Publications by authors named "Marek Wieczorek"

38 Publications

Influence of chitosan average molecular weight on degradation and stability of electrodeposited conduits.

Carbohydr Polym 2020 Sep 29;244:116484. Epub 2020 May 29.

Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Wroblewskiego 15 Street, 93-590, Lodz, Poland.

Tubular chitosan-based hydrogels, obtained in an electrodeposition process, are subject of degradation and stability studies. The implants are prepared from polymer with different average molecular weight. This approach allows fabricating structures that vary in mass and wall thickness. The obtained implants are incubated in phosphate buffered solution (pH 7.4) with or without lysozyme up to 56 days at 37 °C. Subsequently, chemical, physical as well as mechanical properties of implants are evaluated. Although the initial physicomechanical properties are different, they change upon incubation and remain similar over its period. Finally, in vitro biocompatibility of implants is proven after assessing their action towards mHippoE-18 embryonic hippocampal cells and THP1-XBlue™ monocytes. Since dimensions of nerves and the gap length differ across the body and injury, respectively, the possibility to control properties of chitosan applied gives a tool to prepare implants with wall thickness adjusted to the specific peripheral nerve injury case.
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http://dx.doi.org/10.1016/j.carbpol.2020.116484DOI Listing
September 2020

Multiple Sclerosis CD49dCD154 As Myelin-Specific Lymphocytes Induced During Remyelination.

Cells 2019 12 19;9(1). Epub 2019 Dec 19.

Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Poland, ul. Pomorska 251, 92-213 Lodz, Poland.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49dCD154 lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49dCD154 lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49dCD154 lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49dCD154 lymphocyte proliferation. We confirmed, in vivo, the presence of CD49dCD154 cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d/CD154 cells were found to be co-localized with O4 cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49dCD154 lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.
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http://dx.doi.org/10.3390/cells9010015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017443PMC
December 2019

MS CD49dCD154 Lymphocytes Reprogram Oligodendrocytes into Immune Reactive Cells Affecting CNS Regeneration.

Cells 2019 11 25;8(12). Epub 2019 Nov 25.

Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Poland, Pomorska Str. 251, 92-213 Lodz, Poland.

The critical aspect in multiple sclerosis (MS) progression involves insufficient regeneration of CNS resulting from deficient myelin synthesis by newly generated oligodendrocytes (OLs). Although many studies have focused on the role of autoreactive lymphocytes in the inflammatory-induced axonal loss, the problem of insufficient remyelination and disease progression is still unsolved. To determine the effect of myelin-specific lymphocytes on OL function in MS patients and in a mouse model of MS, we cultured myelin induced MS CD49dCD154 circulating lymphocytes as well as Experimental Autoimmune Encephalomyelitis (EAE) mouse brain-derived T and memory B cells with maturing oligodendrocyte precursor cells (OPCs). We found that myelin-specific CD49dCD154 lymphocytes affected OPC maturation toward formation of immune reactive OLs. Newly generated OLs were characterized by imbalanced myelin basic protein (MBP) and proteolipid protein (PLP) production as well as proinflammatory chemokine/cytokine synthesis. The analysis of cellular pathways responsible for OL reprogramming revealed that CD49dCD154 lymphocytes affected miRNA synthesis by dysregulation of polymerase II activity. miR-665 and ELL3 turned out to be the main targets of MS myelin-specific lymphocytes. Neutralization of high intracellular miR-665 concentration restored miRNA and MBP/PLP synthesis. Together, these data point to new targets for therapeutic intervention promoting CNS remyelination.
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http://dx.doi.org/10.3390/cells8121508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953114PMC
November 2019

Characterization of Single Amino Acid Variations in an EDTA-Tolerating Non-specific Nuclease from the Ice-Nucleating Bacterium Pseudomonas syringae.

Mol Biotechnol 2020 Jan;62(1):67-78

Miltenyi Biotec B.V. & Co. KG, Friedrich-Ebert-Straße 68, 51429, Bergisch Gladbach, Germany.

Non-specific nuclease (NSN) can be applied in industrial downstream processing to remove nucleic acids from crude protein extracts or in cell-sorting systems to degrade nucleic acids derived from lysed cells. PsNuc from the ice-nucleating bacterium Pseudomonas syringae has the ability to decompose double- and single-stranded DNA in linear or circular form and RNA. It is not affected by the presence of metal-ion chelators such as EDTA and tolerates several protease inhibitors and reducing agents. A multiple sequence alignment of PsNuc with closely related enzymes (97-99% identity on the protein level) within the family Pseudomonaceae revealed the presence of only six amino acid residues that are variable in putative NSN from different members of the genus Pseudomonas. Single amino acid variants were produced in recombinant form in Escherichia coli, purified, and characterized. They showed similar activity compared to PsNuc, but a single variant even displayed an improved performance with an activity of > 20,000 U/mg at 35 °C, while amino acid residues S148 and V161 were found to be essential for enzymatic functionality. These results suggest that homologous nucleases from Pseudomonaceae display high activity levels in a metal-ion-independent manner and are therefore of interest for applications in biotechnology.
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http://dx.doi.org/10.1007/s12033-019-00229-8DOI Listing
January 2020

Peripheral and central compensatory mechanisms for impaired vagus nerve function during peripheral immune activation.

J Neuroinflammation 2019 Jul 19;16(1):150. Epub 2019 Jul 19.

Department of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.

Background: Determining the etiology and possible treatment strategies for numerous diseases requires a comprehensive understanding of compensatory mechanisms in physiological systems. The vagus nerve acts as a key interface between the brain and the peripheral internal organs. We set out to identify mechanisms compensating for a lack of neuronal communication between the immune and the central nervous system (CNS) during infection.

