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On the mechanisms of protein interactions: Predicting their affinity from unbound tertiary structures

  • Marín López, Manuel Alejandro, 1987-
  • Planas Iglesias, Joan, 1980-
  • Aguirre Plans, Joaquim
  • Bonet Martínez, Jaume, 1982-
  • García-García, Javier, 1982-
  • Fernández Fuentes, Narcís
  • Oliva Miguel, Baldomero
MOTIVATION: The characterization of the protein-protein association mechanisms is crucial to understanding how biological processes occur. It has been previously shown that the early formation of non-specific encounters enhances the realization of the stereospecific (i.e. native) complex by reducing the dimensionality of the search process. The association rate for the formation of such complex plays a crucial role in the cell biology and depends on how the partners diffuse to be close to each other. Predicting the binding free energy of proteins provides new opportunities to modulate and control protein-protein interactions. However, existing methods require the 3D structure of the complex to predict its affinity, severely limiting their application to interactions with known structures. RESULTS: We present a new approach that relies on the unbound protein structures and protein docking to predict protein-protein binding affinities. Through the study of the docking space (i.e. decoys), the method predicts the binding affinity of the query proteins when the actual structure of the complex itself is unknown. We tested our approach on a set of globular and soluble proteins of the newest affinity benchmark, obtaining accuracy values comparable to other state-of-art methods: a 0.4 correlation coefficient between the experimental and predicted values of ΔG and an error < 3 Kcal/mol. AVAILABILITY AND IMPLEMENTATION: The binding affinity predictor is implemented and available at http://sbi.upf.edu/BADock and https://github.com/badocksbi/BADock. CONTACT: j.planas-iglesias@warwick.ac.uk or baldo.oliva@upf.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online., The work has been supported by grants BIO2014-57518-R and BIO2011-22568 of the Spanish Ministry of Economy (MINECO), INB 2015-2017 of ISCIII, and 2014SGR1161 of Generalitat de Catalunya.
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Rapid transcriptional plasticity of duplicated gene clusters enables a clonally reproducing aphid to colonise diverse plant species

  • Mathers, Thomas C.
  • Gabaldón Estevan, Juan Antonio, 1973-
  • Julca, Irene
  • Loska, Damian
  • Hogenhout, Saskia A.
BACKGROUND: The prevailing paradigm of host-parasite evolution is that arms races lead to increasing specialisation via genetic adaptation. Insect herbivores are no exception and the majority have evolved to colonise a small number of closely related host species. Remarkably, the green peach aphid, Myzus persicae, colonises plant species across 40 families and single M. persicae clonal lineages can colonise distantly related plants. This remarkable ability makes M. persicae a highly destructive pest of many important crop species. RESULTS: To investigate the exceptional phenotypic plasticity of M. persicae, we sequenced the M. persicae genome and assessed how one clonal lineage responds to host plant species of different families. We show that genetically identical individuals are able to colonise distantly related host species through the differential regulation of genes belonging to aphid-expanded gene families. Multigene clusters collectively upregulate in single aphids within two days upon host switch. Furthermore, we demonstrate the functional significance of this rapid transcriptional change using RNA interference (RNAi)-mediated knock-down of genes belonging to the cathepsin B gene family. Knock-down of cathepsin B genes reduced aphid fitness, but only on the host that induced upregulation of these genes. CONCLUSIONS: Previous research has focused on the role of genetic adaptation of parasites to their hosts. Here we show that the generalist aphid pest M. persicae is able to colonise diverse host plant species in the absence of genetic specialisation. This is achieved through rapid transcriptional plasticity of genes that have duplicated during aphid evolution.
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Array-CGH in patients with Kabuki-like phenotype: Identification of two patients with complex rearrangements including 2q37 deletions and no other recurrent aberration

