Quantitative analyses in basic, translational and clinical biomedical research: metabolism, vaccine design and preterm delivery prediction

2 t.There is nothing more important than preserving life, and the thesis here presented is framed in the field of quantitative biomedicine (or systems biomedicine), which has as objective the application of physico-mathematical techniques in biomedical research in order to enhance the understanding of life's basis and its pathologies, and, ultimately, to defend human health. In this thesis, we have applied physico-mathematical methods in the three fundamental levels of Biomedical Research: basic, translational and clinical. At a basic level, since all pathologies have their basis in the cell, we have performed two studies to deepen in the understanding of the cellular metabolic functionality. In the first work, we have quantitatively analyzed for the first time calcium-dependent chloride currents inside the cell, which has revealed the existence of a dynamical structure characterized by highly organized data sequences, non-trivial long-term correlation that last in average 7.66 seconds, and "crossover" effect with transitions between persistent and anti-persistent behaviors. In the second investigation, by the use of delay differential equations, we have modeled the adenylate energy system, which is the principal source of cellular energy. This study has shown that the cellular energy charge is determined by an oscillatory non-stationary invariant function, bounded from 0.7 to 0.95. At a translational level, we have developed a new method for vaccine design that, besides obtaining high coverages, is capable of giving protection against viruses with high mutability rates such as HIV, HCV or Influenza. Finally, at a clinical level, first we have proven that the classic quantitative measure of uterine contractions (Montevideo Units) is incapable of predicting preterm labor immediacy. Then, by applying autoregressive techniques, we have designed a novel tool for premature delivery forecasting, based only in 30 minutes of uterine dynamics. Altogether, these investigations have originated four scientific publications, and as far as we know, our work is the first European thesis which integrates in the same framework the application of mathematical knowledge to biomedical fields in the three main stages of Biomedical Research: basic, translational and clinical

Quantitative analyses in basic, translational and clinical biomedical research: metabolism, vaccine design and preterm delivery prediction

2 t.There is nothing more important than preserving life, and the thesis here presented is framed in the field of quantitative biomedicine (or systems biomedicine), which has as objective the application of physico-mathematical techniques in biomedical research in order to enhance the understanding of life's basis and its pathologies, and, ultimately, to defend human health. In this thesis, we have applied physico-mathematical methods in the three fundamental levels of Biomedical Research: basic, translational and clinical. At a basic level, since all pathologies have their basis in the cell, we have performed two studies to deepen in the understanding of the cellular metabolic functionality. In the first work, we have quantitatively analyzed for the first time calcium-dependent chloride currents inside the cell, which has revealed the existence of a dynamical structure characterized by highly organized data sequences, non-trivial long-term correlation that last in average 7.66 seconds, and "crossover" effect with transitions between persistent and anti-persistent behaviors. In the second investigation, by the use of delay differential equations, we have modeled the adenylate energy system, which is the principal source of cellular energy. This study has shown that the cellular energy charge is determined by an oscillatory non-stationary invariant function, bounded from 0.7 to 0.95. At a translational level, we have developed a new method for vaccine design that, besides obtaining high coverages, is capable of giving protection against viruses with high mutability rates such as HIV, HCV or Influenza. Finally, at a clinical level, first we have proven that the classic quantitative measure of uterine contractions (Montevideo Units) is incapable of predicting preterm labor immediacy. Then, by applying autoregressive techniques, we have designed a novel tool for premature delivery forecasting, based only in 30 minutes of uterine dynamics. Altogether, these investigations have originated four scientific publications, and as far as we know, our work is the first European thesis which integrates in the same framework the application of mathematical knowledge to biomedical fields in the three main stages of Biomedical Research: basic, translational and clinical