Methods: We assessed biochemical and central neurotransmitter changes resulting from subdiaphragmatic vagotomy and whether they are modulated by intraperitoneal infection. We performed a series of subdiaphragmatic vagotomy or sham operations on male Wistar rats. Next, after full, 30-day recovery period, they were randomly assigned to receive an injection of Escherichia coli lipopolysaccharide or saline. Two hours later, animal were euthanized and we measured the plasma concentration of prostaglandin E2 (with HPLC-MS), interleukin-6 (ELISA), and corticosterone (RIA). We also had measured the concentration of monoaminergic neurotransmitters and their metabolites in the amygdala, brainstem, hippocampus, hypothalamus, motor cortex, periaqueductal gray, and prefrontal medial cortex using RP-HPLC-ED. A subset of the animals was evaluated in the elevated plus maze test immediately before euthanization.

Results: The lack of immunosensory signaling of the vagus nerve stimulated increased activity of discrete inflammatory marker signals, which we confirmed by quantifying biochemical changes in blood plasma. Behavioral results, although preliminary, support the observed biochemical alterations. Many of the neurotransmitter changes observed after vagotomy indicated that the vagus nerve influences the activity of many brain areas involved in control of immune response and sickness behavior. Our studies show that these changes are largely eliminated during experimental infection.

Conclusions: Our results suggest that in vagotomized animals with blocked CNS, communication may transmit via a pathway independent of the vagus nerve to permit restoration of CNS activity for peripheral inflammation control.
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http://dx.doi.org/10.1186/s12974-019-1544-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642550PMC
July 2019

Distinct editing functions of natural HLA-DM allotypes impact antigen presentation and CD4 T cell activation.

Cell Mol Immunol 2020 02 22;17(2):133-142. Epub 2018 Nov 22.

Laboratory of Protein Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Thielallee 63, 14195, Berlin, Germany.

Classical human leukocyte antigen (HLA) molecules of the major histocompatibility class II (MHCII) complex present peptides for the development, surveillance and activation of CD4 T cells. The nonclassical MHCII-like protein HLA-DM (DM) catalyzes the exchange and loading of peptides onto MHCII molecules, thereby shaping MHCII immunopeptidomes. Natural variations of DM in both chains of the protein (DMA and DMB) have been hypothesized to impact peptide presentation, but no evidence for altered function has been reported. Here we define the presence of DM allotypes in human populations covered by the 1000 Genomes Project and probe their activity. The functional properties of several allotypes are investigated and show strong enhancement of peptide-induced T cell activation for a particular combination of DMA and DMB. Biochemical evidence suggests a broader pH activity profile for the new variant relative to that of the most commonly expressed DM allotype. Immunopeptidome analysis indicates that the compartmental activity of the new DM heterodimer extends beyond the late endosome and suggests that the natural variation of DM has profound effects on adaptive immunity when antigens bypass the canonical processing pathway.
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http://dx.doi.org/10.1038/s41423-018-0181-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000412PMC
February 2020

Assessment of the antigenic and neuroprotective activity of the subunit anti-Toxoplasma vaccine in T. gondii experimentally infected mice.

Vet Parasitol 2018 Apr 1;254:82-94. Epub 2018 Mar 1.

Department of Immunoparasitology, Faculty of Biology and Environmental Protection, University of Lodz, 90-237 Łódź, Banacha 12/16, Poland. Electronic address:

The aim of this study was to evaluate the immunogenic and immunoprotective activities and to determine the neuroprotective capacity of the tetravalent vaccine containing selected recombinant T. gondii antigens (ROP2 + ROP4 + SAG1 + MAG1) administered with safe adjuvants (MPL and alum) using male and female inbred mice. The tested antigenic combination provided partial protection against brain cyst formation, especially in males (reduction in cyst burden by 72%). The decrease in cyst burden was observed for the whole brain as well as for specified brain regions associated with natural defensive behaviors, emotion processing and integration of motor and sensory stimuli. The vaccine triggered a strong, specific immune response, regardless of sex, which was characterized by the antigen-specific in vitro synthesis of cytokines (IL-2, IFN-γ and IL-10) and in vivo production of systemic IgG1 and IgG2a immunoglobulins. Immunization prior to the parasite challenge seemed to influence T. gondii - associated behavioral and neurochemical changes, although the impact of vaccination strongly depended on sex and time post-infection. Interestingly, in the vaccinated and T. gondii infected mice there was a significant delay in the parasite-induced loss of aversion toward cat smell (cats are the definitive hosts of the parasite). The regained attraction toward feline scent in vaccinated males, observed during chronic parasite invasion, correlated with the increase in the dopamine metabolism.
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http://dx.doi.org/10.1016/j.vetpar.2018.02.043DOI Listing
April 2018

Expression of hypoxia inducible factor 1α and 2α and its association with vitamin C level in thyroid lesions.

J Biomed Sci 2017 Oct 30;24(1):83. Epub 2017 Oct 30.

Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236, Lodz, Poland.

Background: Cells adapt to hypoxia by transcriptional induction of genes that participate in regulation of angiogenesis, glucose metabolism and cell proliferation. The primary factors mediating cell response to low oxygen tension are hypoxia inducible factors (HIFs), oxygen-dependent transcription activators. The stability and activity of the α subunits of HIFs are controlled by hydroxylation reactions that require ascorbate as a cofactor. Therefore, deficiency of intracellular vitamin C could contribute to HIFs overactivation. In this study, we investigated whether vitamin C content of human thyroid lesions is associated with HIF-1α and HIF-2α protein levels.

Methods: Expression of HIF-1α and HIF-2α as well as vitamin C content was analyzed in thyroid lesions and cultured thyroid carcinoma cell lines (FTC-133 and 8305c) treated with hypoxia-mimetic agent (cobalt chloride) and ascorbic acid. The expression of HIFs and hypoxia-induced glucose transporters were determined by Western blots while quantitative real-time PCR (qRT-PCR) was performed to detect HIFs mRNA levels. Ascorbate and dehydroascorbate levels were measured by HPLC method.

