Phosphorylation of more than one site is required for tight interaction of human tau protein with 14-3-3ζ

AbstractSerine residues phosphorylated by protein kinase A (PKA) in the shortest isoform of human tau protein (τ3) were sequentially replaced by alanine and interaction of phosphorylated τ3 and its mutants with 14-3-3 was investigated. Mutation S156A slightly decreased interaction of phosphorylated τ3 with 14-3-3. Double mutations S156A/S267A and especially S156A/S235A, strongly inhibited interaction of phosphorylated τ3 with 14-3-3. Thus, two sites located in the Pro-rich region and in the pseudo repeats of τ3 are involved in phosphorylation-dependent interaction of τ3 with 14-3-3. The state of τ3 phosphorylation affects the mode of 14-3-3 binding and by this means might modify tau filament formation.Structured summaryMINT-7233358, MINT-7233372, MINT-7233384: 14-3-3 zeta (uniprotkb:P63104) and Tau 3 (uniprotkb:P10636-3) bind (MI:0407) by molecular sieving (MI:0071)MINT-7233323, MINT-7233334, MINT-7233346: Tau 3 (uniprotkb:P10636-3) and 14-3-3 zeta (uniprotkb:P63104) bind (MI:0407) by crosslinking studies (MI:0030)MINT-7233285, MINT-7233297, MINT-7233310: 14-3-3 zeta (uniprotkb:P63104) and Tau 3 (uniprotkb:P10636-3) bind (MI:0407) by comigration in non-denaturing gel electrophoresis (MI:0404

A numerical study of two different specimen fixtures for the modified compact tension test – their influence on concrete fracture parameters

The modified compact tension test (MCT) may represent a new test configuration for the performance of static and other kinds of fatigue tests on concrete-like materials. Core drilling can be employed to obtain specimens which are cylindrical in shape and have a standard diameter of 150 mm, this being appropriate for the determination of the residual life of structures. This contribution focuses on the evaluation of MCT specimen fracture behavior during static tests. Cracks evolution are simulated numerically using ATENA finite element (FE) software, while the results are represented as L-COD diagrams, i.e. load vs. crack opening displacement measured on the loading axis. After numerical calculations, the results for two different fixtures are compared and the advantages or drawbacks for each solution are discussed

The image of Alexander the Great in the poem by Abai Kunanbayuly

This article is devoted to the study of the work of the great Kazakh poet Abai Kunanbayuly. In the course of the study, the works of prominent Russian-Soviet orientalists V.V. Bartold, E.E. Bertels, and I.S. Braginsky were used. Based on a comparative analysis, the corresponding conclusions were drawn on the artistic-figurative component of many works written on the theme of Iskander. The features and differences of medieval and national literature in the interpretation of the same image are revealed. The versatility and the humanistic spirit of Abai’s creativity in the context of his poem are shown.Este artículo está dedicado al estudio de la obra del gran poeta kazajo Abai Kunanbayuly. En el curso del estudio, los trabajos de prominentes orientalistas ruso-soviéticos V.V. Bartold, E.E. Bertels y I.S. Braginsky fueron utilizados. Basado en un análisis comparativo, las conclusiones correspondientes se extrajeron del componente artístico-figurativo de muchas obras escritas sobre el tema de Iskander. Se revelan las características y diferencias de la literatura medieval y nacional en la interpretación de la misma imagen. Se muestra la versatilidad y el espíritu humanista de la creatividad de Abai en el contexto de su poema

Recommendations for managing cutaneous disorders associated with advancing age

Philippe Humbert,1 Brigitte Dréno,2 Jean Krutmann,3 Thomas Anton Luger,4 Raoul Triller,5 Sylvie Meaume,6 Sophie Seité71Research and Studies Centre on the Integument (CERT), Clinical Investigation Centre (CIC BT506), Department of Dermatology, Besançon University Hospital, University of Franche-Comté, Besançon, France; 2Department of Dermato-Cancerology, Nantes University Hospital, Nantes, France; 3IUF-Leibniz Research Institute for Environmental Medicine, Heinrich-Heine-University, Düsseldorf, Germany; 4Department of Dermatology, University of Münster, Münster, Germany; 5International Centre of Dermatology, Hertford British Hospital, Levallois, France; 6Geriatric Service, Wounds and Healing, Rothschild Hôspital, Paris, France; 7La Roche-Posay Dermatological Laboratories, Asnières, FranceAbstract: The increasingly aged population worldwide means more people are living with chronic diseases, reduced autonomy, and taking various medications. Health professionals should take these into consideration when managing dermatological problems in elderly patients. Accordingly, current research is investigating the dermatological problems associated with the loss of cutaneous function with age. As cell renewal slows, the physical and chemical barrier function declines, cutaneous permeability increases, and the skin becomes increasingly vulnerable to external factors. In geriatric dermatology, the consequences of cutaneous aging lead to xerosis, skin folding, moisture-associated skin damage, and impaired wound healing. These problems pose significant challenges for both the elderly and their carers. Most often, nurses manage skin care in the elderly. However, until recently, little attention has been paid to developing appropriate, evidence-based, skincare protocols. The objective of this paper is to highlight common clinical problems with aging skin and provide some appropriate advice on cosmetic protocols for managing them. A review of the literature from 2004 to 2014 using PubMed was performed by a working group of six European dermatologists with clinical and research experience in dermatology. Basic topical therapy can restore and protect skin barrier function, which relieves problems associated with xerosis, prevents aggravating moisture-associated skin damage, and enhances quality of life. In conclusion, the authors provide physicians with practical recommendations to assist them in implementing basic skin care for the elderly in an integrated care approach.Keywords: elderly, skin, cosmetic managemen

Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages

The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of the cytokine tumor necrosis factor (TNF). TNF production occurs within 1 h of TLR stimulation and is sustained for 1 d. Here we document a function for the TNF family member 4-1BB ligand (4-1BBL) in sustaining TLR-induced TNF production. TLR signaling induced 4-1BBL, and 4-1BBL interacted with TLRs on the macrophage surface. The influence of 4-1BBL on TNF production was independent of its receptor (4-1BB) and did not require the adaptors MyD88 or TRIF. It did not influence TLR4-induced activation of transcription factor NF-kappa B (an early response) but was required for TLR4-induced activation of transcription factors CREB and C/EBP ( a late event). Transient TLR4-MyD88 complexes appeared during the first hour after lipopolysaccharide stimulation, and TLR4-4-1BBL interactions were detected between 2 h and 8 h after lipopolysaccharide stimulation. Our results indicate that two different TLR4 complexes sequentially form and selectively control early and late TNF production

Properties of the Monomeric Form of Human 14-3-3ζ Protein and Its Interaction with Tau and HspB6

Dimers formed by seven isoforms of the human 14-3-3 protein participate in multiple cellular processes. The dimeric form has been extensively characterized; however, little is known about the structure and properties of the monomeric form of 14-3-3. The monomeric form is involved in the assembly of homo- and heterodimers, which could partially dissociate back into monomers in response to phosphorylation at Ser58. To obtain monomeric forms of human 14-3-3ζ, we produced four protein constructs with different combinations of mutated (M) or wild-type (W) segments E⁵, ¹²LAE¹⁴, and ⁸²YREKIE⁸⁷. Under a wide range of expression conditions in <i>Escherichia coli</i>, the MMM and WMM mutants were insoluble, whereas WMW and MMW mutants were soluble, highly expressed, and purified to homogeneity. WMW and MMW mutants remained monomeric over a wide range of concentrations while retaining the α-helical structure characteristic of wild-type 14-3-3. However, WMW and MMW mutants were highly susceptible to proteolysis and had much lower thermal stabilities than the wild-type protein. Using WMW and MMW mutants, we show that the monomeric form interacts with the tau protein and with the HspB6 protein, in both cases forming complexes with a 1:1 stoichiometry, in contrast to the 2:1 and/or 2:2 complexes formed by wild-type 14-3-3. Significantly, this interaction requires phosphorylation of tau protein and HspB6. Because of minimal changes in structure, MMW and especially WMW mutant proteins are promising candidates for analyzing the effect of monomerization on the physiologically important properties of 14-3-3ζ

Properties of the Monomeric Form of Human 14-3-3ζ Protein and Its Interaction with Tau and HspB6

Dimers formed by seven isoforms of the human 14-3-3 protein participate in multiple cellular processes. The dimeric form has been extensively characterized; however, little is known about the structure and properties of the monomeric form of 14-3-3. The monomeric form is involved in the assembly of homo- and heterodimers, which could partially dissociate back into monomers in response to phosphorylation at Ser58. To obtain monomeric forms of human 14-3-3ζ, we produced four protein constructs with different combinations of mutated (M) or wild-type (W) segments E⁵, ¹²LAE¹⁴, and ⁸²YREKIE⁸⁷. Under a wide range of expression conditions in <i>Escherichia coli</i>, the MMM and WMM mutants were insoluble, whereas WMW and MMW mutants were soluble, highly expressed, and purified to homogeneity. WMW and MMW mutants remained monomeric over a wide range of concentrations while retaining the α-helical structure characteristic of wild-type 14-3-3. However, WMW and MMW mutants were highly susceptible to proteolysis and had much lower thermal stabilities than the wild-type protein. Using WMW and MMW mutants, we show that the monomeric form interacts with the tau protein and with the HspB6 protein, in both cases forming complexes with a 1:1 stoichiometry, in contrast to the 2:1 and/or 2:2 complexes formed by wild-type 14-3-3. Significantly, this interaction requires phosphorylation of tau protein and HspB6. Because of minimal changes in structure, MMW and especially WMW mutant proteins are promising candidates for analyzing the effect of monomerization on the physiologically important properties of 14-3-3ζ