Optimización combinatoria en el diseño computacional de vacunas

133 p.A pesar de la creciente presencia de las matemáticas en el resto de ciencias, y en particular, en las ciencias biomédicas, a día de hoy la relación entre ambas sigue viéndose como una rareza. Sin embargo, ésta debería considerarse como una nueva oportunidad para dar soluciones eficientes a los problemas más relevantes de la humanidad, a saber, los que afectan a la salud de todos. En esta tesis, hemos profundizado en dicha relación, aplicando las matemáticas al diseño computacional de vacunas. En particular, hemos presentado un criterio para el diseño computacional de vacunas que permite tener en cuenta características biológicas al realizar la búsqueda de candidatos, al mismo tiempo que protege contra todas las variantes del virus consideradas. Esta metodología ha sido testada experimentalmente en un candidato a vacuna contra el SARS-CoV-2. Además, hemos realizado otro estudio donde se ha diseñado una vacuna personalizada contra el melanoma, y la hemos testado ex vivo, corroborando la eficiencia de las técnicas cuantitativas en el diseño de vacunas. Como resultado, en esta tesis presentamos tres publicaciones donde se han utilizado las matemáticas en el diseño de vacunas, que posteriormente se han testado, ofreciendo resultados prometedores. A través de dichos trabajos, se espera evidenciar la sinergia (cada vez más difícilmente discutible) entre las ciencias exactas y las ciencias de la salud

Problem-Based Teaching through Video Podcasts for Coding and Cryptography

In this work we present the development and preliminary evaluation of several problem-based video podcasts addressed to students of the subject “Coding and Cryptography”. Specifically, this experiment has been carried out with the students of both the Bachelor’s degree in Mathematics and the Master’s degree of Mathematical Research and Modelling, Statistics and Computation, at the University of the Basque Country (UPV/EHU). Our results suggest that students found these complementary videos helpful for their learning process, indicating that this methodology could be appropriate for subjects treating complex concepts, such as those in the last years of degree or in master courses.The authors are supported by the University of the Basque Country, UPV/EHU (Convocatoria de Ayudas para Proyecto de Innovación Educativa, PIE-2018, Código 2), and also by the Basque Government grant IT974-16

How Do We Create Experiences for Students That Connect with What They Care About?

The main aim of this work is to describe the process by which some students, participating in a teaching experiment, recreate with guidance material and personal attendance some advanced concepts at the doctoral level. More precisely, the students deal with concepts related to pure abstract algebra, beginning with an exploration of the well known mathematical game of the Hanoi Towers on the three rods.The authors are supported by the University of the Basque Country, UPV/EHU (Convocatoria de Ayudas para Proyecto de Innovación Educativa, PIE-2018, Código 2)

CALE: Learning by Example in Mathematics with Applets in Mathematical Computational Packages

In this work we present a methodology of “learning by example” assisted by computers in the study of mathematics. We propose the use of mathematical computational packages to program applets aimed to solve mathematical problems. Each time the student runs the applet, a new random instance of the problem is generated, and he is guided, step by step to solve it. The student can repeat the process as many times as necessary until his knowledge is consolidated, by taking a more active role in the process after the first repetitions of several instances.The authors are supported by the University of the Basque Country, UPV/EHU (PIE-2018, Código 2) and by the Basque Government, grant IT974-16

Meta-Analysis of the Embryo Freezing Transfer Interval

Background The decision of whether frozen embryo transfer (FET) should be performed in the cycle immediately after OPU or at least one cycle later is controversial. FET could improve pregnancy rates in IVF; however, how much time is needed for the endometrium to return to optimal receptivity after ovarian stimulation is not known. Methods Electronic search in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials to identify studies providing data on the influence of the interval between embryo freezing (or OPU) and FET in FET cycles published between January 1, 2007, and February 1, 2020. Main findings Data analyzed indicated that in the immediate FET cycles, there was a trend to an increased biochemical pregnancy rate (RR = 1.08; CI = 1.00-1.18), whereas the clinical pregnancy rate was somewhat higher, but without reaching statistical significance (RR = 1.07; CI = 0.99-1.15). The live birth rate was similar in the two groups (RR = 1.05; CI = 0.95-1.15), as was the implantation rate (RR = 0.98; CI = 0.83-1.16). Stratifying by embryo stage or FET type (freeze-all or FET after failed fresh transfer) showed no differences. Conclusion Systematically delaying FET does not offer benefits to IVF outcomes. In addition, immediate transfer is associated with a nonsignificant trend to better clinical pregnancy rate and it also avoids the psychological effects of prolonging the stress on prospective parents