Results: We found an inverse correlation between vitamin C level and HIF-1α but not HIF-2α expression in thyroid lesions. These results agree with our in vitro study showing that vitamin C induced a dose - dependent decrease of HIF-1α but not HIF-2α protein level in thyroid cancer cells FTC-133 and 8305C. The decreased HIF-1α expression was correlated with reduced expression of hypoxia-related glucose transporter 1 (GLUT1) in thyroid cancer cells.

Conclusion: The results demonstrate that HIF-1α activation is associated with vitamin C content in thyroid lesions. Our study suggests that high tumor tissue ascorbate level could limit the expression of HIF-1α and its targets in thyroid lesions.
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http://dx.doi.org/10.1186/s12929-017-0388-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663109PMC
October 2017

Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation.

Front Immunol 2017 17;8:292. Epub 2017 Mar 17.

Protein Biochemistry, Institute for Biochemistry, Freie Universität Berlin , Berlin , Germany.

Antigen presentation by major histocompatibility complex (MHC) proteins is essential for adaptive immunity. Prior to presentation, peptides need to be generated from proteins that are either produced by the cell's own translational machinery or that are funneled into the endo-lysosomal vesicular system. The prolonged interaction between a T cell receptor and specific pMHC complexes, after an extensive search process in secondary lymphatic organs, eventually triggers T cells to proliferate and to mount a specific cellular immune response. Once processed, the peptide repertoire presented by MHC proteins largely depends on structural features of the binding groove of each particular MHC allelic variant. Additionally, two peptide editors-tapasin for class I and HLA-DM for class II-contribute to the shaping of the presented peptidome by favoring the binding of high-affinity antigens. Although there is a vast amount of biochemical and structural information, the mechanism of the catalyzed peptide exchange for MHC class I and class II proteins still remains controversial, and it is not well understood why certain MHC allelic variants are more susceptible to peptide editing than others. Recent studies predict a high impact of protein intermediate states on MHC allele-specific peptide presentation, which implies a profound influence of MHC dynamics on the phenomenon of immunodominance and the development of autoimmune diseases. Here, we review the recent literature that describe MHC class I and II dynamics from a theoretical and experimental point of view and we highlight the similarities between MHC class I and class II dynamics despite the distinct functions they fulfill in adaptive immunity.
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http://dx.doi.org/10.3389/fimmu.2017.00292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355494PMC
March 2017

MHC class II complexes sample intermediate states along the peptide exchange pathway.

Nat Commun 2016 11 9;7:13224. Epub 2016 Nov 9.

Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.

The presentation of peptide-MHCII complexes (pMHCIIs) for surveillance by T cells is a well-known immunological concept in vertebrates, yet the conformational dynamics of antigen exchange remain elusive. By combining NMR-detected H/D exchange with Markov modelling analysis of an aggregate of 275 microseconds molecular dynamics simulations, we reveal that a stable pMHCII spontaneously samples intermediate conformations relevant for peptide exchange. More specifically, we observe two major peptide exchange pathways: the kinetic stability of a pMHCII's ground state defines its propensity for intrinsic peptide exchange, while the population of a rare, intermediate conformation correlates with the propensity of the HLA-DM-catalysed pathway. Helix-destabilizing mutants designed based on our model shift the exchange behaviour towards the HLA-DM-catalysed pathway and further allow us to conceptualize how allelic variation can shape an individual's MHC restricted immune response.
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http://dx.doi.org/10.1038/ncomms13224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105163PMC
November 2016

Human leukocyte Antigen-DM polymorphisms in autoimmune diseases.

Open Biol 2016 08;6(8)

Protein Biochemistry Group, Institute for Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany

Classical MHC class II (MHCII) proteins present peptides for CD4(+) T-cell surveillance and are by far the most prominent risk factor for a number of autoimmune disorders. To date, many studies have shown that this link between particular MHCII alleles and disease depends on the MHCII's particular ability to bind and present certain peptides in specific physiological contexts. However, less attention has been paid to the non-classical MHCII molecule human leucocyte antigen-DM, which catalyses peptide exchange on classical MHCII proteins acting as a peptide editor. DM function impacts the presentation of both antigenic peptides in the periphery and key self-peptides during T-cell development in the thymus. In this way, DM activity directly influences the response to pathogens, as well as mechanisms of self-tolerance acquisition. While decreased DM editing of particular MHCII proteins has been proposed to be related to autoimmune disorders, no experimental evidence for different DM catalytic properties had been reported until recently. Biochemical and structural investigations, together with new animal models of loss of DM activity, have provided an attractive foundation for identifying different catalytic efficiencies for DM allotypes. Here, we revisit the current knowledge of DM function and discuss how DM function may impart autoimmunity at the organism level.
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http://dx.doi.org/10.1098/rsob.160165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008016PMC
August 2016

Epineurium-mimicking chitosan conduits for peripheral nervous tissue engineering.

Carbohydr Polym 2016 Nov 2;152:119-128. Epub 2016 Jul 2.

Department of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland. Electronic address:

In this investigation, we report on a fabrication method of epineurium-mimicking tubular conduits based on electrodeposition from chitosan solution. The pre-enrichment of electrodeposition solution with hyaluronic acid and/or collagen components results in structures which structural, morphological, and physicochemical properties can be controlled. In order to determine the optimal composition of the initial chitosan solution resulting in conduits meeting the requirements imposed on peripheral nerve implants, we perform chemical, physical, and biological studies. Both the molecular weight of hyaluronic acid and the concentration of additives are found to be crucial for the final mechanical as well as biological performance of conduits. Because, the obtained structures show biocompatibility when contacting with a mouse hippocampal cell line (mHippoE-18), we further plan to test their application potential on an animal model.
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http://dx.doi.org/10.1016/j.carbpol.2016.07.002DOI Listing
November 2016

Assessment of degradation and biocompatibility of electrodeposited chitosan and chitosan-carbon nanotube tubular implants.

J Biomed Mater Res A 2016 11 5;104(11):2701-11. Epub 2016 Jul 5.

Department of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236, Lodz, Poland.

