Recognition dynamics of cancer mutations on the ERp57-Tapasin interface

Down regulation of the major histocompatibility class (MHC) I pathway plays an important role in tumour development, and can be achieved by suppression of HLA expression or mutations in the MHC peptide-binding pocket. The peptide-loading complex (PLC) loads peptides on the MHC-I molecule in a dynamic multi-step assembly process. The effects of cancer variants on ERp57 and tapasin components from the MHC-I pathway is less known, and they could have an impact on antigen presentation. Applying computational approaches, we analysed whether the ERp57-tapasin binding might be altered by missense mutations. The variants H408R(ERp57) and P96L, D100A, G183R(tapasin) at the protein–protein interface improved protein stability (ΔΔG) during the initial screen of 14 different variants. The H408R(ERp57) and P96L(tapasin) variants, located close to disulphide bonds, were further studied by molecular dynamics (MD). Identifying intramolecular a-a’ domain interactions, MD revealed open and closed conformations of ERp57 in the presence and absence of tapasin. In wild-type and mutant ERp57-tapasin complexes, residues Val97, Ser98, Tyr100, Trp405, Gly407(ERp57) and Asn94, Cys95, Arg97, Asp100(tapasin) formed common H-bond interactions. Moreover, comparing the H-bond networks for P96L and H408R with each other, suggests that P96L(tapasin) improved ERp57-tapasin binding more than the H408R(ERp57) mutant. During MD, the C-terminus domain (that binds MHC-I) in tapasin from the ERp57(H408R)-tapasin complex moved away from the PLC, whereas in the ERp57-tapasin(P96L) system was oppositely displaced. These findings can have implications for the function of PLC and, ultimately, for the presentation of MHC-I peptide complex on the tumour cell surface

Fractura por avulsión del cuerpo del isquión

Se presenta un caso de fractura por arrancamiento del cuerpo del isquion en un paciente de 16 años de edad. El tratamiento fue conservador, evolucionando el paciente de forma satisfactoria.The authors report a case of an avulsion-fracture of the body of the ischium in a 16-year-old patient. The treatment was conservative and the final result was satisfactory

Tratamiento de las fracturas abiertas de libia, grados I y II: estudio comparativo entre enclavijado con Ender y fijación externa

Un total de 73 fracturas abiertas de tibia grados I y II han sido estudiadas retrospectivamente, 41 tratadas mediante enclavijado endomedular (Ender) y 32 con fijadores externos. Fueron clasificadas según Gustilo por su grado de exposición y por los criterios AO según el trazo. Han sido valorados en ambos grupos: tiempo de consolidación, retardos de consolidación, pseudoartrosis, infección, callos viciosos y limitaciones funcionales. El grupo de fracturas tratadas mediante enclavijado endomedular presentó un tiempo medio de consolidación de 3,3 meses, no hubo retardos de consolidación y sí 4 pseudoartrosis (10%). Las fracturas tratadas con fijador externo consolidaron en un tiempo medio de 4,1 meses, hubo 2 retardos de consolidación (6%) y 6 pseudoartrosis (19%). En ausencia de infecciones, el enclavijado endomedular se ha mostrado como un tratamiento con mejores resultados de cara a la consolidación de las fracturas abiertas grado I y II de tibia, con respecto a la fijación externa.A total of 73 (grade I-II) open fractures of the tibial shaft, 41 treated by Ender nailing and 32 with external fixation, were retrospectively studied. Regarding the type of bone exposition, fractures were classified according to Gustilo. Fractures were also grouped following AO criteria with regard to the fracture line. Different factors such as time period for fracture healing, delay in union, pseudoarthrosis, infection, and functional disability were assessed in both groups of patients. Fractures treated by flexible endomedullar nailing had a mean time period for healing of 3,3 months. There was no cases with union delay, but 4 patients (10%) developed pseudoarthrosis. In fractures treated with external fixation the mean time period for consolidation was 4.1 months. In this group, there were 2 cases (6%) disclosing delay in union and 6 developing pseudoarthrosis (19%). In absence of infection, endomedullary flexible nailing has been shown to give better results than external fixation in the healing process of grade I-II open fractures of the tibial shaft

Interpreting BERT architecture predictions for peptide presentation by MHC class I proteins

The major histocompatibility complex (MHC) class-I pathway supports the detection of cancer and viruses by the immune system. It presents parts of proteins (peptides) from inside a cell on its membrane surface enabling visiting immune cells that detect non-self peptides to terminate the cell. The ability to predict whether a peptide will get presented on MHC Class I molecules helps in designing vaccines so they can activate the immune system to destroy the invading disease protein. We designed a prediction model using a BERT-based architecture (ImmunoBERT) that takes as input a peptide and its surrounding regions (N and C-terminals) along with a set of MHC class I (MHC-I) molecules. We present a novel application of well known interpretability techniques, SHAP and LIME, to this domain and we use these results along with 3D structure visualizations and amino acid frequencies to understand and identify the most influential parts of the input amino acid sequences contributing to the output. In particular, we find that amino acids close to the peptides' N- and C-terminals are highly relevant. Additionally, some positions within the MHC proteins (in particular in the A, B and F pockets) are often assigned a high importance ranking - which confirms biological studies and the distances in the structure visualizations.Comment: 10 page