Self-Organization and Information Processing: from Basic Enzymatic Activities to Complex Adaptive Cellular Behavior

One of the main aims of current biology is to understand the origin of the molecular organization that underlies the complex dynamic architecture of cellular life. Here, we present an overview of the main sources of biomolecular order and complexity spanning from the most elementary levels of molecular activity to the emergence of cellular systemic behaviors. First, we have addressed the dissipative self-organization, the principal source of molecular order in the cell. Intensive studies over the last four decades have demonstrated that self-organization is central to understand enzyme activity under cellular conditions, functional coordination between enzymatic reactions, the emergence of dissipative metabolic networks (DMN), and molecular rhythms. The second fundamental source of order is molecular information processing. Studies on effective connectivity based on transfer entropy (TE) have made possible the quantification in bits of biomolecular information flows in DMN. This information processing enables efficient self-regulatory control of metabolism. As a consequence of both main sources of order, systemic functional structures emerge in the cell; in fact, quantitative analyses with DMN have revealed that the basic units of life display a global enzymatic structure that seems to be an essential characteristic of the systemic functional metabolism. This global metabolic structure has been verified experimentally in both prokaryotic and eukaryotic cells. Here, we also discuss how the study of systemic DMN, using Artificial Intelligence and advanced tools of Statistic Mechanics, has shown the emergence of Hopfield-like dynamics characterized by exhibiting associative memory. We have recently confirmed this thesis by testing associative conditioning behavior in individual amoeba cells. In these Pavlovian-like experiments, several hundreds of cells could learn new systemic migratory behaviors and remember them over long periods relative to their cell cycle, forgetting them later. Such associative process seems to correspond to an epigenetic memory. The cellular capacity of learning new adaptive systemic behaviors represents a fundamental evolutionary mechanism for cell adaptation.This work was supported by the University of Basque Country UPV/EHU and Basque Center of Applied Mathematics, grant US18/2

Associative Conditioning Is a Robust Systemic Behavior in Unicellular Organisms: An Interspecies Comparison

The capacity to learn new efficient systemic behavior is a fundamental issue of contemporary biology. We have recently observed, in a preliminary analysis, the emergence of conditioned behavior in some individual amoebae cells. In these experiments, cells were able to acquire new migratory patterns and remember them for long periods of their cellular cycle, forgetting them later on. Here, following a similar conceptual framework of Pavlov’s experiments, we have exhaustively studied the migration trajectories of more than 2000 individual cells belonging to three different species: Amoeba proteus, Metamoeba leningradensis, and Amoeba borokensis. Fundamentally, we have analyzed several relevant properties of conditioned cells, such as the intensity of the responses, the directionality persistence, the total distance traveled, the directionality ratio, the average speed, and the persistence times. We have observed that cells belonging to these three species can modify the systemic response to a specific stimulus by associative conditioning. Our main analysis shows that such new behavior is very robust and presents a similar structure of migration patterns in the three species, which was characterized by the presence of conditioning for long periods, remarkable straightness in their trajectories and strong directional persistence. Our experimental and quantitative results, compared with other studies on complex cellular responses in bacteria, protozoa, fungus-like organisms and metazoans that we discus here, allow us to conclude that cellular associative conditioning might be a widespread characteristic of unicellular organisms. This new systemic behavior could be essential to understand some key principles involved in increasing the cellular adaptive fitness to microenvironments.This work was supported by a grant of the University of Basque Country (UPV/EHU), GIU17/066, the Basque Government grant IT974-16, the UPV/EHU and Basque Center of Applied Mathematics, grant US18/21, and the Israel Science Foundation (536/19)Peer reviewe