Designing three-dimensional tubular materials made of chitosan is still a challenging task. Availability of such forms is highly desired by tissue engineering, especially peripheral nerve tissue engineering. Aiming at this problem, we use an electrodeposition phenomenon in order to obtain chitosan and chitosan-carbon nanotube hydrogel tubular implants. The in vitro biocompatibility of the fabricated structures is assessed using a mouse hippocampal cell line (mHippoE-18). As both implants do not induce significant cytotoxicity, they are next subjected to in vitro degradation studies in the environment simulating in vivo conditions for specified periods of time: 7, 14, and 28 days. The mass loss of implants indicates their stability at the tested time period; therefore, the materials are subcutaneously implanted in Sprague Dawley rats. The explants are collected after 7, 14, and 28 days. The assessment of composition and changes in tissues surrounding the implanted materials is made in respect to surrounding tissue thickness as well as the number of blood vessels, macrophages, lymphocytes, and neutrophils. No symptoms of acute inflammation are noticed at any point in time. The observed regular healing process allows concluding that both chitosan and chitosan-carbon hydrogel tubular implants are biocompatible with high application potential in tissue engineering. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2701-2711, 2016.
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http://dx.doi.org/10.1002/jbm.a.35812DOI Listing
November 2016

Novel candidate genes for alcoholism--transcriptomic analysis of prefrontal medial cortex, hippocampus and nucleus accumbens of Warsaw alcohol-preferring and non-preferring rats.

Pharmacol Biochem Behav 2015 Dec 9;139(Pt A):27-38. Epub 2015 Oct 9.

Department of Pharmacology and Physiology of the Nervous System, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland.

Objective: Animal models provide opportunity to study neurobiological aspects of human alcoholism. Changes in gene expression have been implicated in mediating brain functions, including reward system and addiction. The current study aimed to identify genes that may underlie differential ethanol preference in Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP) rats.

Methods: Microarray analysis comparing gene expression in nucleus accumbens (NAc), hippocampus (HP) and medial prefrontal cortex (mPFC) was performed in male WHP and WLP rats bred for differences in ethanol preference.

Results: Differential and stable between biological repeats expression of 345, 254 and 129 transcripts in NAc, HP and mPFC was detected. Identified genes and processes included known mediators of ethanol response (Mx2, Fam111a, Itpr1, Gabra4, Agtr1a, LTP/LTD, renin-angiotensin signaling pathway), toxicity (Sult1c2a, Ces1, inflammatory response), as well as genes involved in regulation of important addiction-related brain systems such as dopamine, tachykinin or acetylcholine (Gng7, Tac4, Slc5a7).

Conclusions: The identified candidate genes may underlie differential ethanol preference in an animal model of alcoholism.

Comment: Names of genes are written in italics, while names of proteins are written in standard font. Names of human genes/proteins are written in all capital letters. Names of rodent genes/proteins are written in capital letter followed by small letters.
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http://dx.doi.org/10.1016/j.pbb.2015.10.003DOI Listing
December 2015

Effect of Glucose on GLUT1-Dependent Intracellular Ascorbate Accumulation and Viability of Thyroid Cancer Cells.

Nutr Cancer 2015 18;67(8):1333-41. Epub 2015 Sep 18.

a Department of Cytobiochemistry , Faculty of Biology and Environmental Protection, University of Lodz , Lodz , Poland.

Enhanced glucose requirement of cancer cells is associated with an increased glucose transport across plasma membrane that is mediated by a family of facilitated glucose transporter proteins, named GLUTs. GLUT1 is the main transporter in thyroid cancer cells. Glucose is the principal physiological substrate of GLUT1; however, it is also capable of transporting of oxidized form of vitamin C [i.e., dehydroascorbic acid (DHAA) which inside the cells is reduced to ascorbic acid (AA)]. The objective of this study was to determine the effect of normo-, hypo-, and hyperglycemia conditions on GLUT1-dependent intracellular ascorbate accumulation and viability of thyroid cancer cells. GLUT1 seems to be the main DHAA transporter in thyroid cancer cells because its knockdown by RNAi reduced DHAA accumulation by more than 80%. The results showed that in thyroid cancer cells high glucose inhibits both transport of AA and DHAA. Inhibition of vitamin C transport by glucose had a cytotoxic effect on the cells. However, stabilization of vitamin C in one of 2 forms (i.e., AA or DHAA) abolished this effect. These results suggest that cytotoxic effect is rather associated with extracellular accumulation of vitamin C and changes of its oxidation state than with intracellular level of ascorbate.
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http://dx.doi.org/10.1080/01635581.2015.1078823DOI Listing
September 2016

Peptide-polymer ligands for a tandem WW-domain, an adaptive multivalent protein-protein interaction: lessons on the thermodynamic fitness of flexible ligands.

Beilstein J Org Chem 2015 18;11:837-47. Epub 2015 May 18.

Institute of Pharmacy & Institute of Chemistry and Biochemistry, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany ; Department of Medicinal Chemistry, Leibniz Institut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125 Berlin, Germany.

Three polymers, poly(N-(2-hydroxypropyl)methacrylamide) (pHPMA), hyperbranched polyglycerol (hPG), and dextran were investigated as carriers for multivalent ligands targeting the adaptive tandem WW-domain of formin-binding protein (FBP21). Polymer carriers were conjugated with 3-9 copies of the proline-rich decapeptide GPPPRGPPPR-NH2 (P1). Binding of the obtained peptide-polymer conjugates to the tandem WW-domain was investigated employing isothermal titration calorimetry (ITC) to determine the binding affinity, the enthalpic and entropic contributions to free binding energy, and the stoichiometry of binding for all peptide-polymer conjugates. Binding affinities of all multivalent ligands were in the µM range, strongly amplified compared to the monovalent ligand P1 with a K D > 1 mM. In addition, concise differences were observed, pHPMA and hPG carriers showed moderate affinity and bound 2.3-2.8 peptides per protein binding site resulting in the formation of aggregates. Dextran-based conjugates displayed affinities down to 1.2 µM, forming complexes with low stoichiometry, and no precipitation. Experimental results were compared with parameters obtained from molecular dynamics simulations in order to understand the observed differences between the three carrier materials. In summary, the more rigid and condensed peptide-polymer conjugates based on the dextran scaffold seem to be superior to induce multivalent binding and to increase affinity, while the more flexible and dendritic polymers, pHPMA and hPG are suitable to induce crosslinking upon binding.
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http://dx.doi.org/10.3762/bjoc.11.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464424PMC
June 2015

HLA-DMA polymorphisms differentially affect MHC class II peptide loading.

