QUANTITATIVE STRUCTURE–PHARMACOKINETICS MODELING OF THE UNBOUND CLEARANCE FOR NEUTRAL DRUGS

Objective: Prediction of pharmacokinetic behaviour of new candidate drugs is an important step in drug design. Clearance is a key pharmacokinetic parameter, controlling drug exposure in the body. It depends on numerous factors and is frequently restricted by plasma protein binding. The study is focused on the development of quantitative structure-pharmacokinetic relationship (QSPkR) for the unbound clearance (CLu) of neutral drugs.Methods: The dataset consisted of 117 neutral drugs, divided into training set (n = 94) and external test set (n = 23). Chemical structures were encoded by 113 theoretical descriptors. Genetic algorithm and step-wise multiple linear regression were applied for model development. The model was evaluated by cross-validation in the training set and external test set.Results: Significant, predictive and interpretable QSPkR model was developed with explained variance r2 = 0.617, cross-validated correlation coefficient q2LOO-CV = 0.554, external test set predictive coefficient r2pred = 0.656, and root mean square error in prediction RMSEP = 1.89. The model was able to predict CLu for 56% of the drugs in the external test set within the 2-fold error of experimental values.Conclusion: The model reveals the main molecular features governing CLu of neutral drugs. CLu is favoured by lipophilicity, the presence of fused aromatic rings, ester groups, dihydropyridine moieties and nine-member ring systems, while polarity, molecular size and strong electron withdrawing atoms and groups as substituents in aromatic rings affect negatively C

Some examples of utilization of fruit and vegetable waste

Generating an increasing amount of waste from different spheres of anthropogenic activity, including fruit and vegetable production and processing, poses questions about their management, minimizing and seeking ways to harvest them. Based on the analysis, systematization and aggregation of information from various scientific publications, the main directions in the treatment and utilization of waste products from fruits and vegetables could be the production of biofuels, soil fertilizers and improvers, use in animal feed, extraction of various valuable components. The purpose of this paper is to present some examples of the possibilities for utilization of fruit and vegetable waste. Efficient use of fruit and vegetable waste can be achieved by developing an integrated methodology for managing them through joint implementation of different approaches and strategies

QUANTITATIVE STRUCTURE–PHARMACOKINETICS RELATIONSHIP FOR PLASMA PROTEIN BINDING OF NEUTRAL DRUGS

Objective: Plasma protein binding (PPB) of drugs is important pharmacokinetic (PK) phenomena controlling the free drug concentration in plasma and the overall PK and pharmacodynamic profile. Prediction of PPB at the very early stages of drug development process is of paramount importance for the success of new drug candidates. The study presents a quantitative structure–pharmacokinetics relationship (QSPkR) modelling of PPB for neutral drugs.Methods: The dataset consists of 117 compounds, described by 138 molecular descriptors. Genetic algorithm and stepwise multiple linear regression are used for variable selection and QSPkR models development. The QSPkRs are evaluated by internal and external validation procedures.Results: A robust, significant and predictive QSPkR with explained variance r2 0.768, cross-validated q2LOO-CV 0.731,and geometric mean fold error of prediction (GMFEP) 1.79 is generated, which is able to predict the extent of PPB for 67.6% of the drugs in the dataset within the 2-fold error of experimental values. A simple empiric rule is proposed for distinguishing between drugs with different binding affinity, which allowed correct classification of 78% of the high binders and 87.5% of the low binders.Conclusions: PPB of neutral drugs is favored by lipophilicity, dipole moment, the presence of substituted aromatic and fused rings and a nine-member ring system, and is disfavored by the presence of aromatic N-atoms. Keywords: Plasma protein binding (PPB), Quantitative structure–pharmacokinetics relationship (QSPkR), In silico prediction, Human serum albumin (HSA), Alpha-1-acid glycoprotein (AGP)

