Machine Learning Methodologies for Interpretable Compound Activity Predictions

Machine learning (ML) models have gained attention for mining the pharmaceutical data that are currently generated at unprecedented rates and potentially accelerate the discovery of new drugs. The advent of deep learning (DL) has also raised expectations in pharmaceutical research. A central task in drug discovery is the initial search of compounds with desired biological activity. ML algorithms are able to find patterns in compound structures that are related to bioactivity, the so-called structure-activity relationships (SARs). ML-based predictions can complement biological testing to prioritize further experiments. Moreover, insights into model decisions are highly desired for further validation and identification of activity-relevant substructures. However, the interpretation of complex ML models remains essentially prohibitive. This thesis focuses on ML-based predictions of compound activity against multiple biological targets. Single-target and multi-target models are generated for relevant tasks including the prediction of profiling matrices from screening data and the discrimination between weak and strong inhibitors for more than a hundred kinases. Moreover, the relative performance of distinct modeling strategies is systematically analyzed under varying training conditions, and practical guidelines are reported. Since explainable model decisions are a clear requirement for the utility of ML bioactivity models in pharmaceutical research, methods for the interpretation and intuitive visualization of activity predictions from any ML or DL model are introduced. Taken together, this dissertation presents contributions that advance in the application and rationalization of ML models for biological activity and SAR predictions

Support Vector Machine Classification and Regression Prioritize Different Structural Features for Binary Compound Activity and Potency Value Prediction

In computational chemistry and chemoinformatics, the support vector machine (SVM) algorithm is among the most widely used machine learning methods for the identification of new active compounds. In addition, support vector regression (SVR) has become a preferred approach for modeling nonlinear structure−activity relationships and predicting compound potency values. For the closely related SVM and SVR methods, fingerprints (i.e., bit string or feature set representations of chemical structure and properties) are generally preferred descriptors. Herein, we have compared SVM and SVR calculations for the same compound data sets to evaluate which features are responsible for predictions. On the basis of systematic feature weight analysis, rather surprising results were obtained. Fingerprint features were frequently identified that contributed differently to the corresponding SVM and SVR models. The overlap between feature sets determining the predictive performance of SVM and SVR was only very small. Furthermore, features were identified that had opposite effects on SVM and SVR predictions. Feature weight analysis in combination with feature mapping made it also possible to interpret individual predictions, thus balancing the black box character of SVM/SVR modeling

The influence of in vitro gastrointestinal digestion on the chemical composition and antioxidant and enzyme inhibitory capacities of carob liqueurs obtained with different elaboration techniques

Carob liqueur is a traditional Mediterranean alcoholic beverage obtained via a wide range of production techniques contributing to the different organoleptic attributes of the final product. The aim of this research was to evaluate the stability of the chemical composition and biological capacities (antioxidant and enzyme inhibition) under in vitro simulated gastrointestinal digestion of liqueurs prepared by flavouring the fig spirit with carob pulp by maceration, distillation, percolation, or aqueous and hydro-alcoholic infusions. For this purpose, the phenolic and furanic compositions, the total phenolic (TPC) and flavonoid (TFC) contents, antioxidant capacity (AC), and enzyme inhibitory potential against acethylcholinesterase, tyrosinase, α-glucosidase and α-amylase enzymes were evaluated. The content of gallic acid decreased after gastrointestinal digestion, while TPC, TFC, and AC significantly increased after each digestion phase. Overall, no significantly different enzyme inhibitions (p < 0.05) were observed among digested liqueurs, with moderate inhibition against acethylcholinesterase and tyrosinase (enzymes related with neurodegenerative diseases), and potent and low inhibitory capacities for α-glucosidase and α-amylase, respectively (ideal conditions employed in antidiabetic therapy). The study indicates that hydro-alcoholic infusion and maceration were the most appropriate methods to obtain liqueurs with higher values of the aforementioned parameters and safe levels of toxic furanics.Fundação para a Ciência e a Tecnologia, I.P.: SFRH/BPD/103086/2014; DL 57/2016/CP1361/CT0022; project INTERREG-MD.NET: When Brand Meets Peopleinfo:eu-repo/semantics/publishedVersio

Modeling the heat transfer by conduction of nanocellular polymers with bimodal cellular structures

Nanocellular polymers are a new generation of materials with the potential of being used as very efficient thermal insulators. It has been proved experimentally that these materials present the Knudsen effect, which strongly reduces the conductivity of the gas phase. There are theoretical equations to predict the thermal conductivity due to this Knudsen effect, but all the models consider an average cell size. In this work, we propose a model to predict the thermal conductivity due to the conduction mechanisms of nanocellular materials with bimodal cellular structures, that is, with two populations of cells, micro and nanocellular. The novelty of our work is to consider not only the average cell size, but the cell size distribution. The predictions of the model are compared with the experimental conductivity of two real bimodal systems based on poly(methyl methacrylate) (PMMA), and it is proved that this new model provides more accurate estimations of the conductivity than the models that do not consider the bimodality. Furthermore, this model could be applied to monomodal nanocellular polymers. In particular, for monomodal materials presenting a wide cell size distribution and at low densities, the model predicts important variations in comparison with the current models in the literature. This result indicates that the cell size distribution must be included in the estimations of the thermal conductivity of nanocellular polymer