J Immunol 2015 Jan 10;194(2):803-16. Epub 2014 Dec 10.

Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany; and Leibniz Institute for Molecular Pharmacology, 13125 Berlin, Germany

During the adaptive immune response, MHCII proteins display antigenic peptides on the cell surface of APCs for CD4(+) T cell surveillance. HLA-DM, a nonclassical MHCII protein, acts as a peptide exchange catalyst for MHCII, editing the peptide repertoire. Although they map to the same gene locus, MHCII proteins exhibit a high degree of polymorphism, whereas only low variability has been observed for HLA-DM. As HLA-DM activity directly favors immunodominant peptide presentation, polymorphisms in HLA-DM (DMA or DMB chain) might well be a contributing risk factor for autoimmunity and immune disorders. Our systematic comparison of DMA*0103/DMB*0101 (DMA-G155A and DMA-R184H) with DMA*0101/DMB*0101 in terms of catalyzed peptide exchange and dissociation, as well as direct interaction with several HLA-DR/peptide complexes, reveals an attenuated catalytic activity of DMA*0103/DMB*0101. The G155A substitution dominates the catalytic behavior of DMA*0103/DMB*0101 by decreasing peptide release velocity. Preloaded peptide-MHCII complexes exhibit ∼2-fold increase in half-life in the presence of DMA*0103/DMB*0101 when compared with DMA*0101/DMB*0101. We show that this effect leads to a greater persistence of autoimmunity-related Ags in the presence of high-affinity competitor peptide. Our study therefore reveals that HLA-DM polymorphic residues have a considerable impact on HLA-DM catalytic activity.
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http://dx.doi.org/10.4049/jimmunol.1401389DOI Listing
January 2015

Social stress increases expression of hemoglobin genes in mouse prefrontal cortex.

BMC Neurosci 2014 Dec 4;15:130. Epub 2014 Dec 4.

Department of Molecular Biology, Institute of Genetics and Animal Breeding, Jastrzebiec, ul. Postepu 36A, 05-552, Magdalenka, Poland.

Background: In order to better understand the effects of social stress on the prefrontal cortex, we investigated gene expression in mice subjected to acute and repeated social encounters of different duration using microarrays.

Results: The most important finding was identification of hemoglobin genes (Hbb-b1, Hbb-b2, Hba-a1, Hba-a2, Beta-S) as potential markers of chronic social stress in mice. Expression of these genes was progressively increased in animals subjected to 8 and 13 days of repeated stress and was correlated with altered expression of Mgp (Mglap), Fbln1, 1500015O10Rik (Ecrg4), SLC16A10, and Mndal. Chronic stress increased also expression of Timp1 and Ppbp that are involved in reaction to vascular injury. Acute stress did not affect expression of hemoglobin genes but it altered expression of Fam107a (Drr1) and Agxt2l1 (Etnppl) that have been implicated in psychiatric diseases.

Conclusions: The observed up-regulation of genes associated with vascular system and brain injury suggests that stressful social encounters may affect brain function through the stress-induced dysfunction of the vascular system.
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http://dx.doi.org/10.1186/s12868-014-0130-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269175PMC
December 2014

Susceptibility to HLA-DM protein is determined by a dynamic conformation of major histocompatibility complex class II molecule bound with peptide.

J Biol Chem 2014 Aug 7;289(34):23449-64. Epub 2014 Jul 7.

From the Program in Immunology and Microbiology and Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01605,

HLA-DM mediates the exchange of peptides loaded onto MHCII molecules during antigen presentation by a mechanism that remains unclear and controversial. Here, we investigated the sequence and structural determinants of HLA-DM interaction. Peptides interacting nonoptimally in the P1 pocket exhibited low MHCII binding affinity and kinetic instability and were highly susceptible to HLA-DM-mediated peptide exchange. These changes were accompanied by conformational alterations detected by surface plasmon resonance, SDS resistance assay, antibody binding assay, gel filtration, dynamic light scattering, small angle x-ray scattering, and NMR spectroscopy. Surprisingly, all of those changes could be reversed by substitution of the P9 pocket anchor residue. Moreover, MHCII mutations outside the P1 pocket and the HLA-DM interaction site increased HLA-DM susceptibility. These results indicate that a dynamic MHCII conformational determinant rather than P1 pocket occupancy is the key factor determining susceptibility to HLA-DM-mediated peptide exchange and provide a molecular mechanism for HLA-DM to efficiently target unstable MHCII-peptide complexes for editing and exchange those for more stable ones.
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http://dx.doi.org/10.1074/jbc.M114.585539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156084PMC
August 2014

Stress susceptibility-specific phenotype associated with different hippocampal transcriptomic responses to chronic tricyclic antidepressant treatment in mice.

BMC Neurosci 2013 Nov 13;14:144. Epub 2013 Nov 13.

Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Postepu 36A, 05-552, Magdalenka, Jastrzebiec n/Warsaw, Poland.

Background: The effects of chronic treatment with tricyclic antidepressant (desipramine, DMI) on the hippocampal transcriptome in mice displaying high and low swim stress-induced analgesia (HA and LA lines) were studied. These mice displayed different depression-like behavioral responses to DMI: stress-sensitive HA animals responded to DMI, while LA animals did not.

