A revised look at the effects of the Channel Model on molecular communication system

Molecular communications, where information is passed between the Transmitter (TX) and the Receiver (RX) via molecules is a promising area with vast potential applications. However, the infancy of the topic within the overall taxonomy of communications has meant that to date, several channel models are in press, each of which is applied under various constraints and/or assumptions. Amongst them is that the arrival of molecules in different time slots can be, or is, considered as independent events. In practice, this assumption is not accurate, as the molecules arriving in the previous slot reduce the possible number of molecules in the next slot and hence make them correlated. In this letter, we analyze a more realistic performance of a molecular communication assuming correlated events. The key result shown, is that the widely used model assuming independent events significantly overestimates the error rates in the channel. This result is thus critical to researchers who focus on energy use at the nano-scale, as the new analysis provides a more realistic prediction and therefore, less energy will be needed to attain a desired error rate, increasing system feasibility

Molecular understanding of cytoneme-based Wnt trafficking

Cell-to-cell communication by signaling proteins is essential to orchestrate development and tissue homeostasis in all multicellular organisms. The highly conserved family of Wnt proteins are important guiding cues to control these processes. Fundamental to this complex signaling network are relatively small and defined signaling centers in a given tissue that produce and distribute Wnt proteins. Adjacent, larger groups of cells respond to these spatial and temporal information in a concentration-dependent manner and adjust their transcriptional program. However, a regulated sequence of morphogen activity is required to generate a fine tuned communication network. Therefore, a controlled propagation machinery must ensure accurate signal distribution from the source to the surrounding tissue to initiate the correct developmental path. In this thesis, I consolidated the knowledge of the molecular machinery controlling cytoneme formation in zebrafish development. I expanded this principle to other aspects of Wnt signaling such as cancer growth and tissue homeostasis. Via a screening approach, I identified the receptor tyrosine kinase Ror2 as a promoting factor for cellular protrusions in general and particularly for Wnt8a cytonemes in cultured cells and in vivo. Consistently, I described the novel ligand-receptor pair Wnt8a and Ror2 by measuring the affinity for membrane accumulations and by biophysical imaging applications such as fluorescence correlation spectroscopy. Subsequently, functional interaction and transduction of the Wnt/PCP pathway was demonstrated during zebrafish convergence and extension and during non-canonical reporter activation in Xenopus. Wnt8a and Ror2 are considered to act in mutually repressive pathways, although the autocrine interplay for cytoneme formation to facilitate paracrine Wnt/β-catenin dissemination seems to be conserved. Thus, the model can be applied to other systems: The transcriptional β-catenin level and resulting proliferation of gastric cancer cells can be regulated by Ror2, thereby only disrupting the signal transmitting transport machinery in the source cells. Furthermore, I provided evidence of an ex vivo human stem cell organoid system, where growth and survival require cytoneme-mediated Wnt proteins from isolated myofibroblasts. Remarkably, this setup resembles an innovative approach for stem cell maintenance in the murine intestinal crypt and expands the potential roles of cytonemes in development, tissue homeostasis and diseases

Wnt transport mechanisms during vertebrate tissue patterning

Wnt signalling is one of the key pathways regulating numerous important processes during development and adult tissue maintenance. Wnt proteins act as morphogens originating from a Wnt source forming a gradient in the responding tissues to allow pattern formation. The exact mechanism how Wnt proteins are distributed to form gradients is still poorly understood.During my thesis, I analysed in detail how Wnts are distributed to form a gradient

