DATA-DRIVEN ANALYTICAL MODELS FOR IDENTIFICATION AND PREDICTION OF OPPORTUNITIES AND THREATS

During the lifecycle of mega engineering projects such as: energy facilities, infrastructure projects, or data centers, executives in charge should take into account the potential opportunities and threats that could affect the execution of such projects. These opportunities and threats can arise from different domains; including for example: geopolitical, economic or financial, and can have an impact on different entities, such as, countries, cities or companies. The goal of this research is to provide a new approach to identify and predict opportunities and threats using large and diverse data sets, and ensemble Long-Short Term Memory (LSTM) neural network models to inform domain specific foresights. In addition to predicting the opportunities and threats, this research proposes new techniques to help decision-makers for deduction and reasoning purposes. The proposed models and results provide structured output to inform the executive decision-making process concerning large engineering projects (LEPs). This research proposes new techniques that not only provide reliable timeseries predictions but uncertainty quantification to help make more informed decisions. The proposed ensemble framework consists of the following components: first, processed domain knowledge is used to extract a set of entity-domain features; second, structured learning based on Dynamic Time Warping (DTW), to learn similarity between sequences and Hierarchical Clustering Analysis (HCA), is used to determine which features are relevant for a given prediction problem; and finally, an automated decision based on the input and structured learning from the DTW-HCA is used to build a training data-set which is fed into a deep LSTM neural network for time-series predictions. A set of deeper ensemble programs are proposed such as Monte Carlo Simulations and Time Label Assignment to offer a controlled setting for assessing the impact of external shocks and a temporal alert system, respectively. The developed model can be used to inform decision makers about the set of opportunities and threats that their entities and assets face as a result of being engaged in an LEP accounting for epistemic uncertainty

ABC TRANSPORTERS IN GLIOBLASTOMA: ANTICANCER DRUG TRANSPORT AND TRANSPORTER REGULATION AT THE BLOOD-BRAIN BARRIER

Glioblastoma is one of the deadliest cancers, with a median survival of only one year. Even after aggressive treatment consisting of surgical resection, radiation, and chemotherapy, most glioblastoma patients suffer from tumor recurrence within 6-9 months. One reason for treatment failure of anticancer drugs is the blood-brain barrier that protects the brain by impeding xenobiotic uptake from the blood. To this end, efflux transporters at the human blood-brain barrier, such as P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2), prevent many compounds, including anticancer drugs, from entering the brain. Thus far, approaches to deliver anticancer drugs across the blood-brain barrier have been unsuccessful in clinical trials. Therefore, novel therapeutic strategies are needed to overcome the blood-brain barrier for improved glioblastoma treatment. Here, I address this need in 3 independent aims: Elucidate the involvement and cooperation of ABC transporters in anticancer drug transport at the blood-brain barrier Establish and characterize human glioblastoma models Evaluate the impact of dual PI3K/Akt inhibition on brain uptake of anticancer drugs Aim 1: While Abcb1/Abcg2 inhibition improved survival in mouse glioblastoma models, clinical trials had to be terminated due to a lack of efficacy, sparking a discussion that other ABC transporters might be involved in this process. To discern how multiple ABC transporters cooperate in restricting anticancer drug uptake at the blood-brain barrier, I evaluated the effect of several efflux transporters at the blood-brain barrier on the brain level of anticancer drugs using transporter inhibitors or knockout mice. The results from this study suggest that Abcc4 works in concert with Abcb1/Abcg2 in restricting brain access of the tested anticancer drugs in mice. Further experiments are necessary to confirm this cooperation at the human blood-brain barrier. In part, these findings might provide one possible explanation why therapeutic strategies that solely focus on ABCB1/ABCG2 failed to improve treatment outcomes for glioblastoma patients. Aim 2: Successful treatment of glioblastoma requires reliable preclinical animal models to evaluate novel approaches and assess their potential therapeutic benefit. While many different glioblastoma models exist, most are not well characterized and only recapitulate a subset of glioblastoma characteristics. Here, I describe and compare two human glioblastoma models, U87-luc2 and U251-FLuc. While both models behave similarly in vitro, they have different in vivo tumor characteristics, such as invasiveness and blood-brain barrier disruption. Together, the two glioblastoma models recapitulate the tumor characteristics of a majority of patients. Aim 3: Direct transporter inhibition is unsuccessful in improving glioblastoma patient survival due to the low efficacy of inhibitors and adverse effects associated with combination treatment. However, efflux transporter regulation could open a “window-in-time” to allow anticancer drug uptake into the brain. Here, I tested a novel molecular switch approach to overcome Abcb1/Abcg2-mediated efflux at the blood-brain barrier. My data indicate that PI3K/Akt could serve as a molecular switch to transiently turn off Abcb1/Abcg2 at the blood-brain barrier and increase brain levels of anticancer drugs