Results: To investigate the effects of DMI treatment on gene expression profiling, whole-genome Illumina Expression BeadChip arrays and qPCR were used. Total RNA isolated from hippocampi was used. Expression profiling was then performed and data were analyzed bioinformatically to assess the influence of stress susceptibility-specific phenotypes on hippocampal transcriptomic responses to chronic DMI. DMI treatment affected the expression of 71 genes in HA mice and 41 genes in LA mice. We observed the upregulation of Igf2 and the genes involved in neurogenesis (HA: Sema3f, Ntng1, Gbx2, Efna5, and Rora; LA: Otx2, Rarb, and Drd1a) in both mouse lines. In HA mice, we observed the upregulation of genes involved in neurotransmitter transport, the termination of GABA and glycine activity (Slc6a11, Slc6a9), glutamate uptake (Slc17a6), and the downregulation of neuropeptide Y (Npy) and corticotropin releasing hormone-binding protein (Crhbp). In LA mice, we also observed the upregulation of other genes involved in neuroprotection (Ttr, Igfbp2, Prlr) and the downregulation of genes involved in calcium signaling and ion binding (Adcy1, Cckbr, Myl4, Slu7, Scrp1, Zfp330).

Conclusions: Several antidepressant treatment responses are similar in individuals with different sensitivities to stress, including the upregulation of Igf2 and the genes involved in neurogenesis. However, the findings also reveal that many responses to antidepressant treatments, involving the action of individual genes engaged in neurogenesis, neurotransmitter transport and neuroprotection, depend on constitutive hippocampal transcriptomic profiles and might be genotype dependent. The results suggest that, when and if this becomes feasible, antidepressant treatment should take into consideration individual sensitivity to stress.
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http://dx.doi.org/10.1186/1471-2202-14-144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831054PMC
November 2013

A novel mutation (c. 341A>G) in the SRY gene in a 46,XY female patient with gonadal dysgenesis.

Gene 2013 Sep 24;526(2):467-70. Epub 2013 Apr 24.

Department of Clinical Genetics, Medical University of Lodz, Poland.

SRY (sex-determining region Y) gene, MIM 480000, NM_005634) is crucial for sex differentiation which encodes the protein responsible for initiating testis differentiation. SRY mutations are associated with the presence of XY gonadal dysgenesis symptoms. We studied a 46,XY female patient with primary amenorrhoea and negative family history. The clinical, endocrine, histopathologic and cytogenetic data are consistent with gonadal dysgenesis. Using a molecular analysis, a novel (c.341A>G, p. N65D) missense mutation within the HMGbox of SRY gene was detected. Escherichia coli expression of SRY study showed reduced expression of the mutated protein and gel retardation assay method revealed lowered DNA-binding ability in N65D variant of SRY. The novel mutation detected in the SRY gene may be an aetiopathogenic factor in clinically defined 46,XY complete gonadal dysgenesis (CGD). Because of an increased risk of gonadoblastoma, proper early diagnosis and treatment prevent development of malignancies.
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http://dx.doi.org/10.1016/j.gene.2013.04.027DOI Listing
September 2013

Sex-dependent neurotransmitter level changes in brains of Toxoplasma gondii infected mice.

Exp Parasitol 2013 Jan 23;133(1):1-7. Epub 2012 Oct 23.

Department of Immunoparasitology, University of Lodz, 90-237 Lodz, Banacha 12/16, Poland.

The protozoan parasite Toxoplasma gondii has the ability to alter intermediate host behavior, most impressively the natural aversion to cat scent, to favor the predation by the definitive host. However, the underlying mechanism of the observed phenomenon still remains unknown. Since changes in the neurotransmitter level are postulated as a possible contributing factor, the aim of this work was to assess the monoamine systems activity in specified brain regions involved in the natural defense behaviors, emotion evaluation, and motor and sensory stimuli integration in experimentally T. gondii infected mice compared to uninfected controls. Taking into account the natural differences between genders, the experiments were carried out on both male and female mice. Our results revealed statistically significant changes in all tested monoamine systems with regard to both gender and time after T. gondii invasion. Acute toxoplasmosis was accompanied by a decrease in noradrenergic system activity in females and its slight increase in some brain areas of males. Acute invasion also induced a rise in serotonin system activity, mostly in males. The most striking observation was an increase in the dopamine release noted in acutely infected males. We discuss our results in terms of their possible contribution to T. gondii-induced intermediate host behavior alterations and parasite transmission and with regard to postulated relationship between T. gondii seroprevalence and occurrence of certain disorders such as schizophrenia in humans.
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http://dx.doi.org/10.1016/j.exppara.2012.10.005DOI Listing
January 2013

Effects of chronic stress on prefrontal cortex transcriptome in mice displaying different genetic backgrounds.

J Mol Neurosci 2013 May 27;50(1):33-57. Epub 2012 Jul 27.

Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Postepu 1, 05-552 Jastrzebiec n/Warsaw, Warsaw, Poland.

There is increasing evidence that depression derives from the impact of environmental pressure on genetically susceptible individuals. We analyzed the effects of chronic mild stress (CMS) on prefrontal cortex transcriptome of two strains of mice bred for high (HA)and low (LA) swim stress-induced analgesia that differ in basal transcriptomic profiles and depression-like behaviors. We found that CMS affected 96 and 92 genes in HA and LA mice, respectively. Among genes with the same expression pattern in both strains after CMS, we observed robust upregulation of Ttr gene coding transthyretin involved in amyloidosis, seizures, stroke-like episodes, or dementia. Strain-specific HA transcriptome affected by CMS was associated with deregulation of genes involved in insulin secretion (Acvr1c, Nnat, and Pfkm), neuropeptide hormone activity (Nts and Trh), and dopamine receptor mediated signaling pathway (Clic6, Drd1a, and Ppp1r1b). LA transcriptome affected by CMS was associated with genes involved in behavioral response to stimulus (Fcer1g, Rasd2, S100a8, S100a9, Crhr1, Grm5, and Prkcc), immune effector processes (Fcer1g, Mpo, and Igh-VJ558), diacylglycerol binding (Rasgrp1, Dgke, Dgkg, and Prkcc), and long-term depression (Crhr1, Grm5, and Prkcc) and/or coding elements of dendrites (Crmp1, Cntnap4, and Prkcc) and myelin proteins (Gpm6a, Mal, and Mog). The results indicate significant contribution of genetic background to differences in stress response gene expression in the mouse prefrontal cortex.
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http://dx.doi.org/10.1007/s12031-012-9850-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622021PMC
May 2013

Peptide linkage to the α-subunit of MHCII creates a stably inverted antigen presentation complex.