Extracellular trafficking of Wnt signals in gastric cancer

Wnt proteins are secreted glycoproteins which signal in a tissue to regulate multiple cellular processes, such as cell differentiation, migration, and proliferation. However, post-translational modifications result in Wnt ligands being hydrophobic in nature. Thus, their ability to freely diffuse in the aqueous extracellular environment is restricted, and alternative mechanisms of transport have been proposed. In this thesis, I investigate and characterise the use of signalling filopodia – termed cytonemes – in the intercellular transport of Wnt3 ligands by gastric cancer cells, which display overactivated Wnt/β-catenin signalling. Additionally, I identify the membrane scaffolding protein Flotillin-2 (Flot2), which is overexpressed in gastric cancers, as a novel positive regulator of Wnt cytoneme formation and consequently proliferation. Mechanistically, I show that Flot2 is required for the intracellular transport, membrane localisation and thus signalling of the Wnt co-receptor Ror2; a known regulator of Wnt cytonemes. In parallel, I show that Flot2 also has a function in transducing signals in the Wnt- receiving cell. Here, Flot2 co-localises with the Wnt co-receptor Lrp6 and is involved in its endocytic uptake. Additionally, Flot2 knockdown results in the perinuclear accumulation of Lrp6 and its absence from recycling endosomes. Therefore, I suggest Flot2 may also be involved in the endosomal transport of Lrp6 following internalisation. Finally, following my observed co-localisations of both Ror2 and Lrp6 with Flot2, I found that these Wnt co-receptors co-localise with one another, as well as the cognate Wnt receptor Frizzled 7, in Flot2 microdomains. Expression of a mutant Ror2 missing its cysteine-rich domain, however, causes loss of co-localisation with Lrp6 and perturbed Wnt/β-catenin signalling. Together, these findings led me to propose a model whereby Frizzled 7, Ror2 and Lrp6 all interact and form one large complex, which I have termed the Wnt Receptor Supercomplex (WRS). I hypothesise that these receptors may interact, even in the absence of Wnt ligands, to regulate one another’s binding affinities for either Wnt/β-catenin or Wnt/PCP ligands. Here, I propose that flotillin microdomains provide the scaffold necessary for these interactions

Mathematical models for glioma growh and migration inside the brain

284 p.Los gliomas forman el subtipo más prevalente, agresivo e invasivo de tumores cerebrales primarios,caracterizados por una rápida proliferación celular y una elevada capacidad de infiltración. A pesar de los avances de la investigación clínica, estos tumores suelen ser resistentes al tratamiento; la supervivencia media oscila entre 9 y 12 meses, siendo la recurrencia la principal causa de mortalidad.La migración y la invasión de los gliomas en el cerebro son fenómenos complejos y aún se desconocen varios de los mecanismos subyacentes que guían la progresión de estos tumores.En esta tesis, proponemos varios modelos matemáticos para estudiar diversos aspectos de la progresión del glioma en relación con las escalas microscópicas y macroscópicas que caracterizan este proceso. Considerar el carácter intrínsico multiescala de la evolución del glioma permite definir modelos basados en sistemas dinámicos, ecuaciones cinéticas y EDP macroscópicas con diferentes roles dependiendo de los fenómenos a estudiar. Uno de los objetivos principales de esta tesis es integrar datos biológicos y clínicos con los modelos matemáticos. Los datos experimentales utilizados se han obtenido de imágenes por resonancia magnética, de imágenes con tensor de difusión del cerebro humano y de análisis de inmunofluorescencia in vivo de distribuciones de varias proteínas en Drosophila, un modelo fiable para el estudio de la dinámica del glioblastoma.Analizamos las características de anisotropía del tejido nervioso, utilizando los datos del tensor de difusión, y la influencia de la estructura de las fibras en la dinámica de las células tumorales.Mostramos cómo la red de fibras guía la migración celular a lo largo de rutas preferenciales,reproduciendo los patrones ramificados y heterogéneos típicos de la evolución del glioma; asimismo,demostramos cómo los tratamientos multimodales pueden reducir este comportamiento.Estudiamos la interdependencia entre la acidez del microambiente y la vascularización en el proceso de angiogénesis tumoral. Para ello, construimos un modelo capaz de reproducir la influencia de estos mecanismos en el desarrollo de la heterogeneidad intratumoral y de características típicas de la progresión del glioma relacionadas con la hipoxia (e.g. la necrosis). Este estudio permite formular una clasificación de los tumores basada en el nivel de necrosis, así como la investigación de terapias multimodales que incluyan efectos antiangiogénicos.Investigamos la influencia de las protrusiones celulares desde una perspectiva no local.Analizamos su rol en el fenómeno de la guía por contacto y en la manifestación de efectos colaborativos o competitivos entre dos estímulos que determinan cambios de dirección de la velocidad celular.Utilizando el análisis experimental de las distribuciones de varias proteínas, evaluamos la relación de las protrusiones celulares con las integrinas y las proteasas como principales mecanismos de progresión del glioblastoma. Mostramos cómo las interacciones bioquímicas y biomecánicas de estos agentes dan como resultado el desarrollo de frentes de propagación tumoral, que pueden presentar una evolución dinámica y heterogénea en relación a los cambios ambientales.bcam:basque center for applied mathematics; La Caixa Foundatio

