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Robust Conditional Independence maps of single-voxel Magnetic Resonance Spectra to elucidate associations between brain tumours and metabolites

Scientists of CIBER-BBN, Ana Paula Candiota and Margarida Juliá managing Nanbiosis ICTS U25 NMR: Biomedical Applications I have participated in the research carried out by Liverpool John Moores University and University of Valencia to elucidate associations between brain tumours and metabolites, published by the journal Plos One.

The aim of the paper is two-fold. First, to show that structure finding with the PC algorithm can be inherently unstable and requires further operational constraints in order to consistently obtain models that are faithful to the data. The authors propose a methodology to stabilise the structure finding process, minimising both false positive and false negative error rates. This is demonstrated with synthetic data. Second, to apply the proposed structure finding methodology to a data set comprising single-voxel Magnetic Resonance Spectra of normal brain and three classes of brain tumours, to elucidate the associations between brain tumour types and a range of observed metabolites that are known to be relevant for their characterisation. The data set is bootstrapped in order to maximise the robustness of feature selection for nominated target variables. Specifically, Conditional Independence maps (CI-maps) built from the data and their derived Bayesian networks have been used. A Directed Acyclic Graph (DAG) is built from CI-maps, being a major challenge the minimization of errors in the graph structure. This work presents empirical evidence on how to reduce false positive errors via the False Discovery Rate, and how to identify appropriate parameter settings to improve the False Negative Reduction. In addition, several node ordering policies are investigated that transform the graph into a DAG. The obtained results show that ordering nodes by strength of mutual information can recover a representative DAG in a reasonable time, although a more accurate graph can be recovered using a random order of samples at the expense of increasing the computation time.

Article of reference:

Robust Conditional Independence maps of single-voxel  Magnetic  Resonance  spectra  to  elucidate  associations  between  brain  tumours  and  metabolites. Raúl Vicente Casaña-Eslava, Sandra Ortega-Martorell, Paulo J. Lisboa, Ana Paula Candiota, Margarida Julià-Sapé, José David Martín-Guerrero, Ian H. Jarman 2020, PLoS ONE  https://doi.org/10.1371/journal.pone.0235057

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A new method simple and efficient for the preparation of Oligonucleotide-protein conjugates

Oligonucleotide-protein conjugates have important applications in biomedicine. Four units of NANBIOSIS have collaborated to come across with more simple and efficient methods for the preparation of these conjugates.

In the publication of the research results, a new method is described in which a bifunctional linker is attached to thiol-oligonucleotide to generate a reactive intermediate that is used to link to the protein. Having similar conjugation efficacy compared with the classical method in which the bifunctional linker is attached first to the protein, this new approach produces significantly more active conjugates with higher batch to batch reproducibility. In a second approach, direct conjugation is proposed using oligonucleotides carrying carboxyl groups. These methodologies have been applied to prepare nanoconjugates of an engineered nanoparticle protein carrying a T22 peptide with affinity for the CXCR4 chemokine receptor and oligomers of the antiproliferative nucleotide 2′-deoxy-5-fluorouridine in a very efficient way. The protocols have potential uses for the functionalization of proteins, amino-containing polymers or amino-lipids in order to produce complex therapeutic nucleic acid delivery systems.

Protein production and DLS have been partially performed by the NANBIOSIS Units of CIBER-BBN  U1 Protein Production Platform (PPP) at IBB-UAB  and  U6 Biomaterial Processing and Nanostructuring Unit of CIBER-BBN and ICMAB-CSIC. Also, NANBIOSIS U18 of Nanotoxicology at the Hospital de la Santa Creu i Sant Pau has been used and the team of researcher counted with the NANBIOSIS expertise of U29 Oligonucleotide Synthesis Platform (OSP) at IQAC-CSIC

Article of reference:

Avino, Anna; Unzueta, Ugutz; Cespedes, Maria Virtudes; Casanova, Isolda; Vazquez, Esther; Villaverde, Antonio; Mangues, Ramon; Eritja, Ramon. Efficient bioactive oligonucleotide-protein conjugation for cell-targeted cancer therapy. CHEMISTRYOPEN 8, 3 (382-387), 2019

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