Social, economic, and health impact of the respiratory syncytial virus: a systematic search

BACKGROUND: Bronchiolitis caused by the respiratory syncytial virus (RSV) and its related complications are common in infants born prematurely, with severe congenital heart disease, or bronchopulmonary dysplasia, as well as in immunosuppressed infants. There is a rich literature on the different aspects of RSV infection with a focus, for the most part, on specific risk populations. However, there is a need for a systematic global analysis of the impact of RSV infection in terms of use of resources and health impact on both children and adults. With this aim, we performed a systematic search of scientific evidence on the social, economic, and health impact of RSV infection. METHODS: A systematic search of the following databases was performed: MEDLINE, EMBASE, Spanish Medical Index, MEDES-MEDicina in Spanish, Cochrane Plus Library, and Google without time limits. We selected 421 abstracts based on the 6,598 articles identified. From these abstracts, 4 RSV experts selected the most relevant articles. They selected 65 articles. After reading the full articles, 23 of their references were also selected. Finally, one more article found through a literature information alert system was included. RESULTS: The information collected was summarized and organized into the following topics: 1. Impact on health (infections and respiratory complications, mid- to long-term lung function decline, recurrent wheezing, asthma, other complications such as otitis and rhino-conjunctivitis, and mortality; 2. Impact on resources (visits to primary care and specialists offices, emergency room visits, hospital admissions, ICU admissions, diagnostic tests, and treatments); 3. Impact on costs (direct and indirect costs); 4. Impact on quality of life; and 5. Strategies to reduce the impact (interventions on social and hygienic factors and prophylactic treatments). CONCLUSIONS: We concluded that 1. The health impact of RSV infection is relevant and goes beyond the acute episode phase; 2. The health impact of RSV infection on children is much better documented than the impact on adults; 3. Further research is needed on mid- and long-term impact of RSV infection on the adult population, especially those at high-risk; 4. There is a need for interventions aimed at reducing the impact of RSV infection by targeting health education, information, and prophylaxis in high-risk populations.The project was funded by an unrestricted grant from AbbVie.S

Knowledge Graph Embeddings in the Biomedical Domain: Are They Useful? A Look at Link Prediction, Rule Learning, and Downstream Polypharmacy Tasks

Knowledge graphs are powerful tools for representing and organising complex biomedical data. Several knowledge graph embedding algorithms have been proposed to learn from and complete knowledge graphs. However, a recent study demonstrates the limited efficacy of these embedding algorithms when applied to biomedical knowledge graphs, raising the question of whether knowledge graph embeddings have limitations in biomedical settings. This study aims to apply state-of-the-art knowledge graph embedding models in the context of a recent biomedical knowledge graph, BioKG, and evaluate their performance and potential downstream uses. We achieve a three-fold improvement in terms of performance based on the HITS@10 score over previous work on the same biomedical knowledge graph. Additionally, we provide interpretable predictions through a rule-based method. We demonstrate that knowledge graph embedding models are applicable in practice by evaluating the best-performing model on four tasks that represent real-life polypharmacy situations. Results suggest that knowledge learnt from large biomedical knowledge graphs can be transferred to such downstream use cases. Our code is available at https://github.com/aryopg/biokge

La casa completa: Vive et labora. 40 viviendas en mudanza a la periferia de Zaragoza.

En los últimos años, el cambio en el paradigma laboral ha alterado por completo las necesidades habitacionales de las personas. Es necesaria una fórmula habitable que responda a las necesidades del usuario actual. Se identifican dos realidades, dos TEJIDOS: la ciudad y el Gállego. El proyecto busca establecer un diálogo dibujando un límite entre ellas, una costura que una esos tejidos, y que va a ser el espacio donde convivan y dialoguen el “vive”, relacionado con la naturaleza del Gállego, y el “labora”, con la ciudad. Para ello, nace de una plataforma de hormigón una malla de madera capaz de albergar distintos tipos de células habitables. Un LÍMITE HABITADO ENTRE TEJIDOS VIVOS para dar cabida a este nuevo tipo de usuario. <br /

La casa completa: Vive et Labora. 40 viviendas en mudanza a la periferia de Zaragoza.

La mudanza a la casa completa se plantea en un lugar limitado por dos mundos totalmente diferentes: la periferia de la ciudad y el entorno natural del río Gállego. Ciudad y naturaleza, tan cerca el uno del otro y a la vez tan opuestos actualmente, se conectan en el proyecto a través de la construcción de un biombo de viviendas que miran, protegen y viven del lugar.<br /