Modular wireless networks for infrastructure-challenged environments

While access to Internet and cellular connectivity is easily achieved in densely-populated areas, provisioning of communication services is much more challenging in remote rural areas. At the same time Internet access is of critical importance to residents of such rural communities. People's curiosity and realization of the opportunities provided by Internet and cellular access is the key ingredient to adoption. However, poor network performance can easily impede the process of adoption by discouraging people to access and use connectivity. With this in mind, we evaluate performance and adoption of various connectivity technologies in rural developing regions and identify avenues that need immediate attention to guarantee smoother technology adoption. In light of this analysis we propose novel system designs that meet these needs. In this thesis we focus on cellular and broadband Internet connectivity. Commercial cellular networks are highly centralized, which requires costly backhaul. This, coupled with high price for equipment, maintenance and licensing renders cellular network access commercially-infeasible in rural areas. At the same time rural cellular communications are highly local: 70% of the rural-residential calls have an originator-destination pair within the same antenna. In line with this observation we design a low-cost cellular network architecture dubbed Kwiizya, to provide local voice and text messaging services in a rural community. Where outbound connectivity is available, Kwiizya can provide global services. While commercial networks are becoming more available in rural areas they are often out of financial reach of rural residents. Furthermore, these networks typically provide only basic voice and SMS services and no mobile data. To address these challenges, our proposed work allows Kwiizya to operate in coexistence with commercial cellular networks in order to extend local coverage and provide more advanced services that are not delivered by the commercial networks. Internet connectivity in rural areas is typically provided through slow satellite links. The challenges in performance and adoption of such networks have been previously studied. We add a unique dataset and consequent analysis to this spectrum of work, which captures the upgrade of the gateway connectivity in the rural community of Macha, Zambia from a 256kbps satellite link to a more capable 2Mbps terrestrial link. We show that the improvement in performance and user experience is not necessarily proportional to the bandwidth increase. While this increase improved the network usability, it also opened opportunities for adoption of more demanding services that were previously out of reach. As a result the network performance was severely degraded over the long term. To address these challenges we employ white space communication both for connectivity to more capable remote gateways, as well as for end user connectivity. We develop VillageLink, a distributed method that optimizes channel allocation to maximize throughput and enables both remote gateway access as well as end user coverage. While VillageLink features lightweight channel probing, we also consider external sources of channel availability. We design a novel approach for estimation of channel occupancy called TxMiner, which is capable of extracting transmitter characteristics from raw spectrum measurements. We study the adoption and implications of network connectivity in rural communities. In line with the results of our analyses we design and build system architectures that are geared to meet critical needs in these communities. While the focus of analysis in this thesis is on rural sub-Saharan Africa, the proposed designs and system implementations are more general and can serve in infrastructure-challenged communities across the world

Diseño de app móvil para trabajar regulación emocional en jóvenes de 14 a 18 años