  • Cuscó Martí, Ivon, 1973-
  • Campo Casanelles, Miguel del, 1966-
  • Vilardell Nogales, Mireia
  • González, Eva
  • Gener, Blanca
  • Galán, Enrique
  • Toledo, Laura
  • Pérez Jurado, Luis Alberto
Background: Kabuki syndrome (KS) is a multiple congenital anomaly syndrome characterized by specific facial features, mild to moderate mental retardation, postnatal growth delay, skeletal abnormalities, and unusual dermatoglyphic patterns with prominent fingertip pads. A 3.5 Mb duplication at 8p23.1-p22 was once reported as a specific alteration in KS but has not been confirmed in other patients. The molecular basis of KS remains unknown. Methods: We have studied 16 Spanish patients with a clinical diagnosis of KS or KS-like to search for genomic imbalances using genome-wide array technologies. All putative rearrangements were confirmed by FISH, microsatellite markers and/or MLPA assays, which also determined whether the imbalance was de novo or inherited. Results: No duplication at 8p23.1-p22 was observed in our patients. We detected complex rearrangements involving 2q in two patients with Kabuki-like features: 1) a de novo inverted duplication of 11 Mb with a 4.5 Mb terminal deletion, and 2) a de novo 7.2 Mb-terminal deletion in a patient with an additional de novo 0.5 Mb interstitial deletion in 16p. Additional copy number variations (CNV), either inherited or reported in normal controls, were identified and interpreted as polymorphic variants. No specific CNV was significantly increased in the KS group. Conclusion: Our results further confirmed that genomic duplications of 8p23 region are not a common cause of KS and failed to detect other recurrent rearrangement causing this disorder. The detection of two patients with 2q37 deletions suggests that there is a phenotypic overlap between the two conditions, and screening this region in the Kabuki-like patients should be considered., This work was funded by grants from the Spanish Ministry of Health (FIS PI042063), Genome Spain and the European Commission (FP6-2005-037627). IC was supported by a Juan de la Cierva Postdoctoral fellowship.
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ArchDB 2014: structural classification of loops in proteins

  • Bonet Martínez, Jaume, 1982-
  • Planas Iglesias, Joan, 1980-
  • García-García, Javier, 1982-
  • Marín López, Manuel Alejandro, 1987-
  • Fernández Fuentes, Narcís
  • Oliva Miguel, Baldomero
The function of a protein is determined by its three-dimensional structure, which is formed by regular (i.e. β-strands and α-helices) and non-periodic structural units such as loops. Compared to regular structural elements, non-periodic, non-repetitive conformational units enclose a much higher degree of variability--raising difficulties in the identification of regularities, and yet represent an important part of the structure of a protein. Indeed, loops often play a pivotal role in the function of a protein and different aspects of protein folding and dynamics. Therefore, the structural classification of protein loops is an important subject with clear applications in homology modelling, protein structure prediction, protein design (e.g. enzyme design and catalytic loops) and function prediction. ArchDB, the database presented here (freely available at http://sbi.imim.es/archdb), represents such a resource and has been an important asset for the scientific community throughout the years. In this article, we present a completely reworked and updated version of ArchDB. The new version of ArchDB features a novel, fast and user-friendly web-based interface, and a novel graph-based, computationally efficient, clustering algorithm. The current version of ArchDB classifies 149,134 loops in 5739 classes and 9608 subclasses., This work has been funded by the Spanish Ministry of Science and Innovation (MICINN) [FEDER BIO2008-0205, FEDER BIO2011-22568, EUI2009-04018]; FI-DGR 2012 fellowship from/n‘Generalitat de Catalunya’ (to M.A.M.L.). Funding for open access charge: Spanish Ministry of Science and Innovation
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Contribution of rare copy number variants to isolated human malformations