Mathematical models for glioma growth and migration inside the brain

Gliomas are the most prevalent, aggressive, and invasive subtype of primary brain tumors, characterized by rapid cell proliferation and great infiltration capacity. De- spite the advances of clinical research, these tumors are often resistant to treatment, the median survival ranges between 9 and 12 months, and recurrence is the main cause of mortality. Glioma migration and invasion into the brain tissue is a complex phenomenon and little is still known about the underlying mechanisms that lead to tumor progression. In this thesis, we propose several mathematical models studying various aspects of glioma progression in relation to the microscopic and macroscopic scales charac- terizing this process. Exploiting the inherently multiscale nature of glioma evolution allows to define models based on dynamical systems, kinetic equations, and macro- scopic PDEs with different roles depending on the considered phenomena. The in- tegration of biological and clinical data with the mathematical models is one of the key objectives of this thesis. The experimental data at hand are obtained from mag- netic resonance and diffusion tensor images of the human brain and from in-vivo im- munofluorescence analysis of protein distributions in Drosophila, a reliable model for the study of glioblastoma dynamics. We analyze the anisotropic characteristics of the brain tissue, using the diffusion tensor data, and the influence of the fiber structures on tumor cell dynamics. We show how the fiber network directs cell migration along preferential paths, reproducing the branched and heterogeneous patterns typical of glioma evolution, and how multi- modal treatments can reduce this behavior. We study the interdependency of microenvironmental acidity and vasculature in tumor angiogenesis, defining a model capable of reproducing their influence on the emergence of phenotypic heterogeneity and hypoxia-related features (like necrosis) typical of glioma progression. This study enables the testing of a necrosis-based tumor grading and the investigation of multi-modal therapies with anti-angiogenic effects. We investigated the role of cell protrusions from a non-local perspective. We ex- plore their influence on the contact guidance phenomenon and on the emergence of collaborative or competitive effects between two cues driving cell velocity changes. Using the experimental analysis of protein distributions, we evaluate cell protru- sion relationship with integrins and proteases as leading mechanisms of glioblastoma progression. We show how the biochemical and biomechanical interactions of these agents result in the emergence of tumor propagation fronts, which can feature a dy- namical and heterogenous evolution in relation to environmental changes.European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 713673. ”la Caixa” Foundation (ID 100010434), with fellowship code LCF/BQ/IN17/11620056