J Mol Biol 2012 Oct 20;423(3):294-302. Epub 2012 Jul 20.

Protein Biochemistry Group, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.

Class II proteins of the major histocompatibility complex (MHCII) typically present exogenous antigenic peptides to cognate T cell receptors of CD4-T lymphocytes. The exact conformation of peptide-MHCII complexes (pMHCII) can vary depending on the length, register and orientation of the bound peptide. We have recently found the self-peptide CLIP (class-II-associated invariant chain-derived peptide) to adopt a dynamic bidirectional binding mode with regard to the human MHCII HLA-DR1 (HLA, human leukocyte antigen). We suggested that inversely bound peptides could activate specific T cell clones in the context of autoimmunity. As a first step to prove this hypothesis, pMHC complexes restricted to either the canonical or the inverted peptide orientation have to be constructed. Here, we show that genetically encoded linkage of CLIP and two other antigenic peptides to the HLA-DR1 α-chain results in stable complexes with inversely bound ligands. Two-dimensional NMR and biophysical analyses indicate that the CLIP-bound pMHC(inv) complex (pMHC(inv), inverted MHCII-peptide complex) displays high thermodynamic stability but still allows for the exchange against higher-affinity viral antigen. Complemented by comparable data on a corresponding β-chain-fused canonical HLA-DR1/CLIP complex, we further show that linkage of CLIP leads to a binding mode exactly the same as that of the corresponding unlinked constructs. We suggest that our approach constitutes a general strategy to create pMHC(inv) complexes. Such engineering is needed to create orientation-specific antibodies and raise T cells to study phenomena of autoimmunity caused by isomeric pMHCs.
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http://dx.doi.org/10.1016/j.jmb.2012.07.008DOI Listing
October 2012

Poly(amido)amine dendrimers generation 4.0 (PAMAM G4) reduce blood hyperglycaemia and restore impaired blood-brain barrier permeability in streptozotocin diabetes in rats.

Int J Pharm 2012 Oct 19;436(1-2):508-18. Epub 2012 Jun 19.

Department of Haemostasis and Haemostatic Disorders, Medical University of Lodz, Faculty of Health Sciences, 113 Zeromskiego Street, 90-549 Lodz, Poland.

We hypothesized that BBB is impaired in rat model of streptozotocin-induced diabetes and can be sealed by poly(amido)amine dendrimers G4.0 (PAMAM G4), which reveal anti-glycation activity. The BBB permeabilization was monitored in rats with the 60-day streptozotocin-diabetes and non-diabetic animals, using three fluorescent dyes (given intraperitoneally) differing in molecular weight: fluorescein, fluorescein isothiocyanate (FITC)-dextran and Evans blue. All animals were administered for 2 months with either PAMAM G4 dendrimer or placebo. The fluorescence intensities of the injected fluorescent markers were recorded in the homogenates of selected brain regions. The highest accumulations of the used fluorescent dyes were observed for fluorescein, predominantly in thalamus, hippocampus, frontal cortex, striatum and cerebellum. FITC-dextran leaked to much smaller extent, however, higher permeabilization for FITC-dextran was revealed in pons-medulla oblongata, frontal and parietal cortex of diabetic compared to control animals. Evans blue leaked very slowly into striatum and pons-medulla oblongata in diabetic rats. The treatment of diabetic animals with PAMAM G4 significantly reduced blood glucose concentration and hallmarks of late diabetic complications, compared to non-treated diabetic animals. PAMAM G4 significantly reduced diabetes-induced permeabilization of BBB, which remained in line with the reduced blood glucose and the amelioration of the biochemical hallmarks of severe hyperglycaemia.
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http://dx.doi.org/10.1016/j.ijpharm.2012.06.033DOI Listing
October 2012

Behavioral changes in mice caused by Toxoplasma gondii invasion of brain.

Parasitol Res 2012 Jul 6;111(1):53-8. Epub 2012 Jan 6.

Department of Immunoparasitology, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland.

Toxoplasma gondii, a protozoan parasite, is capable of infecting a broad range of intermediate warm-blooded hosts including humans. The parasite undergoes sexual reproduction resulting in genetic variability only in the intestine of the definitive host (a member of the cat family). The parasite seems to be capable of altering the natural behavior of the host to favor its transmission in the environment. The aim of this study was to evaluate the number of parasite cysts formed in the hippocampus and amygdala of experimentally infected mice as these regions are involved in defense behaviors control and emotion processing, and to assess the influence of the infection on mice behavior. The obtained results revealed the presence of parasite cysts both in the hippocampus and the amygdala of infected mice; however, no clear region-dependent distribution was observed. Furthermore, infected mice showed significantly diminished exploratory activity described by climbing and rearing, smaller preference for the central, more exposed part of the OF arena and engaged in less grooming behavior compared to uninfected controls.
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http://dx.doi.org/10.1007/s00436-011-2800-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378833PMC
July 2012

Selection for stress-induced analgesia affects the mouse hippocampal transcriptome.

J Mol Neurosci 2012 May 16;47(1):101-12. Epub 2011 Dec 16.

Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Poland.