  • Serra Juhé, Clara, 1984-
  • Rodríguez Santiago, Benjamín
  • Cuscó Martí, Ivon, 1973-
  • Vendrell, Teresa
  • Camats, Núria
  • Torán, Núria
  • Pérez Jurado, Luis Alberto
Background: Congenital malformations are present in approximately 2–3% of liveborn babies and 20% of stillborn fetuses. The mechanisms underlying the majority of sporadic and isolated congenital malformations are poorly understood, although it is hypothesized that the accumulation of rare genetic, genomic and epigenetic variants converge to deregulate developmental networks. Methodology/Principal Findings: We selected samples from 95 fetuses with congenital malformations not ascribed to a specific syndrome (68 with isolated malformations, 27 with multiple malformations). Karyotyping and Multiplex Ligation-dependent Probe Amplification (MLPA) discarded recurrent genomic and cytogenetic rearrangements. DNA extracted from the affected tissue (46%) or from lung or liver (54%) was analyzed by molecular karyotyping. Validations and inheritance were obtained by MLPA. We identified 22 rare copy number variants (CNV) [>100 kb, either absent (n = 7) or very uncommon (n = 15, <1/2,000) in the control population] in 20/95 fetuses with congenital malformations (21%), including 11 deletions and 11 duplications. One of the 9 tested rearrangements was de novo while the remaining were inherited from a healthy parent. The highest frequency was observed in fetuses with heart hypoplasia (8/17, 62.5%), with two events previously related with the phenotype. Double events hitting candidate genes were detected in two samples with brain malformations. Globally, the burden of deletions was significantly higher in fetuses with malformations compared to controls./nConclusions/Significance: Our data reveal a significant contribution of rare deletion-type CNV, mostly inherited but also de novo, to human congenital malformations, especially heart hypoplasia, and reinforce the hypothesis of a multifactorial etiology in most cases., This work was supported by grants from the Spanish Ministry of Health (PI042063), the CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras)(U735-3) and the VI Framework Programme of the European Union (LSHG-CT-2006-037627). CS-J and BR-S were supported by predoctoral (FIS FI08/00365) and posdoctoral fellowships (FIS CD06/00019) of the Fondo de Investigación Sanitaria, respectively
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VORFFIP-driven dock: V-D2OCK, a fast and accurate protein docking strategy.

  • Segura, Joan
  • Marín López, Manuel Alejandro, 1987-
  • Jones, Pamela F.
  • Oliva Miguel, Baldomero
  • Fernández Fuentes, Narcís
The experimental determination of the structure of protein complexes cannot keep pace with the generation of interactomic data, hence resulting in an ever-expanding gap. As the structural details of protein complexes are central to a full understanding of the function and dynamics of the cell machinery, alternative strategies are needed to circumvent the bottleneck in structure determination. Computational protein docking is a valid and valuable approach to model the structure of protein complexes. In this work, we describe a novel computational strategy to predict the structure of protein complexes based on data-driven docking: VORFFIP-driven dock (V-D2OCK). This new approach makes use of our newly described method to predict functional sites in protein structures, VORFFIP, to define the region to be sampled during docking and structural clustering to reduce the number of models to be examined by users. V-D2OCK has been benchmarked using a validated and diverse set of protein complexes and compared to a state-of-art docking method. The speed and accuracy compared to contemporary tools justifies the potential use of VD2OCK for high-throughput, genome-wide, protein docking. Finally, we have developed a web interface that allows users to browser and visualize V-D2OCK predictions from the convenience of their web-browsers., This work was supported by Research Councils UK (RCUK) under the RCUK Academic Fellowship program (NFF) and a PhD scholarship awarded by the University of Leeds (JS). BO acknowledges support from the Spanish Ministry ofEconomy and Competitiveness; grant number BIO2011-22568 and MAML a PhD scholarship awarded by the Generalitat of Catalonia (FI-DGR2012).
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Starcode: sequence clustering based on all-pairs search

  • Zorita, Eduard
  • Cuscó Pons, Pol, 1987-
  • Filion, Guillaume
Motivation: The increasing throughput of sequencing technologies offers new applications and challenges for computational biology. In many of those applications, sequencing errors need to be/ncorrected. This is particularly important when sequencing reads from an unknown reference such as random DNA barcodes. In this case, error correction can be done by performing a pairwise comparison/nof all the barcodes, which is a computationally complex problem. Results: Here, we address this challenge and describe an exact algorithm to determine which pairs of sequences lie within a given Levenshtein distance. For error correction or redundancy reduction purposes, matched pairs are then merged into clusters of similar sequences. The efficiency of starcode is attributable to the poucet search, a novel implementation of the Needleman–Wunsch algorithm performed on the nodes of a trie. On the task of matching random barcodes, starcode outperforms sequence clustering algorithms in both speed and precision. Availability and implementation: The C source code is available at http://github.com/gui11aume/starcode.
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Principal component analysis of the effects of environmental enrichment and (-)-epigallocatechin-3-gallate on age-associated learning deficits in a mouse model of down syndrome.

