Pan-cancer functional analysis of somatic mutations in G protein-coupled receptors.

G Protein-coupled receptors (GPCRs) are the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used a dataset of mutations found in patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 genomes project. We explored cancer-related mutation patterns in all GPCR classes combined and individually. While the location of the mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment in cancer patients was observed among class-specific conserved motifs in GPCRs such as the Class A "DRY" motif. A Two-Entropy Analysis confirmed the correlation between residue conservation and cancer-related mutation frequency. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). Our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, but also discovered novel GPCRs which had not been linked to cancer before such as the P2Y Receptor 10 (P2RY10). Overall, this study presents a list of GPCRs that are amenable to experimental follow up to elucidate their role in cancer.

Efecto del uso de instrumentos de viento en las malocusiones dentarias: revisión de la literatura / Effect of the use of wind instruments in dental malocclusion: Literature review

El diseño de la embocadura adecuada, requiere por parte de los músicos muchos años y horas de práctica, desarrollando y manteniendo posturas prolongadas que suponen una sobrecarga para órganos que no están diseñados para el esfuerzo continuado. El presente artículo refleja estudios realizados, donde se recabó información que refleja la relación entre las maloclusiones y el uso de instrumentos viento madera, observando como influye en la maloclusión que padece cada paciente, el instrumento que toca, el número de horas semanales que práctica, la edad del inicio de la ejecución, el tipo de boquilla que posee el instrumento. Se puede resaltar que los resultados de estudios previos arrojaron como resultado que la maloclusión con mayor prevalencia es la Clase I tipo I, seguida por la clase II División 2 . Según los resultados se puede concluir que los instrumentos musicales de viento deben ser tomados en cuenta como factores postnatales ambientales etiológicos de maloclusiones dentarias

The design of the mouth proper, required by musicians for many years and hours of practice, developing and maintaining long positions that can strain bodies are not designed for continuous effort. This article reflects studies where information was collected that reflects the relationship between malocclusions and the use of woodwind instruments, observing how malocclusion affects each patient suffering, the instrument he plays, the number of hours a week practicing, age of onset of implementation, nozzle type which has the instrument. One may notice that the results of previous studies yielded the result that the most prevalent malocclusion is Class I type I, followed by Class II Division 2. According to the results we can conclude that the wind instruments should be taken into account as environmental etiologic postnatal factors of dental malocclusion

Computational inhibitor design against malaria plasmepsins.

Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I-IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.

Molecular diversity sample generation on the basis of quantum-mechanical computations and principal component analysis.

The present study introduces a new strategy of selection of a maximum diversity sample of n compounds from N available in a molecular database. This strategy can be useful in pharmacological screening, combinatorial chemistry or parallel synthesis planning. It consists of first describing the compounds by means of parameters derived from quantum mechanical computations (water solvation deltaG, benzene solvation deltaG, octanol solvation deltaG, dipolar moment), as well as standard molecular parameters such as solvent-accessible surface area and molecular weight. Solvation parameters are used because of the importance of this phenomenon in the pharmacological behaviour. Redundant information in the description of the compounds is eliminated by using principal components (PC) instead of the original descriptors. Based on the similarity between the N compounds in the PC space, they are classified into n groups by k-means cluster analysis. The compounds that are nearest to the centroid of each cluster constituted the maximum diversity sample. When practical difficulties exist for the use of one of the proposed compounds, another also close to the cluster centroid can substitute for it. This strategy has been tested in the selection of a sample of 50 amines from the 923 available in the Aldrich catalogue. The results have been contrasted with those obtained from an optimal, distance-based experimental design, resulting in an 86% of agreement between both approaches. An R(2)-like diversity coefficient has been used to assess the quality of the proposed solutions.

[Effects produced by Spinitectus jamundensis (Nematoda, Cystidicolidae) in the stomach of the shad, Prochilodus lineatus (Pisces, Prochilodidae)]. / Efectos producidos por Spinitectus jamundensis (Nematoda, Cystidicolidae) en el estómago del sábalo, prochilodus lineatus (Pisces, Prochilodidae).

The presence of the nematode Spinitectus jamundensis in cardial and pyloric regions of the stomach of Prochilodus lineatus is observed. Samples of the parasitized stomach were analyzed by histological techniques using Hematoxilin-Eosin and Mallory (Azan) Heidenhain's stainnigs. The macroscopical description of the inner surface of the stomach showing damages in the parasites penetration sites, were observed. Histological observations show that the parasite enters the mucous membrane reaching muscular mucous membrane of the cardial region or the epithelial plaits in the pyloric region reaching up to the muscular layer without crossing it. In this way, the parasite remains confined by a thin layer of connective tissue and in almost direct contact with tissue liquids. Sometimes, in host tissues as response to the parasite presence, an increased level in the amount of lymphocytes in the surrounding tissues is observed.

Sigmoid volvulus in the high altitude of the Andes. Review of 230 cases.

Sigmoid volvulus (SV) is uncommon in the United States. Little has been published in the English literature about the high incidence of SV among rural areas of the Bolivian and Peruvian Andes at 13,000 feet above sea level. A review of 230 cases of SV in a Bolivian hospital is presented. SV accounted for 79 percent of all intestinal obstructions. Nonoperative reduction was attempted in all patients except those with peritonitis. Nonoperative reduction alone was performed in 31 percent of the patients, and 69 percent underwent surgical intervention, 66 percent as an emergency and 3 percent electively. Surgical treatment consisted of sigmoidectomy and primary anastomosis (50 percent), Hartmann's procedure (12 percent), and operative detorsion with sigmoid plication (38 percent). Overall mortality was 13.5 percent. Fifty-seven of the surgically treated patients developed significant complications. The etiology of SV is unclear. High altitude, along with other etiologic factors, may play an important role in SV. To our knowledge, this series represents the highest incidence of SV in bowel obstruction.