New mathematical methods for the study of stem cell differentiation

The question of how the fertilized egg develops into an adult organism is one of the most fundamental ones in Biology. A very important stage in the development of the embryo is cell differentiation, in which unspecialised cells, called stem cells, become specialised ones, such as skin or nerve cells depending on the signals that they receive. This is controlled by a very large network of genes that interact with each other, the state of which defines the characteristics of the cell. With the recent development of experimental techniques that allow us to obtain very detailed information about the changes in cells, new data analysis methods and mathematical models are required for the understanding of stem cell differentiation. A common approach to the mathematical modelling of stem cell differentiation is by means of gene regulatory network (GRN) models describing the gene regulation behind the process. However, the number of variables and parameters in these models rapidly scales up as one tries to study more genes in the network, difficulting its analysis. This thesis aims to assess these problems and it is structured into two main parts. In the first one, which comprises Chapters 3 and 4, we will develop a phenotypic quasi-potential landscape model for vulval development in C. elegans to illustrate how catastrophe theory can be a powerful tool to construct and understand these recently emerging types of models. Moreover, will use advanced statistical techniques to fit the built model to the experimental data. The second part, in Chapter 5, will be devoted to developing a methodology to understand protein expression data in order to reverse engineer the gene regulatory network from it and create a mathematical model that explains such experimental data

Potato virus X (PVX) elimination as short and long term effects of hydrogen peroxide and salicylic acid is differentially mediated by oxidative stress in synergism with thermotherapy

Articulo científico indezadoAbstract Short and long term effects of hydrogen peroxide (H2O2) and salicylic acid (SA) were examined in: thermotolerance, virus X (PVX)-free microplants obtained by in vitro thermotherapy, catalase activity (CAT) and H2O2 concentration. Short term effects (STE) were tested as follows: (a) nodal explants were cultivated 30 d on MS medium containing SA 10−5 or 10−6 M; and (b) nodal explants were waterlogged for 1 h in 1 or 5 mMH2O2 solution and subsequently cultured in MS for 30 d. Long term effects were tested as follows (LTE): the experimental regime was identical to STE but SA and H2O2 treated plants were subcultured for an additional 30 d period onMS. All treatments were followed by thermotherapy (32–42 C) for 35 d. Results showed SA and H2O2 induced thermotolerance during thermotherapy. The percentage of PVX-free plants obtained in H2O2 was significantly higher than in SA in STE and LTE by 3-and 4 fold respectively. CAT activity was differentially mediated by SA and H2O2.This research was supported by a grant from Recursos Fiscales, INIFAP

The Hall of the Kingdoms of the Buen Retiro Palace as an improvised 3D-model room (1779-1803)

[EN] During the Modern Age, various European courts consolidated the tradition of the manufacture of plans-reliefs of fortified cities as a complement to other forms of representation (maps and plans) used within the military field. In this context, the Hall of Kingdoms of the Buen Retiro Palace functioned as an improvised 3D-model room at the end of the 18th century. The plan-relief of Cadiz was installed therein as the sole model built as part of the global project promoted by King Charles of Spain III in 1776 for the manufacture of models of strongholds of the kingdom. After the usefulness of this first model was questioned, the project was abandoned, although the room did later house another seven models. The identity of these deposited models, the time period, and the circumstances under which this room was utilised as a 3D-model room constitute the subject of this research.[ES] Durante la Edad Moderna diversas cortes europeas consolidaron como tradición la fabricación de planos en relieve de ciudades fortificadas, complemento a otras formas de representación -mapas y planos- empleadas dentro del ámbito militar. En este contexto, el Salón de los Reinos del Palacio del Buen Retiro funcionó como un improvisado cuarto de modelos a finales del siglo XVIII. En él quedó instalado el modelo de Cádiz, único elaborado al amparo del proyecto global para la fabricación de maquetas de plazas fuertes del Reino, promovido por Carlos III (1776). Tras cuestionarse la utilidad de este primer modelo el proyecto fue abortado, si bien la estancia albergó siete modelos más con posterioridad. La identidad de las maquetas depositadas, el periodo de tiempo y las circunstancias en las que fue utilizado como cuarto de modelos son objeto de investigación.Granado-Castro, G.; Aguilar-Camacho, J.; Cabrera-Revuelta, E. (2023). El Salón de los Reinos del Palacio del Buen Retiro como improvisado cuarto de maquetas (1779-1803). EGA Expresión Gráfica Arquitectónica. 28(49):138-149. https://doi.org/10.4995/ega.2023.19030138149284

Dual Beam Sinusoidally Modulated Reactance Surface Antenna

In this work, a planar dual beam Sinusoidally Modulated Reactance Surface (SMRS) antenna is presented. Our method is based on the implementation of a surface impedance modulated by the superposition of two sinusoidal functions. In particular, the full process of designing a dual beam antenna that radiates at -14 and 28 off broadside at 10 GHz is described. In a second proposed structure, manipulation of the side lobe level (SLL) is achieved by varying the leakage constant along the antenna with negligible changes in the pointing directions. SLL reductions of 3.4 dB and 1.8 dB for each of the synthesised beams are obtained through full wave simulations, as well as gains 13.4 dBi and 13.6 dBi respectively. An excellent agreement between theoretical and simulated results is observed.This project has received funding from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU), the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER) (Programa Estatal de I+D+i Orientada a los Retos de la Sociedad) under grant RTI2018-097098-JI00. It has also been undertaken within the context of a Research Collaboration Grant of the I Plan Propio de Investigación y Transferencia of the University of Málaga