Needles in a haystack of protein diversity: Interrogation of complex biological samples through specialized strategies in bottom-up proteomics uncover peptides of interest for diverse applications

Peptide identification is at the core of bottom-up proteomics measurements. However, even with state-of the-art mass spectrometric instrumentation, peptide level information is still lost or missing in these types of experiments. Reasons behind missing peptide identifications in bottom-up proteomics include variable peptide ionization efficiencies, ion suppression effects, as well as the occurrence of chimeric spectra that can lower the efficacy of database search strategies. Peptides derived from naturally abundant proteins in a biological system also have better chances of being identified in comparison to the ones produced from less abundant proteins, at least in regular discovery-based proteomics experiments. This dissertation focused on the recovery of the “missing or hidden proteome” information in complex biological matrices by approaching this challenge under a peptide-centric view and implementing different liquid chromatography tandem mass spectrometry (LC-MS/MS) experimental workflows. In particular, the projects presented here covered: (1) The feasibility of applying a liquid chromatography-multiple reaction monitoring MS methodology for the targeted identification of peptides serving as surrogates of protein biomarkers in environmental matrices with unknown microbial diversities; (2) the evaluation of selecting unique tryptic peptides in-silico that can distinguish groups of proteins, instead of individual proteins, for targeted proteomics workflows; (3) maximizing peptide identification in spectral data collected from different LC-MS/MS setups by applying a multi-peptide-spectrum-match algorithm, and (4) showing that LC-MS/MS combined with de novo assisted-database searches is a feasible strategy for the comprehensive identification of peptides derived from native proteolytic mechanisms in biological systems

Advanced Operation and Maintenance in Solar Plants, Wind Farms and Microgrids

This reprint presents advances in operation and maintenance in solar plants, wind farms and microgrids. This compendium of scientific articles will help clarify the current advances in this subject, so it is expected that it will please the reader

Phospholipases: From Structure to Biological Function

Phospholipases are a ubiquitous group of enzymes that hydrolyze ester bonds within membrane phospholipids. These enzymes serve multiple biological functions that go far beyond a mere membrane remodeling role in cellular homeostasis; they also play key functions in nutrient digestion and the regulated formation of bioactive lipids involved in cell signaling. It is to the latter function, critical to life, that this book is primarily concerned with. All the chapters are written by renowned experts in the area, and provide forefront information on the role phospholipases in a number of physiological and pathophysiological settings

Sustainable development under the conditions of European integration. Part II

This collective monograph offers the description of sustainable development in the condition of European integration. The authors of individual chapters have chosen such point of view for the topic which they considered as the most important and specific for their field of study using the methods of logical and semantic analysis of concepts, the method of reflection, textual reconstruction and comparative analysis. The theoretical and applied problems of sustainable development in the condition of European integration are investigated in the context of economics, education, cultural, politics and law

