the human β2-AR T4 lysozyme fusion protein with bound (S)-carazolol (PDB ID: 2RH1) and more recently reported structure of a nanobody-stabilized active state of the β2-AR with the bound full agonist BI-167107 (PDB ID: 3P0G). The docking procedure allowed us to study the similarities and differences in the recognition binding site(s) for tested ligands. The agonist molecules occupied the same binding region, between TM III, TM V, TM VI and TM VII. The residues identified by us during docking procedure (Ser203, Ser207, Asp113, Lys305, Asn312, Tyr308, Asp192) were experimentally indicated in functional and biophysical studies as being very important for the agonist-receptor interactions. Moreover, the additional space, an extension of the orthosteric pocket, was identified and described. Furthermore, the molecular dynamics simulations were used to study the molecular mechanism of interaction between ligands ((R,R’)- and (S,S’)-fenoterol) and β2-AR. Our research offers new insights into the ligand stereoselective interaction with one of the most important GPCR member. This study may also facilitate the design of improved selective medications, which can be used to treat, prevent and control heart failure symptoms.

1.
Soko\lowska, B., Rekawek, A. & Jóźwik, A. Recognition of the Ventilatory Response to the Intermittent Chemical Stimuli in Awake Animals. Information Technologies in Biomedicine 488–494 (2008).

Abstract: In this study we examined whether it could be possible to recognize a type of chemical stimuli, given in intermittent cycles, on the basis of observed changes in the breathing pattern in an animal model. Ventilatory responses to three chemical stimulus - normoxic cycles (3-min administration of stimulus/8-min normoxic recovery) in awake rats were investigated. Two types of chemical stimuli were given: (a) gas mixtures of 14% or 9% O2 in N2 (i.e. hypoxia), and (b) 5% or 10% CO2 in O2 (i.e. hypercapnia), each one in a separate run of the intermittent stimulus. Ventilatory features: respiratory frequency, tidal volume, minute ventilation, inspired and expired times, were used for recognition of ventilatory responses to exposures of the intermittent stimuli. The quality of recognition was evaluated by a probability of misclassification that was estimated experimentally. As a classifier we used the k nearest neighbor (k-NN) rule that is one of most powerful method offered by the pattern recognition theory. Satisfactory recognition was obtained for recovery periods and stronger stimuli. The best recognition was observed for the intermittent hypercapnia. In conclusion, the approach based on k-NN rule has appeared to be useful tool for recognition changes of ventilatory responses to exposures of the intermittent chemical stimuli.

1.
Niebroj-Dobosz, I., Soko\lowska, B., Madej-Pilarczyk, A., Marchel, M. & Hausmanowa-Petrusewicz, I. Letters to the Editor. International Journal of Cardiology 173, 324–325 (2014).
1.
Soko\lowska, B., Czerwosz, L., Hallay-Suszek, M., Sadura-Sieklucka, T. & Księżopolska-Or\lowska, K. Posturography in patients with rheumatoid arthritis and osteoarthritis. Adv Exp Med Biol 833, 63–70 (2015).

Abstract:

The purpose of the paper was to investigate the usefulness of posturographic analysis in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). RA is a chronic inflammatory disorder responsible for destruction of active and passive components of joints. It is the most common autoimmune disease, and the second most common form of arthritis after OA. OA is a chronic disorder characterized by irreversible changes in the joint structure developing with advancing age. Both diseases lead to the destruction of many parts of the motor system, cause pain, weakness, and damage of ligaments, muscles, bones, and articular cartilage. The etiology of the diseases remains unknown. In the present study, evaluation of body balance in the standing position was performed by means of Pro-Med force plate system. Three posturographic tests were applied: with eyes open, closed, and with the biofeedback - under conscious visual control of body movements. The following posturographic parameters were measured: the radius of sways, the developed area, and the total length of posturograms, and also two directional components of sways: the length of left-right (in frontal plane) and forward-backward (in sagittal plane) motions. The results demonstrate that the biofeedback test is most useful in the evaluation of instability in rheumatic patients; it is more powerful than the other posturographic tests evaluated.

1.
Maciejewska, A. M. et al. Chloroacetaldehyde-induced mutagenesis in Escherichia coli: the role of AlkB protein in repair of 3,N(4)-ethenocytosine and 3,N(4)-alpha-hydroxyethanocytosine. Mutation research 684, 24–34 (2010).

Abstract: Etheno (epsilon) adducts are formed in reaction of DNA bases with various environmental carcinogens and endogenously created products of lipid peroxidation. Chloroacetaldehyde (CAA), a metabolite of carcinogen vinyl chloride, is routinely used to generate epsilon-adducts. We studied the role of AlkB, along with AlkA and Mug proteins, all engaged in repair of epsilon-adducts, in CAA-induced mutagenesis. The test system used involved pIF102 and pIF104 plasmids bearing the lactose operon of CC102 or CC104 origin (Cupples and Miller (1989) [17]) which allowed to monitor Lac(+) revertants, the latter arose by GC–>AT or GC–>TA substitutions, respectively, as a result of modification of guanine and cytosine. The plasmids were CAA-damaged in vitro and replicated in Escherichia coli of various genetic backgrounds. To modify the levels of AlkA and AlkB proteins, mutagenesis was studied in E. coli cells induced or not in adaptive response. Formation of varepsilonC proceeds via a relatively stable intermediate, 3,N(4)-alpha-hydroxyethanocytosine (HEC), which allowed to compare repair of both adducts. The results indicate that all three genes, alkA, alkB and microg, are engaged in alleviation of CAA-induced mutagenesis. The frequency of mutation was higher in AlkA-, AlkB- and Mug-deficient strains in comparison to alkA(+), alkB(+), and microg(+) controls. Considering the levels of CAA-induced Lac(+) revertants in strains harboring the pIF plasmids and induced or not in adaptive response, we conclude that AlkB protein is engaged in the repair of epsilonC and HEC in vivo. Using the modified TTCTT 5-mers as substrates, we confirmed in vitro that AlkB protein repairs epsilonC and HEC although far less efficiently than the reference adduct 3-methylcytosine. The pH optimum for repair of HEC and epsilonC is significantly different from that for 3-methylcytosine. We propose that the protonated form of adduct interact in active site of AlkB protein.

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