Quantifying cell transitions in C. elegans with data-fitted landscape models

Increasing interest has emerged in new mathematical approaches that simplify the study of complex differentiation processes by formalizing Waddington’s landscape metaphor. However, a rational method to build these landscape models remains an open problem. Here we study vulval development in C. elegans by developing a framework based on Catastrophe Theory (CT) and approximate Bayesian computation (ABC) to build data-fitted landscape models. We first identify the candidate qualitative landscapes, and then use CT to build the simplest model consistent with the data, which we quantitatively fit using ABC. The resulting model suggests that the underlying mechanism is a quantifiable two-step decision controlled by EGF and Notch-Delta signals, where a non-vulval/vulval decision is followed by a bistable transition to the two vulval states. This new model fits a broad set of data and makes several novel predictions

Statistically derived geometrical landscapes capture principles of decision-making dynamics during cell fate transitions

Fate decisions in developing tissues involve cells transitioning between discrete cell states, each defined by distinct gene expression profiles. The Waddington landscape, in which the development of a cell is viewed as a ball rolling through a valley filled terrain, is an appealing way to describe differentiation. To construct and validate accurate landscapes, quantitative methods based on experimental data are necessary. We combined principled statistical methods with a framework based on catastrophe theory and approximate Bayesian computation to formulate a quantitative dynamical landscape that accurately predicts cell fate outcomes of pluripotent stem cells exposed to different combinations of signaling factors. Analysis of the landscape revealed two distinct ways in which cells make a binary choice between one of two fates. We suggest that these represent archetypal designs for developmental decisions. The approach is broadly applicable for the quantitative analysis of differentiation and for determining the logic of developmental decisions

VALORACIÓN ECONÓMICA DEL ACEITE DE COCINA DE DESECHO EN EL MUNICIPIO TEXCOCO, MÉXICO

By means of a stratified sampling, the total waste cooking oil (ACD) generated in the central zone of the municipality of Texcoco by the restaurant activity was calculated for the period April 2021 to March 2022, which was 394,564.41 L per year, with a variance of 87.65 units and a standard deviation of 9.36 L and a recovery percentage of 28. 05%, to subsequently apply the environmental valuation method “transfer of benefits” and estimate an economic value of the ACD considering the lowest and maximum market price of biodiesel (transfer good) which was $14.22 MNX and$18.22 MNX giving a value of $5,610,705.91 MNX and$7,188,963.55 MNX annually respectively.Finally, the economic value of the ACD was calculated considering the price that this product presented in the surveys applied in the sampling, which was $8.00 MNX/L, representing a value of$3,156,515.28 MNX annually.Por medio de un muestreo estratificado se calculó el total de aceite de cocina de desecho (ACD) generado en la zona centro del municipio de Texcoco por la actividad restaurantera, en el periodo abril 2021 a marzo 2022, que fue de 394,564.41 L anuales, con una varianza de 87.65 unidades y una desviación estándar de 9.36 L y un porcentaje de recuperación de 28.05%, para posteriormente aplicar el método de valoración ambiental “transferencia de beneficios” y estimar un valor económico del ACD considerando el precio de mercado más bajo y máximo del biodiesel (bien de transferencia) que fue $14.22 MNX y$18.22 MNX dando un valor de $5,610,705.91 MNX y$7,188,963.55 MNX anuales respectivamente.Finalmente se calculó el valor económico del ACD considerando el precio que este producto presentó en las encuestas aplicadas en el muestreo, el cual fue de $8.00 MNX/L, representando un valor de$3,156,515.28 MNX anuales

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

COPPADIS Study Group.[Introduction] We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia.[Methods] The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models.[Results] Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02).[Conclusions] Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.This work was supported by the Alzheimer Forschung Initiative e.V. (AFI International Training Grant to MJG), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, PI19/01576, PI20/00613], the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019], the Fundación Alicia Koplowitz and the Fundación “Curemos el Parkinson” (https://www.curemoselparkinson.org). MJG is supported by the “Miguel Servet” program [CP19/00031], MALE by the University of Seville [USE-20046-J], JFM by the “Sara Borrell” program [CD13/00229] and VI-PPIT-US from the University of Seville [USE-18817-A], SJ by the “Acción B-Clínicos-Investigadores” program [B-0007-2019], and DMG by the “Río Hortega” program [CM18/00142].Peer reviewe

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

Introduction: We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson’s disease (PD) without dementia. Methods: The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models. Results: Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r =0.37, p <0.001), and this association remained significant after controlling for several potential confounding variables (p =0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p =0.02). Conclusions: Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition- relevant changes in non-demented PD

Combining MRI and clinical data to detect high relapse risk after the first episode of psychosis

Detecting patients at high relapse risk after the first episode of psychosis (HRR-FEP) could help the clinician adjust the preventive treatment. To develop a tool to detect patients at HRR using their baseline clinical and structural MRI, we followed 227 patients with FEP for 18–24 months and applied MRIPredict. We previously optimized the MRI-based machine-learning parameters (combining unmodulated and modulated gray and white matter and using voxel-based ensemble) in two independent datasets. Patients estimated to be at HRR-FEP showed a substantially increased risk of relapse (hazard ratio = 4.58, P &lt; 0.05). Accuracy was poorer when we only used clinical or MRI data. We thus show the potential of combining clinical and MRI data to detect which individuals are more likely to relapse, who may benefit from increased frequency of visits, and which are unlikely, who may be currently receiving unnecessary prophylactic treatments. We also provide an updated version of the MRIPredict software