  • Catuara Solarz, Silvina, 1986-
  • Espinosa-Carrasco, José
  • Erb, Ionas
  • Langohr, Klaus
  • Notredame, Cedric
  • González Ruiz, Juan Ramón
  • Dierssen, Mara
Down syndrome (DS) individuals present increased risk for Alzheimer's disease (AD) neuropathology and AD-type dementia. Here, we investigated the use of green tea extracts containing (-)-epigallocatechin-3-gallate (EGCG), as co-adjuvant to enhance the effects of environmental enrichment (EE) in Ts65Dn mice, a segmental trisomy model of DS that partially mimics DS/AD pathology, at the age of initiation of cognitive decline. Classical repeated measures ANOVA showed that combined EE-EGCG treatment was more efficient than EE or EGCG alone to improve specific spatial learning related variables. Using principal component analysis (PCA) we found that several spatial learning parameters contributed similarly to a first PC and explained a large proportion of the variance among groups, thus representing a composite learning measure. This PC1 revealed that EGCG or EE alone had no significant effect. However, combined EE-EGCG significantly ameliorated learning alterations of middle age Ts65Dn mice. Interestingly, PCA revealed an increased variability along learning sessions with good and poor learners in Ts65Dn, and this stratification did not disappear upon treatments. Our results suggest that combining EE and EGCG represents a viable therapeutic approach for amelioration of age-related cognitive decline in DS, although its efficacy may vary across individuals., The laboratory of Mara Dierssen is supported by DIUE de la Generalitat de Catalunya (Grups consolidats SGR 2014/1125). This work was supported by Fondation Jérôme Lejeune (Paris, France), MINECO (SAF2013-49129-C2-1-R), CDTI (“Smartfoods”), and EU (Era Net Neuron PCIN-2013-060). The CRG is a Center of Excellence Severo Ochoa SEV-2012-0208. The CIBER of Rare Diseases is an initiative of the ISCIII. The laboratory of Cedric Notredame acknowledges the funding from the Spanish Ministry of Economy and Finance (MINECO), grant number BFU2011-28575. Silvina Catuara-Solarz received a FPI doctoral fellowship from Spanish Ministry of Economy and Finance (MINECO), SAF2010-16427; Jose Espinosa-Carrasco received the FI grant from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) de la Generalitat de Catalunya.
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El Pla de Palau: imatge de la Barcelona del Segle XIX

  • Bada Ortoll, Albert
Treball de fi de grau d'Humanitats. Curs 2015-2016, Directora: Núria F. Rius, El present treball té com a objectiu recopilar les diferents obres d’art realitzades al llarg del segle XIX en les quals es representa el Pla de Palau de Barcelona. Mitjançant l’anàlisi i l’estudi de les següents imatges, es busca comprovar dos objectius: d’una banda, veure si el nombre de representacions de l’espai concorda amb la importància política, econòmica i cultural que va jugar l’espai al llarg del segle XIX dins de la història de Barcelona; i de l’altra, comprovar com els diferents llenguatges artístics propis d’aquest segle s’influencien els uns als altres i es produeixen episodis d’hibridació tècnica i visual. A més a més, mitjançant el comentari més profund de les obres més rellevants, es busca traçar un seguit de línies sobre la cultura visual de la plaça, és a dir, veure com es reprodueixen una sèrie de patrons en les diferents representacions del Pla de Palau.
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Unerzählt: la concepció de l’art de W. G. Sebald i Jan Peter Tripp

  • Puigdomènech Reig, Gemma
Treball de fi de grau d'Humanitats. Curs 2015-2016, Directora: Teresa Vinardell, En aquesta era visual on el segle XXI està immers cal reflexionar sobre el nou paper de la imatge tant com a productora de significat autònoma com des de la vessant que agafa aquest univers visual en posar-se en contacte amb l’espai literari. Aquesta irrupció ha forçat una reinterpretació dels significats propis de cadascun d’aquests mitjans, alhora que una meditació sobre el diàleg que s’estableix entre ambdós. D’aquesta unió emergeixen nous horitzons que cal entendre dins d’una nova concepció que no només engloba dues manifestacions artístiques diferents, sinó que va més enllà i crea un concepte diferent que formula noves preguntes. El significant propi de cadascuna d’aquestes expressions dóna lloc a una idea que busca crear un discurs més transversal, integrador i ampli.
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