Homology modeling, molecular dynamics and docking simulations of rat A2A receptor: a three-dimensional model validation under QSAR studies

Understanding the three-dimensional structure (3-D) of GPCRs (G protein coupled receptors) can aid in the design of applicable compounds for the treatment of several human disorders. To this end, several 3-D models have been obtained in recent years. In this work, we have built the rat adenosine receptor model (rA2AR) by employing computational tools. First, the 3-D rA2AR model was built by homology modeling using the human adenosine receptor (hA2AR) structure (PDB codes: 3EML) as a template. Then, the rA2AR model was refined by molecular dynamics simulations, in which the initial and refined 3-D structures were used for molecular docking simulations and Quantitative structure-activity relationship (QSAR) studies using a set of known experimentally tested ligands to validate this rA2AR model. The results showed that the hindrance effect caused by ribose attached to agonists play an important role in activating the receptor via formation of several hydrogen bonds. In contrast, the lack of this moiety allows blocking of the receptor. The theoretical affinity estimation shows good correlation with reported experimental data. Therefore, this work represents a good example for getting reliable GPCR models under computational procedures.We are grateful for the scholarships and financial support from CONACYT, México (132353), ICyTDF (PIRIVI09-9), COFAA and SIP-IPN (20110786), PAPIIT-DGAPA UNAM-215708 and Posgrado en Ciencias Biológicas UNAM. The authors thank the Centro Nacional de Supercomputo, México, for providing access to the “Argentum” cluster

Contribution of migrant coffee labourers infected with Onchocerca volvulus to the maintenance of the microfilarial reservoir in an ivermectin-treated area of Mexico

BACKGROUND: Since 1991, in Mexico, ivermectin has been administered twice a year to all residents in the onchocerciasis endemic foci which are mainly located in the coffee growing areas. However, the presence of a potentially infected itinerant seasonal labour force which is not treated regularly could jeopardise the attainment of the 85% coverage which is the present target for elimination of the disease. METHODS: The prevalence and intensity of Onchocerca volvulus microfilariae (mf), as well as their transmission from humans to vectors, were assessed during the coffee planting-clearing and harvesting seasons of 1997-1998, and 1998-1999 in two localities (I and II) of Southern Chiapas, Mexico, which regularly receive an influx of untreated migrant coffee labourers. RESULTS: Localities I and II had, respectively, an average of 391 (+/- 32) and 358 (+/- 14) resident inhabitants, and 70 (+/- 52) and 498 (+/- 289) temporary labourers. The ratio of migrants to residents ranged from 0.1:1 in locality I to 2.4:1 in locality II. The proportion of infected Simulium ochraceum s.l. parous flies was significantly lower in locality I than in locality II, and significantly higher during the stay of the migrants than before their arrival or after their departure. Parity and infection were higher in May-July than in November-February (in contrast with the latter being typically considered as the peak onchocerciasis transmission season by S. ochraceum s.l.). CONCLUSION: The presence of significant numbers of untreated and potentially infected migrants may contribute to ongoing transmission, and their incorporation into ivermectin programmes should be beneficial for the attainment of the elimination goals of the regional initiative. However, the possibility that the results also reflect transmission patterns for the area cannot be excluded and these should be analyzed further

Laparoscopic cholecystectomy and common bile duct exploration using choledochotomy and primary closure following failed endoscopic retrograde cholangiopancreatography: A multicentric comparative study using three-port vs multiport

