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Carnemolla A.,Kings College London | Labbadia J.P.,Kings College London | Lazell H.,Kings College London | Neueder A.,Kings College London | And 3 more authors.
Human Molecular Genetics

Ageing is associated with the reduced performance of physiological processes and has been proposed as a major risk factor for disease. An age-related decline in stress response pathways has been widely documented in lower organisms. In particular, the heat shock response (HSR) becomes severely compromised with age in Caenorhabditis elegans. However, a comprehensive analysis of the consequences of ageing on the HSR in higher organisms has not been documented. We used both HS and inhibition of HSP90 to induce the HSR in wild-type mice at 3 and 22 months of age to investigate the extent to which different brain regions, and peripheral tissues can sustain HSF1 activity and HS protein (HSP) expression with age. Using chromatin immunoprecipitation, quantitative reverse transcription polymerase chain reaction, western blotting and enzyme linkedimmunosorbent assay (ELISA),wewere unable to detect a difference in the level or kinetics ofHSPexpression between young and old mice in all brain regions. In contrast, we did observe an age-related reduction in chaperone levels and HSR-related proteins in the heart. This could result in a decrease in the protein folding capacity of old hearts with implications for age-related cardiac disorders. © The Author 2014. Published by Oxford University Press. Source

Neueder A.,Kings College London | Achilli F.,Kings College London | Moussaoui S.,Novartis | Moussaoui S.,Rhenovia Pharma | Bates G.P.,Kings College London
Journal of Biological Chemistry

The heat shock response, resulting in the production of heat shock proteins or molecular chaperones, is triggered by elevated temperature and a variety of other stressors. Its master regulator is heat shock transcription factor 1 (HSF1). Heat shock factors generally exist in multiple isoforms. The two known isoforms of HSF1 differ in the inclusion (HSF1α) or exclusion (HSF1β) of exon 11. Although there are some data concerning the differential expression patterns and transcriptional activities of HSF2 isoforms during development, little is known about the distinct properties of the HSF1 isoforms. Here we present evidence for two novel HSF1 isoforms termed HSF1γα and HSF1γβ, and we show that the HSF1 isoform ratio differentially regulates heat shock protein gene transcription. Hsf1γ isoforms are expressed in various mouse tissues and are translated into protein. Furthermore, after heat shock, HSF1γ isoforms are exported from the nucleus more rapidly or degraded more quickly than HSF1α or HSF1β. We also show that each individual HSF1 isoform is sufficient to induce the heat shock response and that expression of combinations of HSF1 isoforms, in particular HSF1α and HSF1β, results in a synergistic enhancement of the transcriptional response. In addition, HSF1γ isoforms potentially suppress the synergistic effect of HSF1α and HSF1β co-expression. Collectively, our observations suggest that the expression of HSF1 isoforms in a specific ratio provides an additional layer in the regulation of heat shock protein gene transcription. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Atorf J.,Friedrich - Alexander - University, Erlangen - Nuremberg | Scholz M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Garreis F.,Friedrich - Alexander - University, Erlangen - Nuremberg | Lehmann J.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 3 more authors.
Documenta Ophthalmologica

Purpose: To analyse the effects of long-term memantine treatment on the retinal physiology and morphology of DBA/2J mice. Methods: DBA/2J (D2J) mice received i.p. injections of the NMDA receptor antagonist memantine, which protects neurons from abnormally elevated glutamate levels, twice a day over a period of 7 months. At the age of 2, 6 and 10 months, the intraocular pressure (IOP) and electroretinograms (ERGs) were measured in all treated D2J mice, in untreated D2J controls and in C57Bl/6 (B6) wild-type mice. After the last measurement at the age of 10 months, the mice were killed and the retinae and the optic nerves were analysed morphologically. Results: The IOP increased with age in both D2J and B6 mice with a larger increase in the D2J strain. IOPs were not influenced by memantine treatment. The response amplitude of the scotopic flash ERG decreased with age in the D2J strain. This amplitude decrease, particularly that of the b-wave, was smaller in treated D2J mice. The retinae of treated D2J mice exhibited less peripheral degeneration of cone photoreceptors, and optic nerve neuropathy was less frequent. Conlcusions: Application of the NMDA receptor antagonist memantine diminished retinal neurodegeneration in the D2J mice and had a protective effect on the b-wave amplitude of the scotopic flash ERG. This protection may occur secondarily as memantine primarily acts on retinal ganglion cells. © 2013 Springer-Verlag Berlin Heidelberg. Source

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: NMP-2008-2.1-1 | Award Amount: 5.21M | Year: 2009

The aim of SELFMEM is to develop innovation in the field of nanoporous membranes. This will be achieved by taking advantage of the self-assembly properties of block copolymers leading to highly porous membranes with adjustable, regular-sized pores of tailored functionalities. Both polymeric and inorganic (silicon) membranes will be developed. In the case of isoporous polymeric membranes focus will be laid on the formation of integral-asymmetric block copolymer membranes with an isoporous top layer as a function of the block copolymer structure and the preparation conditions. Isoporous inorganic membranes will be prepared by using a thin block copolymer film as a mask for selective etching. The possibilities to systematically vary the pore size and density by varying the block copolymer mask structure will be investigated. The block copolymers will be synthesized by controlled polymerisation techniques (anionic, group transfer, and different radical polymerisations), depending on the chosen monomers. The characterisation during and after formation of the membranes will be carried out by light and various x-ray scattering techniques, by scanning force microscopy, and by different electron microscopic techniques. Both types of membranes will be post-functionalized in order to tune their final properties. The membranes will be tested for their applicability in different areas. Separation of gases (like H2/CO2) and proteins as well as water purification will be addressed in this project. Modeling and theory will support the understanding of the structure formation of these membranes and help to optimise membrane design. The results of SELFMEM will increase European competitiveness in strategic markets such as gas purification, water treatment and molecular biology. The consortium consists of 12 partners from 10 countries, including 4 companies from 3 countries.

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