Factors Influencing Customer Satisfaction towards E-shopping in Malaysia

Online shopping or e-shopping has changed the world of business and quite a few people have decided to work with these features. What their primary concerns precisely and the responses from the globalisation are the competency of incorporation while doing their businesses. E-shopping has also increased substantially in Malaysia in recent years. The rapid increase in the e-commerce industry in Malaysia has created the demand to emphasize on how to increase customer satisfaction while operating in the e-retailing environment. It is very important that customers are satisfied with the website, or else, they would not return. Therefore, a crucial fact to look into is that companies must ensure that their customers are satisfied with their purchases that are really essential from the ecommerce’s point of view. With is in mind, this study aimed at investigating customer satisfaction towards e-shopping in Malaysia. A total of 400 questionnaires were distributed among students randomly selected from various public and private universities located within Klang valley area. Total 369 questionnaires were returned, out of which 341 questionnaires were found usable for further analysis. Finally, SEM was employed to test the hypotheses. This study found that customer satisfaction towards e-shopping in Malaysia is to a great extent influenced by ease of use, trust, design of the website, online security and e-service quality. Finally, recommendations and future study direction is provided. Keywords: E-shopping, Customer satisfaction, Trust, Online security, E-service quality, Malaysia

Infección aguda/reciente por el VIH-1. Características clínicas, virológicas e inmunológicas y efectos del tratamiento inmunomediado

[spa] Durante la infección por VIH se denomina infección aguda al periodo entre la infección y la seroconversión completa (aproximadamente 30 días). Aunque la mayoría de los pacientes presentan un síndrome clínico denominado “síndrome retroviral agudo” y que se compone de fiebre, cefalea, odinofagia, faringitis, adenopatías y erupción cutánea, menos del 3% de los pacientes se detecta durante este periodo. Su identificación es importante ya que desde el punto de vista representa la fase de mayor transmisión, facilita los estudios de incidencia y la vigilancia de resistencia primaria, el inicio de tratamiento precoz mejora los síntomas y además, es una oportunidad única para estudiar la fisiopatología de la infección. El diagnóstico requiere la identificación del virus mediante la detección de ARN viral o antígeno p24, ya que las pruebas que detectan anticuerpos pueden ser negativas durante el primer mes de infección. En Barcelona la prevalencia global de resistencia durante el periodo 1997-2012 fue del 9% aunque los valores fueron más altos antes del 2004, y se redujeron paulatinamente. Por otro lado, la prevalencia de subtipos no-B fueron aumentando hasta alcanzar casi el 20%. Los factores asociados a progresión clínica incluyen la presencia de síntomas y los valores altos de carga viral. El tratamiento precoz mejora la recuperación inmune, reconstituye parcialmente la pérdida linfocitaria asociada a la infección, limita el reservorio viral y evita la progresión clínica. El uso de terapias inmunomediadas con ciclos de suspensión estructurada e IL-2 no mejoró las respuestas inmunoespecíficas ni el control espontáneo de la infección. Es importante seguir explorando nuevas combinaciones enfocadas a lograr la cura funcional del VIH.[eng] Acute HIV infection is defined as the period from the date of infection to the appearance of a full antibody response. Most patients present with symptoms such as fever, headache, pharyngitis, lymphadenopathies and rash but less than the 3% of patients are detected during this period. Identifying patients during this period is important due to epidemiological considerations (higher risk of HIV transmission, best time for surveillance transmitted resistance, represent an in vivo model for understanding the immunological mechanisms of HIV persistence, and allow to initiate early treatment). Diagnosis relies in the detection of viral RNA or p24 antigen. The prevalence of resistance in Barcelona during the 1997-2012 period was 9%, with up to 20% of samples showing non-B subtypes. Factors associated to faster clinical progression were symptomatic infection and high viral load at baseline. Early treatment achieves almost complete immunological reconstitution, limits the size of the reservoir, and avoid clinical progression. Intermittent interruptions of treatment plus IL-2 was not associated with spontaneous viral control after antiretroviral suspension. It is important to continue exploring new combinations targeted to achieve functional cure