Background: Laparoscopic surgery has changed many ways in which we as surgeons manage patients, offering better results, quicker recovery, and fewer complications using minimally invasive techniques, especially in common bile duct (CBD) surgery. Not only can laparoscopic techniques be applied to programed surgery but also emergencies and those following failed endoscopic retrograde cholangiopancreatography (ERCP). Objectives and aims: Describe and compare clinical and surgical results of the laparoscopic CBD exploration with primary closure using a 3-port vs multiport approach. Materials and methods: We present a multicentric comparative study of 197 consecutive patients who underwent a laparoscopic gallbladder removal along with CBD exploration with primary closure following failed (ERCP to extract CBD stones; 104 patients were managed by three-port vs 93 multiport laparoscopic surgery in five centers of Bogotá, Colombia, between 2013 and 2017 with follow-up of 1 year. Results: A total of 197 patients were taken to laparoscopic gallbladder removal along with CBD exploration with primary closure, 104 patients via three-port technique and 93 patients via multiport. All (100%) the patients had previously failed ERCP. The average surgical time on the three-port approach was 106 minutes vs 123 minutes on multiport. Only in the multiport technique we had an average conversion of 2%. Mean hospital stay of 2.5 days, less for the three-port approach vs multiport in 5–7 days. There was a need of reintervention in 1% of the patients who underwent three-port exploration. Conclusion: Postoperative pain, use of an additional port, complication rates, operation time, and cost of the three-port technique were similar to those of the conventional approach. Large randomized controlled trials are needed to examine the true benefits of the three-port technique

Inferencia Automática de Dependencias Inter-Parámetro en APIs REST

La generación automática de casos de prueba para APIs REST es un tema de investigación muy activo. La mayoría de técnicas emplean un enfoque de caja negra basado en la generación aleatoria de peticiones a partir de la especificación de la API. Dichas técnicas tienen una limitación importante: ignoran las dependencias entre parámetros. Como resultado, la mayoría de peticiones viola alguna dependencia y son rechazadas por la API. En este artículo, proponemos inferir automáticamente dichas dependencias únicamente a partir de la especificación de la API y sus entradas y salidas. Nuestra técnica aprende a medida que genera casos de prueba, de forma que el porcentaje de llamadas válidas aumenta progresivamente hasta alcanzar una precisión del 90+ACU en APIs comerciales como GitHub o YouTube. Estos prometedores resultados sugieren que nuestra propuesta podría mejorar significativamente la generación automática de casos de prueba para APIs RES

The Chimalapas Region, Oaxaca, Mexico: a high-priority region for bird conservation in Mesoamerica

The Chimalapas region, in eastern Oaxaca, Mexico, holds lowland rainforests, tropical dry forests, and cloud forests typical of the Neotropics, as well as montane pine and pine-oak forests more typical of the Nearctic. Totaling more than 600,000 ha, much of the region is forested, and in a good state of preservation. The Chimalapas avifauna is by far the most diverse for any region of comparable size in the country, totalling at least 464 species in the region as a whole (with more than 300 species in the lowland rainforest) representing 44% of the bird species known from Mexico. Within the region, the humid Atlantic lowlands hold 317 species, the montane regions 113 species, and the southern dry forested lowlands 216 species. Important species present in the region include Harpy Eagle Harpia harpyja and several other large eagles, Black Penelopina nigra and probably Horned Oreophasis derbianus Guans, Scarlet Macaw Ara macao, Cinnamon-tailed Sparrow Aimophila sumichrasti, Rose-bellied Bunting Passerina rositae, and Resplendent Quetzal Pharomachrus mocinno. The area holds immense lowland rainforests and cloud forests that rank among the largest and best preserved in all of Mesoamerica, including a complete lowland-to-highland continuum, with entire watersheds preserved more or less intact

Intracoronary ultrasound assessment of directional coronary atherectomy: Immediate and follow-up findings

