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Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2013-ITN | Award Amount: 3.51M | Year: 2013

Brain disorders comprise a major burden for the society. Recent analyses of the neuropsychiatric disease-related gene polymorphisms as well as genomics and proteomics have identified the components of the extracellular matrix (ECM) and the cell adhesion molecules (CAMs) in the brain as pivotal for those diseases. The ECM/CAMs span the synaptic cleft and regulate the synaptic dynamics. Furthermore, recent studies have shown that proteolytic activity may release from the ECM/CAMs cryptic ligand(s) that activate cell surface receptors and initiate intracellular signalling cascade(s). Thus, ECM and its enzymatic modifications have emerged as a highly topical research area, also because their extracellular localization makes the development of enzymatic inhibitors more feasible. This proposal brings together a group of well-established academic and industrial partners sharing interest in the ECM and its proteolysis. In the proposal there is clearly an overlapping interest in specific brain conditions and structures to be investigated, making the consortium ideally suited to provide a comprehensive picture for the role of ECM proteolysis in brain function and dysfunctions. While the academic partners focus on specific research questions, the industrial members are to provide the entire consortium with high-throughput techniques and powerful research tools. This combination of conceptual scientific vision, tools and approaches should be of great benefit for the young researchers to be trained. The trainees will be exposed to courses, workshops, joint research meetings and inter-laboratory visits. The focus of the training program is on expanding knowledge and on developing new treatments to anxiety disorders, schizophrenia, mental retardation and Alzheimers. A unifying neurobiological concept in the consorted effort to tackle these conditions is the involvement of abnormal synaptic plasticity.

Barbieri C.,Max Planck Research Group on Comparative Population Linguistics | Vicente M.,Investigacao e Servicos em Ciencias Biologicas Lda | Vicente M.,University of Porto | Rocha J.,University of Porto | And 3 more authors.
American Journal of Human Genetics | Year: 2013

Among the deepest-rooting clades in the human mitochondrial DNA (mtDNA) phylogeny are the haplogroups defined as L0d and L0k, which are found primarily in southern Africa. These lineages are typically present at high frequency in the so-called Khoisan populations of hunter-gatherers and herders who speak non-Bantu languages, and the early divergence of these lineages led to the hypothesis of ancient genetic substructure in Africa. Here we update the phylogeny of the basal haplogroups L0d and L0k with 500 full mtDNA genome sequences from 45 southern African Khoisan and Bantu-speaking populations. We find previously unreported subhaplogroups and greatly extend the amount of variation and time-depth of most of the known subhaplogroups. Our major finding is the definition of two ancient sublineages of L0k (L0k1b and L0k2) that are present almost exclusively in Bantu-speaking populations from Zambia; the presence of such relic haplogroups in Bantu speakers is most probably due to contact with ancestral pre-Bantu populations that harbored different lineages than those found in extant Khoisan. We suggest that although these populations went extinct after the immigration of the Bantu-speaking populations, some traces of their haplogroup composition survived through incorporation into the gene pool of the immigrants. Our findings thus provide evidence for deep genetic substructure in southern Africa prior to the Bantu expansion that is not represented in extant Khoisan populations. © 2013 The American Society of Human Genetics.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: SME-2013-3 | Award Amount: 2.18M | Year: 2014

HILYSENS II is based on the 2-year HILYSENS research and development project (started November 2010) funded by the Research for the Benefit of SMEs program of the European Commissions Seventh Framework Programme (FP7). HILYSENS II proposes Demonstration Activities for the prototype HILYSENS Lab-on-a-Chip developed during the successful research and development project, which was designed as a specific and sensitive diagnostic system for acute, chronic and autoimmunity-associated Lyme disease. The developed prototype comprises a Bio-Chip, which enables specific and sensitive detection of the human serological responses to Borrelia species in patients with Lyme disease, and a portable Reader with user-friendly software, which together enable precise, accurate and reproducible testing of serum samples. Lyme disease is the most common tick-borne infection in Europe, with around 85,000 new cases per year. Current laboratory diagnostic methods for Borrelia species lack the necessary sensitivity and specificity to detect early cases, as well as late manifestations of the disease, such as chronic or autoimmune-related infections. As a consequence, many cases are undiagnosed or misdiagnosed. Late, delayed, or inadequate treatment can lead to serious problems, such as neuroborreliosis or arthritis, which can be disabling and difficult to treat. The HILYSENS II Demonstration Activity, which will involve SMEs from Portugal, Italy, and Spain, will include verification of the Bio-Chip and Reader components, followed by scaling-up of the production of the complete system. This will be followed by clinical validation at partner Borrelia testing centers in Germany and Sweden, and confirmatory testing in Portugal. By the end of the 24-month Demonstration Activity it is expected that the HILYSENS diagnostic system will be submitted for approval by regulatory authorities in Europe and the US and will enter these markets shortly thereafter.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: NMP-2007-4.0-4 | Award Amount: 14.37M | Year: 2008