Immediate Effects of Whole-Body versus Local Dynamic Electrostimulation of the Abdominal Muscles in Healthy People Assessed by Ultrasound: A Randomized Controlled Trial

Dynamic electrostimulation consists of the application of local or global electrostimulation together with physical exercise. This study aimed to investigate the immediate effects of a dynamic electrostimulation session on the thickness of the abdominal musculature, inter-rectus distance, heart rate, blood pressure, and body temperature, and to identify possible differences in its form of application. A total of 120 healthy participants were divided into three groups: the whole-body electrostimulation group, the local electrostimulation group, and the control group without electrical stimulation. All groups performed a single session with the same dynamic exercise protocol. Muscle thickness and inter-rectus distance were evaluated ultrasonographically using the Rehabilitative Ultrasound Imaging technique both at rest and in muscle contraction (the active straight leg raise test) to find the post-intervention differences. The results showed significant differences in immediate post-intervention heart rate, with a smaller increase in the local electrostimulation group compared to the control and whole-body electrostimulation groups. No significant differences were identified between the groups after the interventions in the rest of the variables analyzed. Therefore, a local application, with the same effects as a global application on the abdominal musculature, has fewer contraindications, which makes its use more advisable, especially in populations with cardiorespiratory disorders, for which more research is needed.Sección Deptal. de Radiología, Rehabilitación y Fisioterapia (Enfermería)Fac. de Enfermería, Fisioterapia y PodologíaTRUEProfessional College of Physiotherapists of Castilla y León (Spain).pu

La edición facsímil digital en la biblioteca virtual Miguel de Cervantes

La edición digital facsímil es una de las secciones de la Biblioteca Virtual Miguel de Cervantes, un proyecto nacido en la Universidad de Alicante en 1999. Desde esta sección tratamos de recuperar textos impresos y manuscritos de difícil acceso. Asimismo nuestra intención es aprovechar las nuevas tecnologías para dar una mayor difusión a este tipo de fondos, así como contribuir a su preservación. Como podremos comprobar, el área de edición digital trata de ofrecer ediciones cuidadas, con unos índices desglosados de los contenidos, además de una serie de herramientas muy útiles al investigador, como son los enlaces cruzados. En este artículo veremos los originales de los que partimos (originales, microfilms, ediciones facsímiles, diapositivas...), los medios aplicados para la obtención de las imágenes digitales, cuál es el resultado en Internet, las soluciones adoptadas para conseguir una mayor accesibilidad, las ventajas de este tipo de edición y sus aplicaciones didácticas.The facsimile digital edition is one of the departments in the Miguel de Cervantes Digital Library. This project was born in the University of Alicante in 1999. From this department we try to recover printed texts and manuscripts which have a difficult access. Also our intention is to take the advantage of the new technologies to give a great spreading of this kind of works, as well as to contribute to their preservation. As we can check, the digital edition department tries to offer cared editions, with index of contents, as well as very useful tools for the researchers, as crossing links. In this article we will see all kind of originals we use (original books or manuscripts, microfilms, facsimile editions, slides...), the used ways to get the digital pictures, the outcome in Internet, the chosen solutions for getting a better accesibility, the advantages of this kind of edition and the didactic applications

Fine tuning and validation of an analytical method for determinating heavy metals in food samples by ICP-MS technique

Heavy metals are chemical elements with high density that can be toxic for humans. For that reason consumer and human nutrition agencies have established maximum limits of heavy metals in food. In order to quantify heavy metals, analytical techniques must have low detection limits and high precision and accuracy. In this sense, inductively coupled plasma mass (ICP-MS) is an attractive method as is a multielemental analytical technique wich is able to detect metals and non-metals at concentrations of ppb. The aim of this work is to tune up and validate a method for determining heavy metals (lead, mercury and cadmium) in food by ICP-MS.ICP-MS used was an ICP Mass Spectrometer ELAN DRC-e Axial Field Technology (Perkin Elmer SCIEX, Waltham). This equipment had a cooler recirculator PolyScience (Nile) coupled and a S10 autosampler (Perkin Elmer, Waltham). Operating conditions were Nebulizer gas flow: 0.87, Plasma flow: 15.00, lens voltage: 6.00, ICP radio frequency generator: 1100. Food samples were homogenized with a mixer and digested with a Digi-Prep 50/24 digestor with HNO3:HCl 6:1.In order to tune up the method, calibrating method was studied in the matrices to be analyzed. Linearity was also studied, designing calibration curves and adjusting them by instrumental calibration technique ICP-MS requires. In the same way, the response factor, the relation between the signal of the internal standard and each standard of calibration curve, deviations of parameters of the equation and residuals were done. Once the method was tuned up, validation tests were performed; detection and quantification limits were determined, and recovery of interferences correction, tests of precision and accuracy, uncertainty estimation and definition of criteria for acceptance and rejection were carried out.This study allowed the tuning and establishment of different criteria to give an appropriate measure method, which was validated in order to calculate precision and accuracy of the analytical technique. Which is more, it was possible to verify that the interfering selenium, tin and molybdenum were properly corrected