Stress responsiveness, including pain sensitivity and stress-induced analgesia (SIA), depends on genotype and, partially, is mediated by hippocampus. The present study examined differences in constitutive gene expression in hippocampus in lines of mice bred for high (HA) and low (LA) swim SIA. Between the lines, we found 1.5-fold or greater differences in expression of 205 genes in the hippocampus in nonstressed animals. The identity of these genes indicates that selective breeding for swim SIA affected many aspects of hippocampal neurons physiology, including metabolism, structural changes, and cellular signaling. Genes involved in calcium signaling pathway, including Slc8a1, Slc8a2, Prkcc, and Ptk2b, were upregulated in LA mice. In HA mice, robust upregulation of genes coding some transcription factors (Klf5) or receptors for neurotensin (Ntsr2) and GABA (Gabard) suggests the genetic basis for a novel mechanism of the non-opioid type of SIA in HA animals. Additional groups of differentially expressed genes represented functional networks involved in carbohydrate metabolism, gene expression regulation, and molecular transport. Our data indicate that selection for a single and very specific stress response trait, swim SIA, alters hippocampal gene expression. The results suggest that individual stress responsiveness may be associated with characteristics of the constitutive hippocampal transcriptome.
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http://dx.doi.org/10.1007/s12031-011-9692-2DOI Listing
May 2012

Multivalent binding of formin-binding protein 21 (FBP21)-tandem-WW domains fosters protein recognition in the pre-spliceosome.

J Biol Chem 2011 Nov 14;286(44):38478-38487. Epub 2011 Sep 14.

Protein Engineering Group, Leibniz Institut für Molekulare Pharmakologie and Freie Universität Berlin, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. Electronic address:

The high abundance of repetitive but nonidentical proline-rich sequences in spliceosomal proteins raises the question of how these known interaction motifs recruit their interacting protein domains. Whereas complex formation of these adaptors with individual motifs has been studied in great detail, little is known about the binding mode of domains arranged in tandem repeats and long proline-rich sequences including multiple motifs. Here we studied the interaction of the two adjacent WW domains of spliceosomal protein FBP21 with several ligands of different lengths and composition to elucidate the hallmarks of multivalent binding for this class of recognition domains. First, we show that many of the proteins that define the cellular proteome interacting with FBP21-WW1-WW2 contain multiple proline-rich motifs. Among these is the newly identified binding partner SF3B4. Fluorescence resonance energy transfer (FRET) analysis reveals the tandem-WW domains of FBP21 to interact with splicing factor 3B4 (SF3B4) in nuclear speckles where splicing takes place. Isothermal titration calorimetry and NMR shows that the tandem arrangement of WW domains and the multivalency of the proline-rich ligands both contribute to affinity enhancement. However, ligand exchange remains fast compared with the NMR time scale. Surprisingly, a N-terminal spin label attached to a bivalent ligand induces NMR line broadening of signals corresponding to both WW domains of the FBP21-WW1-WW2 protein. This suggests that distinct orientations of the ligand contribute to a delocalized and semispecific binding mode that should facilitate search processes within the spliceosome.
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http://dx.doi.org/10.1074/jbc.M111.265710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207436PMC
November 2011

Effect of chronic mild stress on hippocampal transcriptome in mice selected for high and low stress-induced analgesia and displaying different emotional behaviors.

Eur Neuropsychopharmacol 2011 Jan 20;21(1):45-62. Epub 2010 Oct 20.

Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Poland.

There is increasing evidence that mood disorders may derive from the impact of environmental pressure on genetically susceptible individuals. Stress-induced hippocampal plasticity has been implicated in depression. We studied hippocampal transcriptomes in strains of mice that display high (HA) and low (LA) swim stress-induced analgesia and that differ in emotional behaviors and responses to different classes of antidepressants. Chronic mild stress (CMS) affected expression of a number of genes common for both strains. CMS also produced strain specific changes in expression suggesting that hippocampal responses to stress depend on genotype. Considerably larger number of genes, biological processes, molecular functions, biochemical pathways, and gene networks were affected by CMS in LA than in HA mice. The results suggest that potential drug targets against detrimental effects of stress include glutamate transporters, and cholinergic, cholecystokinin (CCK), glucocorticoids, and thyroid hormones receptors. Furthermore, some biological processes evoked by stress and different between the strains, such as apoptosis, neurogenesis and chromatin modifications, may be responsible for the long-term, irreversible effects of stress and suggest a role for epigenetic regulation of mood related stress responses.
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http://dx.doi.org/10.1016/j.euroneuro.2010.08.004DOI Listing
January 2011

[Urinary incontinence after obstetric-gynecological surgery--urodynamic studies].

Ginekol Pol 2010 May;81(5):370-3

Akademia Humanistyczno-Ekonomiczna w Łodzi.

Objectives: The aim of the study was to estimate the prevalence rate of patients with urinary incontinence after pelvic surgery as well as the distribution of urinary incontinence types depending on the type of surgery.

Material And Methods: 200 consecutive female patients, aged between 33 and 85 years old, administered to urodynamic diagnostic due to urinary incontinence, were included in the study. After collecting medical history and performing a urogynecological examination, a urodynamic study was done. We estimated the relation between urinary incontinence types, bladder activity and type of surgical procedure.

Results: 35,5% of patients had undergone obstetric-gynecological operations (abdominal hysterectomy was most frequent, followed by vaginal reconstructive operations, Caesarean sections, adnexal operations and vaginal hysterectomy). We observed 56% of stress urinary incontinence (SUI), 35% of mixed urinary incontinence (MUI) and 9% of overactive bladder (OAB). Among patients with SUI, we found 55% women after abdominal hysterectomy, 5% after vaginal hysterectomy, 20% after adnexal operations, 15% after vaginal reconstructive operations and 5% after Caesarean section. In the group with MUI, 40% patients were after vaginal reconstructive operations, 32% after Caesarean sections, 20% after abdominal hysterectomy and 8% after adnexal operations. Among women with OAB we noticed 33% patients after vaginal reconstructive operations, 33% after abdominal hysterectomy, 17% after Cesarean sections and 17% after vaginal hysterectomy.

Conclusions: The results of the study show that patients after obstetric-gynecological surgery procedures make up 30% of all urinary incontinence cases. Distribution of urinary incontinence types in the group of operated women is similar in the entire investigated group. Abdominal hysterectomy and reconstructive vaginal operations are clearly connected with urinary incontinence.
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May 2010