The search for effective therapies and early detection strategies for Alzheimers Disease (AD), the major cause of dementia in Europe, is imperative. It is known that -amyloid (A) peptide plays a central role in neurodegeneration. In AD brain, A is released in a soluble form that progressively becomes insoluble forming aggregates; extracellular plaques mainly composed of A are a hallmark of post-mortem brains. These premises strongly suggest brain A as a possible target for therapy and diagnosis of AD. In addition, it is known that brain and blood A pools are in equilibrium via the blood-brain-barrier (BBB). Accordingly, it has been reported that removal of blood A may withdraw the excess of brain A by a sink effect. Thus, blood A is another potential target. The aim of this project is to utilize nanoparticles (NPs) specifically engineered for targeting brain A, for the combined diagnosis and therapy (theranostics) of AD. NPs (liposomes, solid lipid NPs, polymeric-NPs) will be multiple-functionalized with: i) a large arsenal of molecules (specific lipids, antiamyloidogenic drugs, polyphenols, heteroaromatic compounds, unnatural peptides and peptidomimetics, antibodies) interacting with A in all aggregation forms, ii) PET or MRI contrast agents detecting such interaction, iii) molecules stimulating BBB crossing via the transcytotic route. Several artificial and cellular models will be used to fine-tune such features and to improve NPs biocompatibility, non-immunogenicity, non-toxicity and physical stability. Eventually, absorption, distribution, metabolism and excretion will be studied using animal models of AD. Different routes (i.v., oral, nasal) and protocols (two-step, NPs cocktails, aerosols) of administration will be utilized to boost NPs brain delivery. The prediction is that NPs will detect, disaggregate and remove A brain deposits. In any case, NPs will interact with blood A, withdrawing the excess of brain peptide by a sink effect.

Agency: Cordis | Branch: FP7 | Program: BSG-SME | Phase: SME-1 | Award Amount: 1.55M | Year: 2010

The aim of HILYSENS is to develop a novel lab-on-chip diagnostic tool to improve clinical diagnostic, disease monitoring and treatment of Lyme Disease by enabling specific and sensitive detection of the human serological response against its causative agent Borrelia burgdoferi infections. Lyme Disease is the most common tick-borne infection in Europe with around 85,000 new cases per year and its incidence is increasing due to climate change. Current laboratory diagnostic methods lack sensitivity and specificity to detect early cases as well as late manifestations of the disease such as chronic or autoimmune-related infections. For this reasons, disease incidence is underestimated as many cases go mis- or undiagnosed. Late, delayed, or inadequate treatment can lead to serious symptoms such as neuroborreliosis or arthritis, which can be disabling and difficult to treat. HILYSENS will develop a specific multi-antigen assay in a lab-on-a-chip device to detect Borrelia infections. HILYSENS will provide a compact and robust lab-on-chip system, designed to work with small volumes and without the need of expert operators. This tool together with a portable reader and user-friendly software will enable more precise, accurate and reproducible testing making it possible to become the standard tool for the disease diagnosis. A novel production approach for the lab-on-a-chip will be developed which will enable to target really low mass-production costs, overcoming one of the main issues of the lab-on-a-chip technology and opening great market opportunities for the participant SMEs. Sensitive and reliable patient diagnosis provided by HILYSENS device will optimise resources available to medical practitioners, heavily reducing the current costs of the disease, increasing profitability and most importantly, patients quality of life.