La Regulación Emocional es un factor clave para la prevención de los trastornos psicológicos, sobre todo durante la etapa adolescente, que es donde las estrategias se consolidan y donde más riesgo de desarrollo existe. Las investigaciones realizadas hasta el momento sugieren que la desregulación afecta negativamente a la salud física y mental, y con ello a la calidad de vida. Al mismo tiempo, también puede repercutir de forma negativa al rendimiento académico. Debido a estas consecuencias, el presente trabajo considera la Regulación Emocional como un tratamiento transdiagnóstico y propone diseñar una aplicación móvil gratuita e interactiva siguiendo el modelo ADDIE para mejorar las habilidades de Regulación Emocional en la población juvenil. Se llama ‘‘Better Emotion’’ e incluye 8 módulos, los cuales están compuestos por psicoeducación y actividades prácticas. El tratamiento es individual y personalizado, ya que, pueden distinguirse tres inicios diferentes. Las fases incluidas son: Evaluación Inicial, Tratamiento, Evaluación Final y Seguimiento. Para motivar al alumno se le refuerza positivamente mediante un sistema de obtención de puntos que se puede canjear por personalizaciones del avatar. El pronóstico esperado es muy positivo, ya que, el formato es actual y permite ofrecer un tratamiento rápido, completo y aplicable a múltiples individuos al mismo tiempo. No obstante, es importante tener en cuenta los límites éticos y comprender que la APP es una ayuda complementaria al tratamiento psicológico, no una sustitución de éste.Emotional Regulation is a key factor for preventing psychological disorders, especially during adolescence, which is where strategies are consolidated and where the risk of development is higher. Research so far suggests that dysregulation negatively affects physical and mental health, thus impacting the quality of life. At the same time, it can also have a negative impact on academic performance. Due to these consequences, the present work considers Emotional Regulation as a transdiagnostic treatment and proposes the design of a free and interactive mobile application following the ADDIE model to improve Emotional Regulation skills in the youth population. It is called ‘‘Better Emotion’’ and includes 8 modules, which consist of psychoeducation and practical activities. The treatment is individual and personalized, since three different starting points can be distinguished. The phases included are: Initial Evaluation, Treatment, Final Evaluation and Follow-up. To motivate the student, positive reinforcement is provided through a point-based system that can be exchanged for avatar customizations. The expected prognosis is very positive because the chosen format is recent and allows a fast, complete, and multiple applicable treatment. However, it is important to consider ethical limits and understand the App as a complementary aid to psychological treatment, not a replacement.Psicologí

ZN(II)/AU(I) AND ZN(II)/AG(I) COMPLEXES WITH SALEN SCHIFF BASE EXPRESS PROMISING CYTOTOXIC ACTIVITY IN HUMAN CANCER CELLS

Objective: The aim of our study was to evaluate the influence of two complexes of Zn(II)/Au(I) and Zn(II)/Ag(I) with Schiff base ligand (H2Salen) obtained from the condensation reaction between salicylaldehyde and ethylenediamine (abbreviated ZnSalenAu, ZnSalenAg) on viability and proliferation of cultured human cancer cells.Methods: The following cell lines were used as model systems: Human cervical carcinoma (cervical carcinoma), A549 (non-small cell lung cancer [NSCLC]), glioblastoma multiforme (8MGBA), and A431 (squamous cell carcinoma) and its multidrug-resistant (MDR) clones A431-MDR, A431-MRP, and A431-ABCG2 that express mdr1, mrp1, or abcg2 gene, respectively. The investigations were performed by thiazolyl blue tetrazolium bromide test, neutral red uptake cytotoxicity assay, crystal violet staining, hematoxylin and eosin staining, double staining with acridine orange, and propidium iodide in short-term experiments (12–72 h, with monolayer cell cultures) as well as colony-forming method in long-term experiments (25 days, with three dimensional cancer cell colonies).Results: The results obtained revealed that ZnSalenAu and ZnSalenAg decreased significantly viability and proliferation of the treated cells in a time- and concentration-dependent manner being more active as compared to the free ligand H2Salen.Conclusion: The present study demonstrates for the 1st time the ability of two heterometallic complexes ZnSalenAu and ZnSalenAg to decrease significantly viability and proliferation of cultured cell lines established from some of the most common and aggressive human cancers (NSCLC, carcinoma of uterine cancer, 8MGBA, and squamous cell carcinoma) as well as MDR cancer cells

Integrating Third-party Services Using Brokers in the Serious Games’ Domain

In this paper we demonstrate how to integrate 3rd party services in serious games. We use message queue broker and micro-services in a publish/subscribe manner in order to use real-time 3rd party data into a serious game’s logic. First, we discuss the benefits of service oriented architecture. Then, we analyse and compare different message queues brokers in terms of data latency, throughput, fail-tolerance and scalability for the purpose of serious games. As a sequence, we apply those best practices from other domains in the field of Serious Games (SGs). Finally, we summarize the presented ideas and comparisons and draw conclusions