The reliability of a QSAR classification model depends on its capacity to achieve confident predictions of new compounds not considered in the building of the model. The results of this external ...validation process show the applicability domain (AD) of the QSAR model and, therefore, the robustness of the model to predict the property/activity of new molecules. In this paper we propose the use of the rivality and modelability indexes for the study of the characteristics of the datasets to be correctly modeled by a QSAR algorithm and to predict the reliability of the built model to prognosticate the property/activity of new molecules. The calculation of these indexes has a very low computational cost, not requiring the building of a model, thus being good tools for the analysis of the datasets in the first stages of the building of QSAR classification models. In our study, we have selected two benchmark datasets with similar number of molecules but with very different modelability and we have corroborated the capacity of the predictability of the rivality and modelability indexes regarding the classification models built using Support Vector Machine and Random Forest algorithms with 5-fold cross-validation and leave-one-out techniques. The results have shown the excellent ability of both indexes to predict outliers and the applicability domain of the QSAR classification models. In all cases, these values accurately predicted the statistic parameters of the QSAR models generated by the algorithms.
The current social impact of new technologies has produced major changes in all areas of society, creating the concept of a smart city supported by an electronic infrastructure, telecommunications ...and information technology. This paper presents a review of Bluetooth Low Energy (BLE), Near Field Communication (NFC) and Visible Light Communication (VLC) and their use and influence within different areas of the development of the smart city. The document also presents a review of Big Data Solutions for the management of information and the extraction of knowledge in an environment where things are connected by an "Internet of Things" (IoT) network. Lastly, we present how these technologies can be combined together to benefit the development of the smart city.
This research aims to provide information about changes that may occur on the strategies declared to solve oral production problems by future teachers of English as a foreign language in Primary ...Education according to Nakatani's Inventory of Oral Communication Strategies (2006). The participants are students of English Teaching, these belong to the University of Granada (UGR), the University of Malaga (UMA) and the María Inmaculada de Antequera (Málaga) Associated Teaching Center (CAMMIA). The data was taken in two stages or moments, at the beginning of the Mention of English and at the end of it. In this research, a descriptive study is carried out for the initial phase, since the number of volunteer participants was greater than in the final sample. For the final sample, the results were statistically analyzed and compared. Only in strategies number 3 and 5 some significant changes take place. There have also been changes in the other types of strategies, although no significant changes have been obtained. It could be concluded that perhaps a specific instruction during the Mention would have contributed to the greater differences between the use of this type of strategies between the moment the Mention began and the moment it ended.
Splicing alterations represent an actionable cancer hallmark. Splicing factor 3B subunit 1 (SF3B1) is a crucial splicing factor that can be targeted pharmacologically (e.g. pladienolide-B). Here, we ...show that SF3B1 is overexpressed (RNA/protein) in hepatocellular carcinoma (HCC) in two retrospective (n = 154 and n = 172 samples) and in five in silico cohorts (n > 900 samples, including TCGA) and that its expression is associated with tumor aggressiveness, oncogenic splicing variants expression (KLF6-SV1, BCL-XL) and decreased overall survival. In vitro, SF3B1 silencing reduced cell viability, proliferation and migration and its pharmacological blockade with pladienolide-B inhibited proliferation, migration, and formation of tumorspheres and colonies in liver cancer cell lines (HepG2, Hep3B, SNU-387), whereas its effects on normal-like hepatocyte-derived THLE-2 proliferation were negligible. Pladienolide-B also reduced the in vivo growth and the expression of tumor-markers in Hep3B-induced xenograft tumors. Moreover, SF3B1 silencing and/or blockade markedly modulated the activation of key signaling pathways (PDK1, GSK3b, ERK, JNK, AMPK) and the expression of cancer-associated genes (CDK4, CD24) and oncogenic SVs (KLF6-SV1). Therefore, the genetic and/or pharmacological inhibition of SF3B1 may represent a promising novel therapeutic strategy worth to be explored through randomized controlled trials.
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•The splicing factor SF3B1 is overexpressed in HCC and associated to overall survival.•Genetic silencing of SF3B1 reduces oncogenic potential of HCC cell lines.•SF3B1 pharmacological blockade with pladienolide-B exerts inhibitory effects in HCC.•SF3B1 blockade by pladienolide-B reduces tumor growth in preclinical models.•SF3B1 modulates the expression of key oncogenic splicing variants.
The Expert Consensus Guidelines initiative on MIDH for LDLT was organized with the goal of safe implementation and development of these complex techniques with donor safety as the main priority.
...Following the development of minimally invasive liver surgery, techniques of MIDH were developed with the aim of reducing the short- and long-term consequences of the procedure on liver donors. These techniques, although increasingly performed, lack clinical guidelines.
A group of 12 international MIDH experts, 1 research coordinator, and 8 junior faculty was assembled. Comprehensive literature search was made and studies classified using the SIGN method. Based on literature review and experts opinions, tentative recommendations were made by experts subgroups and submitted to the whole experts group using on-line Delphi Rounds with the goal of obtaining >90% Consensus. Pre-conference meeting formulated final recommendations that were presented during the plenary conference held in Seoul on September 7, 2019 in front of a Validation Committee composed of LDLT experts not practicing MIDH and an international audience.
Eighteen Clinical Questions were addressed resulting in 44 recommendations. All recommendations reached at least a 90% consensus among experts and were afterward endorsed by the validation committee.
The Expert Consensus on MIDH has produced a set of clinical guidelines based on available evidence and clinical expertise. These guidelines are presented for a safe implementation and development of MIDH in LDLT Centers with the goal of optimizing donor safety, donor care, and recipient outcomes.
The recognition of proline-rich sequences by protein–protein interaction modules is essential for many cellular processes. Nonetheless, in spite of the wealth of structural and functional information ...collected over the last two decades, polyproline recognition is still not well understood. The patent inconsistency between the generally accepted description of SH3 interactions, based primarily on the stacking of hydrophobic surfaces, and their markedly exothermic character is a clear illustration of the higher complexity of these systems. Here we review the structural and thermodynamic evidence revealing the need for a revision of the current binding paradigm, incomplete and clearly insufficient for a full understanding of binding affinity and specificity, to include interfacial water molecules as universal and relevant elements in polyproline recognition.
Pathogenesis-related 10 (PR-10) proteins are involved in many aspects of plant biology but their molecular function is still unclear. They are related by sequence and structural homology to mammalian ...lipid transport and plant abscisic acid receptor proteins and are predicted to have cavities for ligand binding. Recently, three new members of the PR-10 family, the Fra a proteins, have been identified in strawberry, where they are required for the activity of the flavonoid biosynthesis pathway, which is essential for the development of color and flavor in fruits. Here, we show that Fra a proteins bind natural flavonoids with different selectivity and affinities in the low μm range. The structural analysis of Fra a 1 E and a Fra a 3-catechin complex indicates that loops L3, L5, and L7 surrounding the ligand-binding cavity show significant flexibility in the apo forms but close over the ligand in the Fra a 3-catechin complex. Our findings provide mechanistic insight on the function of Fra a proteins and suggest that PR-10 proteins, which are widespread in plants, may play a role in the control of secondary metabolic pathways by binding to metabolic intermediates.
Background: Suppression of Fra a gene expression leads to down-regulation of color-producing flavonoid biosynthesis in strawberry.
Results: Fra proteins can bind natural flavonoids, which induce conformational changes in conserved loop regions.
Conclusion: Fra a proteins control flavonoid biosynthesis through binding to metabolic intermediates.
Significance: PR-10 proteins may play a role in the control of secondary metabolism through binding of metabolites to their ligand-binding cavities.
Background
Acute kidney injury (AKI) after liver transplantation (LT) is a common problem with complex management. The aims were to analyze the profile of AKI‐RIFLE categories in the post‐transplant ...setting of a wide multicentre cohort of patients in the MELD era and to specifically determine the effect of tacrolimus‐based (TACRO) immunosuppressive regimes on the development of AKI.
Methods
A retrospective analysis of 550 (2007‐2012) consecutive patients transplanted at Reina Sofia, Cordoba, and King's College Hospital, London, was performed. Inclusion criterion was to have CNI as part of initial immunosuppression immediately after LT.
Results
After exclusion criteria, a total of 477 patients were analyzed. Incidence of AKI within the first 2 weeks after LT was 65.8% (AKI‐Risk), 41.3% (AKI‐Injury), and 12.3% (AKI‐Failure). The development of any type of AKI had no impact on short‐ and/or long‐term survival up to 3 years after the transplant. Moreover, AKI was almost universal in the early post‐transplant period and TACRO trough concentrations during the first 2 weeks after the transplant were not predictors of AKI in none of its categories in the multivariate analyses.
Conclusions
Low‐TACRO‐based regimes were not as useful as expected in the prevention of AKI when analyzed in the context of a large contemporary LT series.
YAP is a WW domain-containing effector of the Hippo tumor suppressor pathway, and the object of heightened interest as a potent oncogene and stemness factor. YAP has two major isoforms that differ in ...the number of WW domains they harbor. Elucidating the degree of co-operation between these WW domains is important for a full understanding of the molecular function of YAP. We present here a detailed biophysical study of the structural stability and binding properties of the two YAP WW domains aimed at investigating the relationship between both domains in terms of structural stability and partner recognition. We have carried out a calorimetric study of the structural stability of the two YAP WW domains, both isolated and in a tandem configuration, and their interaction with a set of functionally relevant ligands derived from PTCH1 and LATS kinases. We find that the two YAP WW domains behave as independent units with different binding preferences, suggesting that the presence of the second WW domain might contribute to modulate target recognition between the two YAP isoforms. Analysis of structural models and phage-display studies indicate that electrostatic interactions play a critical role in binding specificity. Together, these results are relevant to understand of YAP function and open the door to the design of highly specific ligands of interest to delineate the functional role of each WW domain in YAP signaling.
Background
The laparoscopic approach to liver resection has experienced exponential growth in recent years; however, its application is still under debate and objective, evidence-based guidelines for ...its safe future progression are needed.
Objective
The aim of this study was to perform a systematic review and meta-analysis comparing the short- and long-term outcomes of laparoscopic and open liver resections for hepatocellular carcinoma (HCC).
Methods
To identify all the comparative manuscripts reporting on laparoscopic and open liver resection for HCC, all published English-language studies with more than 10 cases were screened. In addition to the primary meta-analysis, four specific subgroup analyses were performed on patients with Child–Pugh A cirrhosis, resections for solitary tumors, and those undergoing minor and major resections. The quality of the studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) methodology and the Newcastle–Ottawa Scale.
Results
From the initial 361 manuscripts, 28 were included in the meta-analysis. Five of these 28 manuscripts were specific to patients with Child–Pugh A cirrhosis (321 cases), 11 focused on solitary tumors (1003 cases), 16 focused on minor resections (1286 cases), and 3 focused on major resections (164 cases). Three manuscripts compared 1079 cases but could not be assigned to any of the above subanalyses. In general terms, short-term outcomes were favorable when using a laparoscopic approach, especially in minor resections. The only advantage seen with an open approach was reduced operative time during major liver resections. No differences in long-term outcomes were observed between the approaches.
Conclusions
Laparoscopic liver resection for HCC is feasible and offers improved short-term outcomes, with comparable long-term outcomes as the open approach.
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