Microwave-Assisted Pillaring of a Montmorillonite with Al-Polycations in Concentrated Media

[EN]A montmorillonite has been intercalated with Al3+ polycations, using concentrated solutions and clay mineral dispersions. The reaction has been assisted by microwave radiation, yielding new intercalated solids and leading to Al-pillared solids after their calcination at 500 C. The solids were characterized by elemental chemical analysis, X-ray diffraction, FTIR spectroscopy, thermal analyses, and nitrogen adsorption. The evolution of the properties of the materials was discussed as a function of the preparation conditions. Microwave treatment for 2.5 min provided correctly pillared solids

Optimal reinsurance under risk and uncertainty

This paper deals with the optimal reinsurance problem if both insurer and reinsurer are facing risk and uncertainty, though the classical uncertainty free case is also included. The insurer and reinsurer degrees of uncertainty do not have to be identical. The decision variable is not the retained (or ceded) risk, but its sensitivity with respect to the total claims. Thus, if one imposes strictly positive lower bounds for this variable, the reinsurer moral hazard is totally eliminated. Three main contributions seem to be reached. Firstly, necessary and sufficient opti- mality conditions are given. Secondly, the optimal contract is often a bang-bang solution, i:e:, the sensitivity between the retained risk and the total claims saturates the imposed constraints. For some special cases the optimal contract might not be bang-bang, but there is always a bang-bang contract as close as desired to the optimal one. Thirdly, the optimal reinsurance problem is equivalent to other linear programming problem, despite the fact that risk, uncertainty, and many premium principles are not linear. This may be impor- tant because linear problems are easy to solve in practice, since there are very efficient algorithms

Caracterización clínica y epidemiológica de neumonías adquiridas en la comunidad.hospital Dr Israel Ranuarez Balza”, Guárico. 2009–2010.

The community-acquired pneumonia are those infections developed lung parenchyma within the general population. In the World is one of the most frequent causes of medical care, a current estimated incidence in the adult population of 2-10 year 1,000 population cases. That is why this research, which aims to characterize clinically and epidemiologically to community-acquired pneumonia arises. "Dr. Israel Ranuarez Balza "State Guárico. 2009-2010. An observational, descriptive, cross-sectional study where 138 stories, of which he took only included in the study 77 was used in the investigation, which had discharge diagnosis of pneumonia acquired in the community who had the inclusion criteria . The data were processed using the statistical package SPSS version 13.0. Obtained as important findings that is more common community-acquired pneumonia in males (63.64%) and in the age group of 25-44 years (40.26%), the most relevant findings are respiratory rate ≥ 20 rpm (78%), leukocytes ≥ 11,000 mm3 (60%), creatinine ≥ 1,2mgs / dl (44%), the most common radiologic localization are infiltrates in the lower lobes (48%) and multiple foci (26%)&nbsp;&nbsp;&nbsp;&nbsp; La neumonía adquirida en la comunidad son aquellas infecciones de parénquima pulmonar desarrolladas en el seno de la población general. En el Mundo constituyen una de las causas más frecuentes de atención médica, estimándose una incidencia actual, en la población adulta, de 2 a 10 casos /1.000 habitantes año. Es por ello que surge esta investigación, que tiene como propósito caracterizar clínica y epidemiológicamente a las neumonías adquiridas en la comunidad. Hospital “Dr. Israel Ranuarez Balza”, Estado Guárico.&nbsp; 2009–2010. En la investigación se utilizó un&nbsp; estudio observacional, descriptivo, de corte transversal, donde se tomó 138 historias, de las cuales sólo se incluyeron en el estudio 77, las cuales tenían diagnóstico de egreso de neumonía adquirida en la comunidad que poseían los criterios de inclusión. Los datos se procesaron a través del paquete estadístico SPSS versión 13.0. Se obtuvo como hallazgos importantes que es más frecuente la Neumonía adquirida en la Comunidad en el género masculino (63,64%) y en el grupo etario de 25-44 años (40,26%), los hallazgos más relevantes son la frecuencia respiratoria ≥ 20 rpm (78%), los leucocitos ≥ 11.000 mm3 (60%), la creatinina ≥ 1,2mgs/dl (44%), la localización radiológica más común son los infiltrados en&nbsp; lóbulos inferiores (48%) y&nbsp; múltiples focos (26%)