AbstractObjectives. This study was conducted to assess the relations among intracoronary ultrasound, angiographic and histologic data obtained from patients with coronary artery disease successfully treated by directional coronary atherectomy. In addition, it was designed to elucidate whether some aspects of intravascular ultrasound or pathologic findings could predict a propensity to restenosis.Background. Intracoronary ultrasound is a useful technique in guiding and assessing atherectomy. However, there is little information about the characterization of the different types of coronary plaques and the changes observed in them after resection. Furthermore, the follow-up ultrasound appearance of previously treated lesions remains undepicted.Methods. Fifty-two patients (54 ± 10 years old) were studied. All were successfully treated by atherectomy with the aid of intracoronary ultrasound guidance. Qualitative and quantitative ultrasound and angiographic variables were derived before and after resection. Quantitative histologic morphometric information was also obtained from the specimens. In 22 patients, a follow-up echoangiographic reevaluation was performed 6 ± 4 months later.Results. Echogenic plaques had a higher collagen and calcium content, whereas echolucent plaques had an increased level of fibrin, nuclel and lipids. Ultrasound plaque reduction after atherectomy was greater in echolucent (76 ± 21%) than in echogenic plaques (60 ± 18%; p < 0.05). That reduction correlated with the weight of the resected material (r = 0.62; p < 0.01). At follow-up study, 13 of 22 patients had angiographic and ultrasound evidence of restenosis. Most recurrent lesions had a stenotic three-layer appearance. The incidence of restenosis of primary lesions treated with atherectomy was higher in echolucent (100%) than in echogenic (33%) plaques. Similarly, a higher proportion of nuclear content in the resected material was observed in patients who developed restenosis (2.1 ± 0.7%) than in patients who had late success after atherectomy (1.2 ± 0.6%).Conclusions. Our findings suggest that echolucent plaques are easier to resect than are echogenic plaques but frequently develop restenosis. In contrast, the resection of echogenic plaques, although often incomplete, is associated with better long-term results

Biliogastrointestinal reconstruction with duodenectomy and pancreas preservation by laparoscopy after open failed coledocoduodenostomy

Las lesiones de la vía biliar y las reconstrucciones biliodigestivas son un reto quirúrgico para el cirujano, además de una situación que exige su máxima habilidad y conocimiento. Presentamos el caso de un paciente con una reconstrucción biliodigestiva por una lesión de vía biliar abierta la cual fue fallida. Se decide llevar a reconstrucción biliodigestiva por laparoscopia, con preservación del páncreas, en un asa con hepatoyeyunostomía y gastroyeyunostomía. Este caso ilustra la posibilidad del manejo con cirugía mínimamente invasiva incluso en los casos más graves; sin embargo, se requiere alta experticia al momento de abordarlo.Bile duct injury and bile duct reconstruction are a surgical challenge for the surgeon, in addition to a situation that demands maximum skill and knowledge. We present a case of a patient with a biliodigestive reconstruction due to an open bile duct injury which was failed, it was decided to take a biliodigestive reconstruction by laparoscopy, with preservation of the pancreas, with hepaticoyejunostomy and gastroyejunostomy. This case illustrates the possibility of handling with minimally invasive surgery even in the most severe cases, however, they require high expertise when addressing it

Computer Vision and Metrics Learning for Hypothesis Testing: An Application of Q-Q Plot for Normality Test

This paper proposes a new procedure to construct test statistics for hypothesis testing by computer vision and metrics learning. The application highlighted in this paper is applying computer vision on Q-Q plot to construct a new test statistic for normality test. Traditionally, there are two families of approaches for verifying the probability distribution of a random variable. Researchers either subjectively assess the Q-Q plot or objectively use a mathematical formula, such as Kolmogorov-Smirnov test, to formally conduct a normality test. Graphical assessment by human beings is not rigorous whereas normality test statistics may not be accurate enough when the uniformly most powerful test does not exist. It may take tens of years for statistician to develop a new and more powerful test statistic. The first step of the proposed method is to apply computer vision techniques, such as pre-trained ResNet, to convert a Q-Q plot into a numerical vector. Next step is to apply metric learning to find an appropriate distance function between a Q-Q plot and the centroid of all Q-Q plots under the null hypothesis, which assumes the target variable is normally distributed. This distance metric is the new test statistic for normality test. Our experimentation results show that the machine-learning-based test statistics can outperform traditional normality tests in all cases, particularly when the sample size is small. This study provides convincing evidence that the proposed method could objectively create a powerful test statistic based on Q-Q plots and this method could be modified to construct many more powerful test statistics for other applications in the future

Pranlukast Antagonizes CD49f and Reduces Sternness in Triple-Negative Breast Cancer Cells

Introduction: Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. Materials and Methods: We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clini-cally tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. Results: Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces con-formational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transacti-vation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. Conclusion: Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients