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Inhibition of human prolyl oligopeptidase activity by the Cyclotide Psysol 2 isolated from Psychotria solitudinum

Cyclotides are head-to-tail cyclized peptides comprising a stabilizing cystine-knot motif. To date, they are well known for their diverse bioactivities such as anti-HIV and immunosuppressive properties. Yet little is known about specific molecular mechanisms, in particular the interaction of cyclotides with cellular protein targets. Native and synthetic cyclotide-like peptides from Momordica plants are potent and selective inhibitors of different serine-type proteinases such as trypsin, chymotrypsin, matriptase, and tryptase-beta. This study describes the bioactivity-guided isolation of a cyclotide from Psychotria solitudinum as an inhibitor of another serine-type protease, namely, the human prolyl oligopeptidase (POP). Analysis of the inhibitory potency of Psychotria extracts and subsequent fractionation by liquid chromatography yielded the isolated peptide psysol 2 (1), which exhibited an IC50 of 25 μM. In addition the prototypical cyclotide kalata B1 inhibited POP activity with an IC50 of 5.6 μM. The inhibitory activity appeared to be selective for POP, since neither psysol 2 nor kalata B1 were able to inhibit the proteolytic activity of trypsin or chymotrypsin. The enzyme POP is well known for its role in memory and learning processes, and it is currently being considered as a promising therapeutic target for the cognitive deficits associated with several psychiatric and neurodegenerative diseases, such as schizophrenia and Parkinson's disease. In the context of discovery and development of POP inhibitors with beneficial ADME properties, cyclotides may be suitable starting points considering their stability in biological fluids and possible oral bioavailability

BCN Rocks: aprendiendo geología urbana a través de una aplicación App interactiva

BCN Rocks is an application (App) for personal mobile devices (Android and iOS versions) suitable for secondary and high school students as well as people without background in Earth Sciences. The main objective of this App is to learn geology using the city facades and pavements of two emblematic spaces of the city of Barcelona, the Passeig de Gràcia and the Barri Gòtic. The application has three main sections (ELEMENTS, EXPLORE, and LABORATORY) that are intended to satisfy the different needs of users. In the first section, Elements, the user will find all the information about rocks forming the selected buildings as well as a brief explanation about the history and architecture of each edifice. The second section, Explore, aims to arise the curiosity of users. In this sense, several routes are proposed according to different criteria including geographic position and age of the edifices. Finally, the third section, Laboratory, allows all users to investigate several geological aspects by means of interactive experiments.Este trabajo se enmarca en un proyecto financiado por la Fundación Española para la Ciencia y la Tecnología, FECYT (ref. 8524) en el que ha participado la Universitat de Barcelona, el Instituto de Ciencias de la Tierra Jaume Almera del Consejo Superior de Investigaciones Científicas (ICTJA-CSIC) y la empresa FUSTA. AG agradece su contrato Ramón y Cajal (RYC-2012-11024).Peer Reviewe

Análisis del fenómeno de la expansividad de materiales en túneles construidos en anhidrita. Consecuencias y experiencias

Los graves problemas geotécnicos sucedidos en numerosos túneles europeos excavados en materiales que generan problemas de estabilidad, como consecuencia de su expansividad, los convierten en canalizadores de aguas. Estos materiales son fácilmente lavables al disolverse los sulfatos con el agua, provocando una decompresión y remoldeo del macizo, agravando y trasladando el problema más allá del inmediato entorno del túnel. En el caso particular de presencia de capas de anhidrita entre argilitas, además de la adopción de medidas de sostenimiento y revestimiento especiales, el sostenimiento primario y el revestimiento posterior deben ser excepcionalmente resistentes a las presiones que pueden llegar a transmitir el terreno a medio y largo plazo. En este artículo se describen los aspectos más relevantes de comportamiento hidromecánico de los suelos y las rocas sulfatadas y se presentan algunas experiencias, concluyendo sobre aspectos asociados al fenómeno de hinchamiento en túneles y su posible tratamiento

Infección periprotésica aguda de rodilla por fusobacterium nucleatum. Revisión de la literatura a propósito de un caso.