Agency: Cordis | Branch: FP7 | Program: BSG-SME | Phase: SME-2012-1 | Award Amount: 1.48M | Year: 2013

Chemotherapy is the standard care for the treatment of non-small cell lung carcinoma (NSCLC) patients, however most of non-small cell lung cancer tumours are not sensitive to this treatment. As an alternative to chemoterapy, target therapy with gefitinib (epidermal growth factor receptor-tyrosine kinase inhibitor) has been used in clinical practice in patients with tumours harbouring mutations in EGFR gene, improving their treatment effectiveness. For that reason EGFR mutations analysis should be perform to support the treatment decision for a patient with NSCLC. Despite all the foreseen benefits of EGFR genotyping, the current PCR-based methods used have been shown some associated bottlenecks: i) use of complex samples (tumour biopsy embedded in Formalin Fixed Paraffin, FFPE), ii) require a better understanding from the clinical geneticist to accurately interpret the information provided and to setup the best line of therapy and treatment and iii) the assays are quite expensive and time-consuming. New age diagnostic tools, such as microfluidic platforms and nanodiagnostics are emerging technologies for DNA analysis requiring lower sample volumes and providing comparable sensitivity and specificity at lower costs. Nonetheless, sample preparation and detection of the result of a chemical analysis on-chip are still weak points in many lab-on-a-chip devices. The current proposal, aiming the integration of all laboratory-based process steps in one single step, is both challenging and feasible: development of a microfluidic chip that combines blood sample processing (DNA extraction/purification, multiplex amplification) and detection of EGFR mutations in tumour DNA by means of gold and silver-nanoparticles (Ag and Au-nanoprobes). Furthermore a microfluidic chip analyser with an integrated user-friendly software to report genotyping results will be developed.

Canovi M.,Instituto Of Ricerche Farmacologiche Mario Negri | Markoutsa E.,University of Patras | Lazar A.N.,French Institute of Health and Medical Research | Pampalakis G.,University of Patras | And 10 more authors.
Biomaterials | Year: 2011

Amyloid β (Aβ) aggregates are considered as possible targets for therapy and/or diagnosis of Alzheimer disease (AD), and nanoparticles functionalized with Aβ-specific ligands are considered promising vehicles for imaging probes and therapeutic agents. Herein, we characterized the binding properties of nanoliposomes decorated with an anti-Aβ monoclonal antibody (Aβ-MAb). The Aβ-MAb was obtained in mice by immunization with Aβ antigen followed by hybridoma fusion. Surface Plasmon Resonance (SPR) studies confirmed the very high affinity of purified Aβ-MAb for both Aβ monomers and fibrils (KD = 0.08 and 0.13 nm, respectively). The affinity of the biotinylated Aβ-MAb, used thereafter for liposome decoration, was lower although still in the low nanomolar range (KD = 2.1 and 1.6 nm, respectively). Biotin-streptavidin ligation method was used to decorate nanoliposomes with Aβ-MAb, at different densities. IgG-decorated liposomes were generated by the same methodology, as control. Vesicles were monodisperse with mean diameters 124-134 nm and demonstrated good colloidal stability and integrity when incubated with serum proteins. When studied by SPR, Aβ-MAb-liposomes, but not IgG-liposomes, markedly bound to Aβ monomers and fibrils, immobilized on the chip. KD values (calculated on Aβ-MAb content) were about 0.5 and 2 nm with liposomes at high and low Aβ-MAb density, respectively. Aβ-MAb-liposome binding to Aβ fibrils was additionally confirmed by ultracentrifugation technique, in which interactions occur in solution under physiological conditions. Moreover, Aβ-MAb-liposomes bound amyloid deposits in post-mortem AD brain samples, confirming the potential of these nanoparticles for the diagnosis and therapy of AD. © 2011 Elsevier Ltd.

Markoutsa E.,University of Patras | Papadia K.,University of Patras | Clemente C.,Investigacao e Servicos em Ciencias Biologicas Lda | Flores O.,Investigacao e Servicos em Ciencias Biologicas Lda | And 2 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2012

Anti-Aβ-MAb (Aβ-MAb)-decorated immunoliposomes (LIP) and dually decorated ones (dd-LIP) with OX-26 and Aβ-MAb were constructed. In both cases, the biotin-streptavidin ligation method was applied. All LIP types were characterized for size distribution, zeta potential, and integrity during incubation with serum proteins. Uptake and transcytosis of both LIP types and control vesicles by human brain endothelial hCMEC/D3 cells were measured. All LIP types had mean diameters below 150-200 nm and low polydispersity. Aβ-MAb-LIP uptake was higher than control PEGylated liposomes, while uptake of dd-LIP was similar to that of OX-26-LIP. Aβ-MAb-LIP and dd-LIP uptake increased significantly when cells were pre-incubated with Aβ1-42 peptides; OX-26-LIP uptake was not modulated. Transcytosis of Aβ-MAb-LIP through monolayers was 2.5 times higher when monolayers were pre-incubated with Aβ1-42. Transport of both probes, FITC-dextran and rhodamine-lipid, was equivalent, indicating that Aβ-MAb-LIP are transferred intact through the BBB model. The Aβ peptide-induced increase in binding (and transport) is regulated by the membrane receptors for Aβ1-42 peptides (RAGE), as proven after blocking RAGE by a specific MAb. Aβ1-42 peptides did not modulate the barrier tightness and integrity, as determined by transendothelial resistance and Lucifer Yellow permeability. Additionally, hCMEC/D3 cell viability was not affected by Aβ peptides or by Aβ-MAb-LIP. © 2012 Elsevier B.V. All rights reserved.