Mathematical models for glioma growh and migration inside the brain

284 p.Los gliomas forman el subtipo más prevalente, agresivo e invasivo de tumores cerebrales primarios,caracterizados por una rápida proliferación celular y una elevada capacidad de infiltración. A pesar de los avances de la investigación clínica, estos tumores suelen ser resistentes al tratamiento; la supervivencia media oscila entre 9 y 12 meses, siendo la recurrencia la principal causa de mortalidad.La migración y la invasión de los gliomas en el cerebro son fenómenos complejos y aún se desconocen varios de los mecanismos subyacentes que guían la progresión de estos tumores.En esta tesis, proponemos varios modelos matemáticos para estudiar diversos aspectos de la progresión del glioma en relación con las escalas microscópicas y macroscópicas que caracterizan este proceso. Considerar el carácter intrínsico multiescala de la evolución del glioma permite definir modelos basados en sistemas dinámicos, ecuaciones cinéticas y EDP macroscópicas con diferentes roles dependiendo de los fenómenos a estudiar. Uno de los objetivos principales de esta tesis es integrar datos biológicos y clínicos con los modelos matemáticos. Los datos experimentales utilizados se han obtenido de imágenes por resonancia magnética, de imágenes con tensor de difusión del cerebro humano y de análisis de inmunofluorescencia in vivo de distribuciones de varias proteínas en Drosophila, un modelo fiable para el estudio de la dinámica del glioblastoma.Analizamos las características de anisotropía del tejido nervioso, utilizando los datos del tensor de difusión, y la influencia de la estructura de las fibras en la dinámica de las células tumorales.Mostramos cómo la red de fibras guía la migración celular a lo largo de rutas preferenciales,reproduciendo los patrones ramificados y heterogéneos típicos de la evolución del glioma; asimismo,demostramos cómo los tratamientos multimodales pueden reducir este comportamiento.Estudiamos la interdependencia entre la acidez del microambiente y la vascularización en el proceso de angiogénesis tumoral. Para ello, construimos un modelo capaz de reproducir la influencia de estos mecanismos en el desarrollo de la heterogeneidad intratumoral y de características típicas de la progresión del glioma relacionadas con la hipoxia (e.g. la necrosis). Este estudio permite formular una clasificación de los tumores basada en el nivel de necrosis, así como la investigación de terapias multimodales que incluyan efectos antiangiogénicos.Investigamos la influencia de las protrusiones celulares desde una perspectiva no local.Analizamos su rol en el fenómeno de la guía por contacto y en la manifestación de efectos colaborativos o competitivos entre dos estímulos que determinan cambios de dirección de la velocidad celular.Utilizando el análisis experimental de las distribuciones de varias proteínas, evaluamos la relación de las protrusiones celulares con las integrinas y las proteasas como principales mecanismos de progresión del glioblastoma. Mostramos cómo las interacciones bioquímicas y biomecánicas de estos agentes dan como resultado el desarrollo de frentes de propagación tumoral, que pueden presentar una evolución dinámica y heterogénea en relación a los cambios ambientales.bcam:basque center for applied mathematics; La Caixa Foundatio

In a Garden of Forking Maps

This article compares the cartographical representations of the Caspian region produced around 1560 in Goa and Venice, with references to other centers of mapmaking such as Lisbon, Seville, and Antwerp. It explores the scientific, cultural, technical, and commercial logics that led to profoundly dissimilar cartographies of the Caspian and its surroundings in different centers of map production around the same time. It asks questions about the contrasts between maritime and terrestrial cartography in the Renaissance, and the cartographical languages associated with each of these cartographical modes. The habitus of maritime cartographers in Goa, Lisbon, and Seville differed profoundly, it is argued, from that of mapmakers in Italy, and particularly Venice, who aimed for an integration of all available data as part of a tradition of commenting on Ptolemy, and produced highly desirable printed maps for a growing consumer audience. The article thus advocates a comparative approach to maps, and critiques the assumption that knowledge “flows” between regions. It proposes instead a “(dis)connected history” of knowledge production and consumption to throw new light on the origins of the cartographical printing revolution. / Cet article compare lesreprésentations cartographiques de la région caspienne produites vers 1560 à Goaet à Venise, en faisant aussi référence à d’autres centres de cartographie telsque Lisbonne, Séville et Anvers. Il explore les logiques scientifiques,culturelles, techniques et commerciales qui ont conduit à des cartographiesprofondément dissemblables de la mer Caspienne et de ses environs dansdifférents lieux de production de cartes à la même époque. Il examine égalementles contrastes entre les cartographies maritime et terrestre à la Renaissanceainsi que les langages cartographiques associés à chacun de ces modescartographiques. L’habitus des cartographes maritimes de Goa, Lisbonne etSéville différait profondément de celui des cartographes d’Italie, enparticulier vénitiens, qui visaient une intégration de toutes les donnéesdisponibles dans le cadre d’une tradition de commentaires sur Ptolémée etentendaient produire des cartes imprimées hautement désirables pour un public deconsommateurs de plus en plus nombreux. L’article propose ainsi une approchecomparative des cartes tout en critiquant l’hypothèse selon laquelle lesconnaissances « circulent » entre les régions. Il défend une « histoire(dis)connectée » de la production et de la consommation des connaissances,éclairant des facteurs rarement étudiés qui furent à l’origine de la révolutionde l’imprimerie cartographique