Fusobacterium Nucleatum is an anaerobic commensal microorganism present in the oral cavity and some mucous membranes with great capacity to form biofilm. In the literature, only one case of acute periprosthetic infection of the knee by Fusobacterium Nucleatum has been reported, providing the second case. A 72-year-old man presented with an acute periprosthetic infection by fusobacterium nucleatum after a second time of a prosthetic knee replacement. Debridement and spacer changes were performed up to 4 times, associating parenteral antibiotic treatment. After ensuring the absence of infection, a modular revision knee prosthesis with stems was placed, with a satisfactory evolution after two years. Currently he has preserved ambulation, joint balance of 0º-50º and is free of infection. Fusobacterium Nucleatum infection is very rare, but aggressive and difficult to resolve, recommending two-stage replacement in acute infection and adequate antibiotic treatment to offer curative treatment

Structural Analysis of Prolyl Oligopeptidases Using Molecular Docking and Dynamics: Insights into Conformational Changes and Ligand Binding

Prolyl oligopeptidase (POP) is considered as an important pharmaceutical target for the treatment of numerous diseases. Despite enormous studies on various aspects of POPs structure and function still some of the questions are intriguing like conformational dynamics of the protein and interplay between ligand entry/egress. Here, we have used molecular modeling and docking based approaches to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana). Despite high sequence and structural similarity, they possess different affinities for the ligands. Interestingly, human POP was found to be more specific, selective and incapable of binding to a few planar ligands which showed extrapolation of porcine POP in human context is more complicated. Possible routes for substrate entry and product egress were also investigated by detailed analyses of molecular dynamics (MD) simulations for the three proteins. Trajectory analysis of bound and unbound forms of three species showed differences in conformational dynamics, especially variations in β-propeller pore size, which was found to be hidden by five lysine residues present on blades one and seven. During simulation, β-propeller pore size was increased by ∼2 Å in porcine ligand-bound form which might act as a passage for smaller product movement as free energy barrier was reduced, while there were no significant changes in human and A. thaliana POPs. We also suggest that these differences in pore size could lead to fundamental differences in mode of product egress among three species. This analysis also showed some functionally important residues which can be used further for in vitro mutagenesis and inhibitor design. This study can help us in better understanding of the etiology of POPs in several neurodegenerative diseases

Molecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain

Producción CientíficaHand, foot and mouth disease (HFMD) is a childhood illness frequently caused by genotypes belonging to the enterovirus A species, including coxsackievirus (CV)-A16 and enterovirus (EV)-71. Between 2010 and 2012, several outbreaks and sporadic cases of HFMD occurred in different regions of Spain. The objective of the present study was to describe the enterovirus epidemiology associated with HFMD in the country. A total of 80 patients with HFMD or atypical rash were included. Detection and typing of the enteroviruses were performed directly in clinical samples using molecular methods. Enteroviruses were detected in 53 of the patients (66%). CV-A6 was the most frequent genotype, followed by CV-A16 and EV-71, but other minority types were also identified. Interestingly, during almost all of 2010, CV-A16 was the only causative agent of HFMD but by the end of the year and during 2011, CV-A6 became predominant, while CV-A16 was not detected. In 2012, however, both CV-A6 and CV-A16 circulated. EV-71 was associated with HFMD symptoms only in three cases during 2012. All Spanish CV-A6 sequences segregated into one major genetic cluster together with other European and Asian strains isolated between 2008 and 2011, most forming a particular clade. Spanish EV-71 strains belonged to subgenogroup C2, as did most of the European sequences circulated. In conclusion, the recent increase of HFMD cases in Spain and other European countries has been due to a larger incidence of circulating species A enteroviruses, mainly CV-A6 and CV-A16, and the emergence of new genetic variants of these viruses

Towards Horizon 2020: challenges and advances for clinical mental health research - outcome of an expert survey

BACKGROUND: The size and increasing burden of disease due to mental disorders in Europe poses substantial challenges to its population and to the health policy of the European Union. This warrants a specific research agenda concerning clinical mental health research as one of the cornerstones of sustainable mental health research and health policy in Europe. The aim of this research was to identify the top priorities needed to address the main challenges in clinical research for mental disorders. METHODS: The research was conducted as an expert survey and expert panel discussion during a scientific workshop. RESULTS: Eighty-nine experts in clinical research and representing most European countries participated in this survey. Identified top priorities were the need for new intervention studies, understanding the diagnostic and therapeutic implications of mechanisms of disease, and research in the field of somatic-psychiatric comorbidity. The 'subjectivity gap' between basic neuroscience research and clinical reality for patients with mental disorders is considered the main challenge in psychiatric research, suggesting that a shift in research paradigms is required. CONCLUSION: Innovations in clinical mental health research should bridge the gap between mechanisms underlying novel therapeutic interventions and the patient experience of mental disorder and, if present, somatic comorbidity. Clinical mental health research is relatively underfunded and should receive specific attention in Horizon 2020 funding programs