Barbieri C.,MPI for Evolutionary Anthropology | Barbieri C.,University of Bologna | Vicente M.,University of Porto | Vicente M.,Investigacao e Servicos em Ciencias Biologicas Lda | And 7 more authors.
PLoS ONE | Year: 2014

Bantu speech communities expanded over large parts of sub-Saharan Africa within the last 4000-5000 years, reaching different parts of southern Africa 1200-2000 years ago. The Bantu languages subdivide in several major branches, with languages belonging to the Eastern and Western Bantu branches spreading over large parts of Central, Eastern, and Southern Africa. There is still debate whether this linguistic divide is correlated with a genetic distinction between Eastern and Western Bantu speakers. During their expansion, Bantu speakers would have come into contact with diverse local populations, such as the Khoisan hunter-gatherers and pastoralists of southern Africa, with whom they may have intermarried. In this study, we analyze complete mtDNA genome sequences from over 900 Bantu-speaking individuals from Angola, Zambia, Namibia, and Botswana to investigate the demographic processes at play during the last stages of the Bantu expansion. Our results show that most of these Bantu-speaking populations are genetically very homogenous, with no genetic division between speakers of Eastern and Western Bantu languages. Most of the mtDNA diversity in our dataset is due to different degrees of admixture with autochthonous populations. Only the pastoralist Himba and Herero stand out due to high frequencies of particular L3f and L3d lineages; the latter are also found in the neighboring Damara, who speak a Khoisan language and were foragers and small-stock herders. In contrast, the close cultural and linguistic relatives of the Herero and Himba, the Kuvale, are genetically similar to other Bantu-speakers. Nevertheless, as demonstrated by resampling tests, the genetic divergence of Herero, Himba, and Kuvale is compatible with a common shared ancestry with high levels of drift, while the similarity of the Herero, Himba, and Damara probably reflects admixture, as also suggested by linguistic analyses. Copyright: © 2014 Barbieri et al.

Bernacka-Wojcik I.,New University of Lisbon | Aguas H.,New University of Lisbon | Carlos F.F.,New University of Lisbon | Carlos F.F.,Investigacao e Servicos em Ciencias Biologicas Lda. | And 8 more authors.
Biotechnology and Bioengineering | Year: 2015

The use of microfluidics platforms combined with the optimal optical properties of gold nanoparticles has found plenty of application in molecular biosensing. This paper describes a bio-microfluidic platform coupled to a non-cross-linking colorimetric gold nanoprobe assay to detect a single nucleotide polymorphism associated with increased risk of obesity fat-mass and obesity-associated (FTO) rs9939609 (Carlos et al., 2014). The system enabled significant discrimination between positive and negative assays using a target DNA concentration of 5ng/μL below the limit of detection of the conventionally used microplate reader (i.e., 15ng/μL) with 10 times lower solution volume (i.e., 3μL). A set of optimization of our previously reported bio-microfluidic platform (Bernacka-Wojcik et al., 2013) resulted in a 160% improvement of colorimetric analysis results. Incorporation of planar microlenses increased 6 times signal-to-loss ratio reaching the output optical fiber improving by 34% the colorimetric analysis of gold nanoparticles, while the implementation of an optoelectronic acquisition system yielded increased accuracy and reduced noise. The microfluidic chip was also integrated with a miniature fiber spectrometer to analyze the assays' colorimetric changes and also the LEDs transmission spectra when illuminating through various solutions. Furthermore, by coupling an optical microscope to a digital camera with a long exposure time (30s), we could visualise the different scatter intensities of gold nanoparticles within channels following salt addition. These intensities correlate well to the expected difference in aggregation between FTO positive (none to small aggregates) and negative samples (large aggregates). © 2015 Wiley Periodicals, Inc.

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