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Soenen S.J.,Catholic University of Leuven | Parak W.J.,University of Marburg | Parak W.J.,CIC Biomagune | Rejman J.,University of Marburg | Manshian B.,Catholic University of Leuven
Chemical Reviews | Year: 2015

An overview of the current understanding of the behavior of iron oxide nanoparticles (IONPs), Q-Dots, silver and ZnO NPs, and Au NPs as a result of highly varying conditions to which they will be exposed when used in biomedical research or when distributed in the environment. It was shown that depending on the nature of the core material degradation of the NPs can occur, and its extent depends on the microenvironment to which they are exposed. In this connection, distinction should be made between degradation of the inorganic core, which highly depends on the material of the core, and degradation of the organic surface coating, which in particular affects colloidal stability and thus biodistribution of the NPs. For degrading NPs, the process of degradation brings along substantial difficulties in understanding their toxicological profile as not only the NP but also its released ions and the combination of the two can all have different biodistributions and toxic effects, which must be studied in detail. Other focus points are NP shape and size, where the ratio of surface area over volume should be kept as low as possible as degradation will occur at the surface of the NPs. Furthermore, the composition of the chemical core can be adjusted by the addition of other metal ions and hereby altering the matrix of the inorganic cores, which can result in enhanced chemical stability against pH-dependent degradation.

Rodriguez-Suarez E.,CIC Biomagune | Whetton A.D.,University of Manchester
Mass Spectrometry Reviews | Year: 2013

The systematic analysis of biological processes requires an understanding of the quantitative expression patterns of proteins, their interacting partners and their subcellular localization. This information was formerly difficult to accrue as the relative quantification of proteins relied on antibody-based methods and other approaches with low throughput. The advent of soft ionization techniques in mass spectrometry plus advances in separation technologies has aligned protein systems biology with messenger RNA, DNA, and microarray technologies to provide data on systems as opposed to singular protein entities. Another aspect of quantitative proteomics that increases its importance for the coming few years is the significant technical developments underway both for high pressure liquid chromatography and mass spectrum devices. Hence, robustness, reproducibility and mass accuracy are still improving with every new generation of instruments. Nonetheless, the methods employed require validation and comparison to design fit for purpose experiments in advanced protein analyses. This review considers the newly developed systematic protein investigation methods and their value from the standpoint that relative or absolute protein quantification is required de rigueur in biomedical research. © 2012 Wiley Periodicals, Inc.

PCNA is an essential factor for DNA replication and repair. It forms a ring shaped structure of 86 kDa by the symmetric association of three identical protomers. The ring encircles the DNA and acts as a docking platform for other proteins, most of them containing the PCNA Interaction Protein sequence (PIP-box). We have used NMR to characterize the interactions of PCNA with several other proteins and fragments in solution. The binding of the PIP-box peptide of the cell cycle inhibitor p21 to PCNA is consistent with the crystal structure of the complex. A shorter p21 peptide binds with reduced affinity but retains most of the molecular recognition determinants. However the binding of the corresponding peptide of the tumor suppressor ING1 is extremely weak, indicating that slight deviations from the consensus PIP-box sequence dramatically reduce the affinity for PCNA, in contrast with a proposed less stringent PIP-box sequence requirement. We could not detect any binding between PCNA and the MCL-1 or the CDK2 protein, reported to interact with PCNA in biochemical assays. This suggests that they do not bind directly to PCNA, or they do but very weakly, with additional unidentified factors stabilizing the interactions in the cell. Backbone dynamics measurements show three PCNA regions with high relative flexibility, including the interdomain connector loop (IDCL) and the C-terminus, both of them involved in the interaction with the PIP-box. Our work provides the basis for high resolution studies of direct ligand binding to PCNA in solution.

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 3.12M | Year: 2015

Based on an international team derived from the COST action BM1003 (www.cost-bm1003.info, 2011-2014) and thus relying on consolidated group interactions and synergies and on a unique combination of chemistry, biology, biophysics, biochemistry and pharmacology expertise, the TOLLerant project aims to gain information on molecular aspects of TLR4 activation and signaling by using synthetic and natural compounds and nanoparticles that interact selectively with some components (mainly MD-2 and CD14) of the TRL4 recognition system. TLR4 is an emerging molecular target related to an impressively broad spectrum of modern day disorders still lacking specific pharmacological treatment. These include autoimmune disorders, chronic inflammations, allergies, asthma, infectious and CNS diseases and cancer. The short-term scientific objective is to develop novel, non-toxic, synthetic and natural TLR4 modulators (agonists or antagonists) and to assess their therapeutic potential on animal models of TLR4-related acute and chronic pathologies that still lack efficient pharmacological treatment. The long-term scientific objective is to develop a new generation of innovative, TLR4-based therapeutics, to be used as vaccine adjuvants, anti-sepsis agents, and anti-inflammatory agents to treat chronic inflammations (allergy, asthma). The training programme will provide Early Stage Researchers (ESR) with broad competences, experience and skills in the cutting-edge, inter-disciplinary research in the field of chemical biology related to the molecular mechanisms of innate immunity and inflammation. During the training, the young researchers will be supported by senior scientists to cultivate their scientific, entrepreneurial and inter-cultural mindset. The non-academic sector will be committed to provide ESRs with entrepreneurship and company management skills, in order to enhance their employability by the private sector or even to motivate them to create own start-up companies.

Agency: Cordis | Branch: H2020 | Program: MSCA-RISE | Phase: MSCA-RISE-2014 | Award Amount: 1.22M | Year: 2015

HYMADE focuses on the development of capsules and engineered colloidal particles for drug delivery combining mesoporous colloids, the Layer by Layer (LbL) technique and virosomes. The capsules and particles have potential applications in cancer and inflammatory diseases such as rheumatoid arthritis and uveitis. The project is based on the secondments of Early Stage Researchers and Experienced Researchers and networking and training activities between European and non European academic institutions. HYMADE aims to profit from the combination of hybrid materials to fabricate advanced drug delivery systems with controlled release and targeting efficiency of biological entities. The project also aims to gain understanding of the self assembly process of hybrid materials and the transport properties of the drug delivery systems.The biological fate, drug release, degradation and therapeutical efficiency of the drug delivery systems will be studied in vitro and in vivo with state of the art imaging techniques. To achieve these goals we have gathered an international multidisciplinary team with scientists at the forefront of Material Science, Self assembly, Physics, Chemistry, Biophysics and Imaging from Germany, Austria, France and Spain on the European side and from United States of America, Argentina and Armenia on the non European side.

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