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

Effect of vitamin E administered to men in infertile couples on sperm and assisted reproduction outcomes: a double-blind randomized study

Objective: To evaluate the influence on sperm parameters and invitro fertilization (IVF) outcomes of the administration of 400 mg/day of vitamin E for 3 months to men from infertile couples who are undergoing IVF. Design: Double-blind, placebo-controlled, randomized study. Setting: Human reproduction unit of a university hospital. Patients: A total of 101 couples, 50 in the vitamin E group and 51 in the placebo group, undergoing IVF, among whom 64.4% of cases had an abnormal spermiogram according to World Health Organization (WHO) criteria. Interventions: Vitamin E (alpha-tocopherol), 400 mg daily by mouth for 3 months, with sperm analysis performed immediately before starting the treatment and 3 months later on the day of IVF. Main Outcome Measures: WHO sperm parameters and IVF outcomes. Results: Although there was a statistically significant increase in progressive motility in the vitamin E group compared with before-treatment values, a similar increase occurred in the placebo group. Normal morphology was even better in the placebo group. Regarding IVF outcomes, better fertilization rates were observed in the placebo group, but the live-birth rate per transfer was statistically significantly higher in the vitamin E group: 17 (41.46%) of 41 versus 9 (20.46%) of 44 in the placebo group. Although the clinical pregnancy rates (both per transfer and per cycle started) and the implantation rate were somewhat higher in the vitamin E group (43.9% and 25%; 36.0% and 22.0%; and 24.7% and 14.1%, respectively), the increase was not statistically significant. Conclusions: The effect of vitamin E on classic sperm parameters was not an improvement over placebo. Nonetheless, vitamin E administration was associated with a statistically significantly higher live-birth rate, and there was a trend toward better results in other IVF parameters

Estimation of preterm labor immediacy by nonlinear methods

Preterm delivery affects about one tenth of human births and is associated with an increased perinatal morbimortality as well as with remarkable costs. Even if there are a number of predictors and markers of preterm delivery, none of them has a high accuracy. In order to find quantitative indicators of the immediacy of labor, 142 cardiotocographies (CTG) recorded from women consulting because of suspected threatened premature delivery with gestational ages comprehended between 24 and 35 weeks were collected and analyzed. These 142 samples were divided into two groups: the delayed labor group (n = 75), formed by the women who delivered more than seven days after the tocography was performed, and the anticipated labor group (n = 67), which corresponded to the women whose labor took place during the seven days following the recording. As a means of finding significant differences between the two groups, some key informational properties were analyzed by applying nonlinear techniques on the tocography recordings. Both the regularity and the persistence levels of the delayed labor group, which were measured by Approximate Entropy (ApEn) and Generalized Hurst Exponent (GHE) respectively, were found to be significantly different from the anticipated labor group. As delivery approached, the values of ApEn tended to increase while the values of GHE tended to decrease, suggesting that these two methods are sensitive to labor immediacy. On this paper, for the first time, we have been able to estimate childbirth immediacy by applying nonlinear methods on tocographies. We propose the use of the techniques herein described as new quantitative diagnosis tools for premature birth that significantly improve the current protocols for preterm labor prediction worldwide.Work by the first author was supported by the Basque Government grant PRE-2015-1-194,and work by the first and second authors by the Basque Government grant IT974-16. This work was also supported in part by FERRING laboratories Madrid, Spain (RM), https://www.ferring.com/en/home/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript