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Hevea brasiliensis, a natural rubber producing species, is widely cultivated due to its high rubber yield potential. Natural rubber is synthesised in the rubber particles of laticifers. Latex diagnosis (LD) was established to characterise the physiological state of the laticiferous system by measuring its physiological parameters, i.e., sucrose, inorganic phosphorous (Pi), thiols and total solid content (TSC). Rubber clones are often classified in three groups i.e., quick starters, medium starters and slow starters. To better understand the genetic bases of latex yield, a biparental population was generated from a cross between the quick-starter clone PB 260 and the medium-starter clone SP 217. LD was performed during the peak latex production season and used to calculate sucrose loading. The agronomic and physiological parameters associated with latex yield led to the classification of genotypes according to the rubber clonal typology and to the identification of quantitative trait loci (QTL) using a high-density map. Inorganic phosphorous content was positively associated with yield during the first year of production thus enabling identification of quick-starter clones. In addition, the LD-based clonal typology led to determine the long-term yield potential and the use of appropriate ethephon stimulation. QTL analysis successfully identified several QTLs related to yield, sucrose, Pi and TSC. One QTL related to sucrose loading was identified in the same position as the QTL for sucrose on linkage group 1. To our knowledge, this is the first study to report QTL analysis for this trait. The use of a high-density map enables the identification of genes underlying QTLs. Several putative genes underlying QTLs related to yield, sucrose and TSC were identified.

Context: Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. Methods: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. Results: The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. Conclusion: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy., SCOPUS: re.j, info:eu-repo/semantics/published

Les GTPases sont un groupe d'hydrolases diverses mais conservées au cours de l'évolution, catalysant la conversion du GTP en GDP. Leur fonction effectrice est régulée par une poche allostérique. L'interaction dynamique entre le GTP et le GDP, dans cette poche, est contrôlée par des protéines appelées facteurs d'échange de Guanine (GEF). Les fonctions des GEF hématopoïétiques et la manière dont ils influencent le développement des cellules B restent obscures. Notre projet de recherche vise à comprendre l'interaction entre ces GEF, notamment Dock2, et les signaux qui façonnent le métabolisme des lymphocytes B et leur répertoire de BCR. La protéine Dock2 est impliquée dans le remodelage du cytosquelette d’actine nécessaire à la migration des lymphocytes en réponse à la signalisation des chimiokines, et à la formation du BCR. Chez l'humain, ce gène est impliqué dans les immunodéficiences sévères combinées. La perturbation de l'intégrité de Dock2 a des répercussions pouvant toucher plusieurs mécanismes moléculaires, allant de la migration à la toxicité cellulaire. La littérature rapporte qu’une mutation inactivante de ce gène, impliquant un codon stop via la duplication des exons 28 et 29, a des répercussions sur le développement des cellules B. Cette variante de Dock2 est importante car en plus de la migration perturbée des lymphocytes B, elle provoque d’autres phénotypes hématopoïétiques tels que la perte de cellules B de la zone marginale et l'augmentation des cellules T CD8+, chez les souris mutantes. Cette mutation est appelée Dock2Hsd en référence à leur origine de chez Harlan Sprague Dawley. Des résultats préliminaires ont montré une perte de fonction et une lymphopénie particulièrement une perte de lymphocytes B de la zone marginale, chez les souris déficientes en Dock2. Sachant que, la robustesse de la réponse humorale est étayée par le métabolisme des cellules B car ces dernières doivent être activées, migrer efficacement et à temps voulu parce que l'absence de, GTPases are a diverse but evolutionarily conserved group of hydrolases catalyzing the conversion of GTP to GDP. Their effector function is tightly regulated by an allosteric pocket. The dynamic interaction between GTP and GDP in this pocket is controlled by proteins known as GEFs (Guanine Exchange Factors). The functions of hematopoietic GEFs and how they influence B cell development remain obscure. Our research project aims to understand the interaction between these GEFs, in particular Dock2, and the signals that shape B cell metabolism and their BCR repertoire. The protein Dock2 is involved in the remodeling of the actin cytoskeleton required for lymphocyte migration in response to chemokine signaling, and BCR formation. In humans, this gene is implicated in severe combined immunodeficiencies. Disruption of Dock2 integrity therefore has repercussions that can affect several molecular mechanisms, from migration to cell toxicity. The literature reports that an inactivating mutation of this gene, involving a stop codon via duplication of exons 28 and 29, has notable repercussions on B cell development. This Dock2 variant is particularly important because, in addition to disrupted B cell migration, it causes other hematopoietic phenotypes such as loss of marginal zone B cells and increased CD8+ T cells, in mutant mice. This mutation is called Dock2Hsd in reference to their origin from Harlan Sprague Dawley. Literature have shown a loss of function and lymphopenia particularly a loss of marginal zone B lymphocytes, in Dock2-deficient mice. The robustness of the humoral response is underpinned by B cell metabolism, since B cells need to be activated, migrate efficiently and in a timely manner. The absence of secondary signals after 9 hours leads to metabolic toxicity and apoptosis. Then we hypothesized that, in addition to loss of function and lymphopenia, Dock2 deficiency would have a significant impact on B cell metabolism. The overall aim is to study how D

Le sepsis se caractérise par une réponse immunitaire dérégulée de l’hôte à une infection qui est associée à une dysfonction d’organes, dont souvent celle du cœur (SIMD). Il est connu que plusieurs altérations du métabolisme énergétique prennent part au développement de la SIMD, notamment la dysfonction mitochondriale qui se caractérise par une diminution des processus oxydatifs intramitochondriaux ainsi que de la capacité des cardiomyocytes (CMA) à utiliser les substrats énergétiques sanguins, principalement le glucose et les acides gras (AG). À l’heure actuelle, le seul traitement disponible pour la SIMD est la dobutamine, mais son efficacité est limitée. Ainsi, une alternative potentielle à cette dernière est les ligands apélinergiques, soit des peptides endogènes connus pour avoir plusieurs effets systémiques, notamment au niveau du système cardiovasculaire, dont le métabolisme cardiomyocytaire. Ainsi, l’objectif du projet de recherche est de démontrer que les dérivés apélinergiques (apéline-13 et ELABELA) peuvent restaurer la flexibilité métabolique du cœur septique et, considérant ce que nous savons sur celles-ci, nous avons émis l’hypothèse qu’elles étaient capables d’améliorer l’utilisation des substrats énergétiques ainsi que la fonction mitochondriale du cœur septique. Afin de valider cette hypothèse, nous avons employé un modèle expérimental de sepsis murin par ponction et ligation coecale (CLP) duquel nous avons effectué des analyses du métabolisme cardiaque in vivo, ex vivo et in vitro. Plus précisément, le volet in vivo comprenait une étude de la métabolomique sanguine systémique ainsi que l’analyse de la captation de glucose et de palmitate marqués par TEP-scan. Le volet ex vivo comprenait l’analyse de l’activité d’enzymes clés et celui in vitro, la captation de glucose et d’acides gras marqués, ainsi que l’évaluation de l’expression des transporteurs GLUT4 et CD36 par immunobuvardage. Nous avons observé que le sepsis semble être associé à une diminuti, Sepsis is characterized by a dysregulated host immune response to an infection that is associated with organ dysfunction, often including sepsis-induced myocardial dysfunction (SIMD). Several alterations in energy metabolism take part in the development of SIMD, in particular mitochondrial dysfunction which is characterized by a decrease in intramitochondrial oxidative capacities as well as in the ability of cardiomyocytes to use blood energy substrates, mainly glucose and fatty acids. Currently, the only treatment available for SIMD is dobutamine, but its efficacy is limited. Thus, a potential alternative to it is the family of endogenous peptides referred to as apelins, which are known to have several systemic effects, notably on the cardiovascular system, including cardiomyocyte’s energy metabolism. The objective of this research is to demonstrate that apelin derivatives (apelin-13 and ELABELA) can restore the metabolic flexibility of the septic heart. Considering what we know about them, we hypothesize that they can improve the use of energy substrates as well as the mitochondrial function of the septic heart. In order to validate this hypothesis, we used an experimental model of murine sepsis by cecal and ligation puncture (CLP) from which we performed in vivo, ex vivo and in vitro analyses of cardiac metabolism. More precisely, the in vivo section included a metabolomic study of systemic blood as well as the analysis of labeled glucose and palmitate uptake by PET-scan. The ex vivo portion included key enzymes activity analyses, while the in vitro section was composed of labeled glucose and fatty acids uptake, as well as the evaluation of the expression of the transporters GLUT4 and CD36 through a Western blot essay. We observed that sepsis seems to be associated with a general decrease in mitochondrial function as well as a prioritization of the fatty acid metabolic pathway. Apelins, on the other hand, promote the entry of glucose and fatty acids int

Le diabète de type 2 est une pathologie complexe dont les causes métaboliques exactes nous échappent toujours. L’altération du métabolisme des acides gras chez les individus prédiabétiques (tolérance altérée au glucose; IGT) est une anomalie métabolique précoce qui découle essentiellement d’une dysfonction de la fonction métabolique des tissus adipeux blancs (TAB). Une autre anomalie retrouvée chez les individus obèses et diabétiques est une activité plus forte du système endocannabinoïde (SEC). Les endocannabinoïdes (ECs) circulants ont été associés de manière répétée avec l’obésité et le syndrome métabolique. De plus, des travaux in vitro et in vivo chez la souris ont montré un lien entre la fonction métabolique des TAB et le SEC. Toutefois, le rôle du SEC dans le métabolisme énergétique des TAB chez l’humain reste à démontrer. Pour déterminer l’association potentielle des endocannabinoïdes circulants sur la fonction métabolique des TAB in vivo chez l’homme et la femme, nous avons évalué la dynamique postprandiale des ECs plasmatiques chez 40 individus avec tolérance normale au glucose (NGT) et avec IGT chez qui la fonction métabolique des TAB a été mesurée à l’aide de méthodes de radiotraceurs en tomographie d’émission par positrons (TEP) et de traceurs isotopiques stables administrés oralement et par voie intraveineuse. Après une cinétique postprandiale de 6 heures, les ECs circulants de la famille des N-AcylÉthanolamines (NAEs) montrent une dynamique qui suit celle des acides gras non-estérifiés (AGNE). La concentration circulante d’ArachidonoylEthanolAmine (AEA) est le facteur prédominant prédisant indépendamment le taux d’apparition du palmitate (Ra palmitate) et est également liée au Ra palmitate issu de la lipolyse intracellulaire des triglycérides (TG) par les TAB. Les ECs de la famille des 2-monoacylglycérols (2-MAGs) montrent quant à eux une dynamique postprandiale qui s’apparente au "spillover" des AGNE au niveau intravasculaire lors de l’hydrolyse des

El present projecte de final de master s’emplaça al municipi de Malgrat de Mar a on, juntament amb la resta de poblacions del Maresme, l’agricultura hi té un paper rellevant en quan al desenvolupament econòmic i l’organització territorial. El delta de la Tordera és una de les àrees més rellevants a nivell hortícola de Catalunya, gràcies a les seves característiques de zona deltaica i la qualitat del freàtic. El conjunt de cooperatives i productors s’agrupa sota l’Espai Agrari de la Baixa Tordera. En analitzar l’impacte ambiental del sector alimentari ens adonem del seu pes en relació a d’altres sectors econòmics. Només la fase de producció ja representa un 14% de les emissions de CO2,eq a escala nacional. Actualment la complexitat del sistema alimentari va en augment a causa, entre d’altres aspectes, de la seva desvinculació amb el territori i la gran quantitat d’agents que hi intervenen. Això s’acaba traduint en l’augment de les emissions de CO2eq associades a les diferents parts del procés, destacant-ne notablement l’etapa del transport. La reducció de la distància entre el lloc de producció i consum és un punt clau per assolir un model alimentari més sostenible, també en l'àmbit social i cultural. Així doncs, amb la nostra actuació, proposem revaloritzar les diferents parts del sistema alimentari de manera local a través de la vinculació entre consumidors i productors. Incidim en l’àmbit educatiu a partir de la creació d’un equipament segregat que doni suport a les activitats docents vinculades amb l’alimentació. D’aquesta manera es vol vincular l’àrea productiva de Malgrat de Mar amb el consum dels menjadors escolars i en conseqüència, amb els hàbits alimentaris de la població en general., El presente proyecto de final de master se emplaza en el municipio de Malgrat de Mar donde, junto con el resto de poblaciones del Maresme, la agricultura tiene un papel relevante en cuando al desarrollo económico y la organización territorial. El delta de la Tordera es una de las áreas más relevantes a nivel hortícola de Cataluña, gracias a sus características de zona deltaica y la calidad del freático. El conjunto de cooperativas y productores se agrupa bajo el Espacio Agrario de la Baja Tordera. Al analizar el impacto ambiental del sector alimentario nos damos cuenta de su peso en relación a otros sectores económicos. Solo la fase de producción ya representa un 14% de las emisiones de CO₂,eq a escala nacional. Actualmente la complejidad del sistema alimentario va en aumento a causa, entre otros de otros aspectos, de su desvinculación con el territorio y la gran cantidad de agentes que intervienen. Esto se acaba traduciendo en el aumento de las emisiones de CO2eq asociadas a las diferentes partes del proceso, destacando notablemente la etapa del transporte. La reducción de la distancia entre el lugar de producción y consumo es un punto clave para lograr un modelo alimentario más sostenible, también en el ámbito social y cultural. Así pues, con nuestra actuación, proponemos revalorizar las diferentes partes del sistema alimentario de manera local a través de la vinculación entre consumidores y productores. Incidimos en el ámbito educativo a partir de la creación de una equipación segregada que apoye a las actividades docentes vinculadas con la alimentación. De este modo se quiere vincular el área productiva de Malgrat de Mar con el consumo de los comedores escolares y en consecuencia, con los hábitos alimentarios de la población en general., This master's final project is located in the municipality of Malgrat de Mar where, together with the rest of the towns of the Maresme, agriculture plays a relevant role in terms of economic development and territorial organization. The Tordera delta is one of the most relevant areas at the horticultural level of Catalonia, thanks to its characteristics of delta area and the quality of the phreatic. The group of cooperatives and producers is grouped under the Agrarian Space of the Baixa Tordera. By analyzing the environmental impact of the food sector we realize its weight in relation to other economic sectors. Only the production phase already accounts for 14% of CO2 emissions at national level. Currently, the complexity of the food system is increasing due, among other aspects, to its decoupling with the territory and the large number of agents involved. This ends up leading to the increase in CO2eq emissions associated with the different parts of the process, notably the transport stage. The reduction of the distance between the place of production and consumption is a key point to achieve a more sustainable food model, also in the social and cultural field. Therefore, with our action, we propose to revalue the different parts of the food system locally through the link between consumers and producers. We focus on the educational field through the creation of a segregated equipment that supports teaching activities related to food. In this way, we want to link the productive area of Malgrat de Mar with the consumption of school canteens and consequently, with the eating habits of the general population.

Pour survivre et croître, les bactéries ont besoin de réguler leur expression génique pour s’adapter à leur environnement. Les riborégulateurs sont un des moyens à la disposition de ces organismes pour atteindre ce but. Les riborégulateurs sont des ARN structurés retrouvés majoritairement en 5’ des gènes qu’ils régulent que ce soit au niveau de la transcription ou de la traduction. Cette régulation est rendue possible par la liaison d’un ligand particulier qui va entraîner le changement de conformation du riborégulateur, changement qui résultera en l’expression ou non du gène en aval. Ces structures sont largement répandues chez les bactéries et quelques exemples existent également chez les plantes. Ceci amène deux questions : quelle est leur importance dans la survie bactérienne et comment s’en servir pour étudier le métabolisme bactérien ? Dans un premier projet appelé KillSwitch, j’ai essayé de déterminer leur impact en procédant à leur délétion pour observer la survie et la compétitivité de la bactérie, lorsque privée de ce moyen de régulation. Si ce projet n’a pas été mené à son terme pour diverses raisons, il semblerait que dans certaines conditions particulières, la bactérie est affectée par la perte de son riborégulateur. D’autres études sont nécessaires pour confirmer et compléter ces premiers résultats. Dans un second projet, j’ai développé un outil basé sur un riborégulateur utilisé comme un biosenseur pour suivre la concentration en ligand en fonction de mutations dans le génome. En effet, cet outil plasmidique a été transféré dans une collection de gènes mutants d’E. coli pour étudier la régulation d’une protéine fluorescente via un riborégulateur TPP. Ceci nous a permis d’identifier un certain nombre de gènes dont l’absence fait varier la concentration en TPP dans la cellule, effets connus pour certains, mais observés pour la première pour d’autres. Ce système peut être adapté à d’autres riborégulateurs qu’ils soient naturels ou synthétiques. Il devrai

Hypertrophic cardiomyopathy (HCM) is a frequently occurring disease of the heart muscle, characterized by asymmetrical left ventricular hypertrophy and diastolic dysfunction. In approximately half of all patients the disease is caused by mutations in genes encoding sarcomere proteins. These patients are referred to as genotype-positive (G-positive). In the other half of patients the disease is not caused by genetic mutations (genotype-negative patients; G-negative). Despite the fact that mutations in sarcomere proteins cause HCM in G-positive patients there is remarkable variation in the extent to which mutation carriers develop HCM. One mutation carrier may develop severe hypertrophy and heart failure at young age, while another remains asymptomatic until old age. Thus, the presence of a mutation itself is not sufficient to cause disease. Clinical studies suggest that traditional cardiovascular risk factors such as obesity and diabetes mellitus type II may contribute substantially to disease penetrance and severity of HCM. These factors have a considerable negative impact on cardiac metabolism. In part 1 of this thesis we explore how metabolic perturbations at the systemic level are involved in triggering G-positive HCM. Hereto we provide an overview of clinical literature and design a theoretical framework outlining cellular mechanisms via which obesity-associated metabolic perturbations may trigger HCM. Subsequently we tested this framework in mouse models of G-positive HCM. Our studies showed that in certain mouse models it is possible to indeed trigger HCM by feeding an unhealthy diet, which was accompanied by marked metabolic alterations in the diseased heart. In part 2 of this thesis we study how metabolic perturbations are related cardiac remodeling in HCM. To this end we used myectomy tissue samples of patients with HCM. Structural and functional analyses showed that mitochondrial dysfunction was linked to disruption of cardiomyocyte architecture. Additiona

Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration-time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect-time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis., SCOPUS: ar.j, info:eu-repo/semantics/published

Aims/hypothesis: We aimed to investigate the association between the abundance of Dysosmobacter welbionis, a commensal gut bacterium, and metabolic health in human participants with obesity and diabetes, and the influence of metformin treatment and prebiotic intervention. Methods: Metabolic variables were assessed and faecal samples were collected from 106 participants in a randomised controlled intervention with a prebiotic stratified by metformin treatment (Food4Gut trial). The abundance of D. welbionis was measured by quantitative PCR and correlated with metabolic markers. The in vitro effect of metformin on D. welbionis growth was evaluated and an in vivo study was performed in mice to investigate the effects of metformin and D. welbionis J115T supplementation, either alone or in combination, on metabolic variables. Results: D. welbionis abundance was unaffected by prebiotic treatment but was significantly higher in metformin-treated participants. Responders to prebiotic treatment had higher baseline D. welbionis levels than non-responders. D. welbionis was negatively correlated with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and fasting blood glucose levels in humans with obesity and type 2 diabetes. In vitro, metformin had no direct effect on D. welbionis growth. In mice, D. welbionis J115T treatment reduced body weight gain and liver weight, and improved glucose tolerance to a better level than metformin, but did not have synergistic effects with metformin. Conclusions/interpretation: D. welbionis abundance is influenced by metformin treatment and associated with prebiotic response, liver health and glucose metabolism in humans with obesity and diabetes. This study suggests that D. welbionis may play a role in metabolic health and warrants further investigation. Clinical trial: NCT03852069 Graphical Abstract: [Figure not available: see fulltext.]., SCOPUS: ar.j, info:eu-repo/semantics/published

info:eu-repo/semantics/published

El model agroalimentari actual, centrat en el mercat global, és un engranatge molt ben calibrat, però alhora fràgil, el qual depèn principalment de dos elements significatius. El primer és el transport a llargues distàncies, ja que només una part dels productes (principalment frescos) són produïts a una distància curta (menys de 100 km). Però en última instància tot el sistema agroalimentari depèn del segon element: l’accés del model energètic a energia (fòssil) a preus baixos. Des del moment de producció fins al consum i processament, l’energia fòssil és omnipresent. Des dels fertilitzants, al combustible pel transport, manteniment en refrigeradors industrials i particulars i finalment amb un sistema de recollida industrialitzat que també requereix altes quantitats d’energia. Aquest model tan fràgil i contaminant, si és revisat, pot passar de ser nociu pel medi ambient globalment i localment a ser beneficiós en la majoria dels seus aspectes. Mirar la manera com ens alimentem des d’una visió crítica, analitzant els potencials dels què disposa el territori pot servir com a eina per a reterritorialitzar-lo i recuperar un model agroalimentari complex, que aporti beneficis a les persones que produeixen el menjar i a les que el consumeixen, però també al territori. En aquest procés de recerca, fem una revisió de quin és l’impacte ambiental de l’alimentació a través de totes les seves etapes per detectar quins són els punts crítics des d’on es pot intervenir com a arquitectes i urbanistes. A partir de la revisió de diversos teòrics urbanistes i geògrafs sensibles amb el metabolisme del territori, s’escull la conca hidrogràfica del riu Tordera com a element d’anàlisi i s’investiga la relació amb l’impacte territorial de la producció alimentària des d’una visió històrica. Finalment, s’explora la possibilitat de reduir l’impacte ambiental del consum d’aliments a la conca a partir de l’augment de la superfície agrícola de la conca., El modelo agroalimentario actual, centrado en el mercado global, es un engranaje muy bien calibrado, pero a la vez frágil, el cual depende principalmente de dos elementos significativos. El primero es el transporte a largas distancias, puesto que solo una parte de los productos (principalmente frescos) son producidos a una distancia corta (menos de 100 km). Pero en última instancia todo el sistema agroalimentario depende del segundo elemento: el acceso del modelo energético a energía (fósil) a precios bajos. Desde el momento de producción hasta el consumo y procesamiento, la energía fósil es omnipresente. Desde los fertilizantes, al combustible por el transporte, mantenimiento en refrigeradores industriales y particulares y finalmente con un sistema de recogida industrializado que también requiere altas cantidades de energía. Este modelo tan frágil y contaminante, si es revisado, puede pasar de ser nocivo por el medio ambiente globalmente y localmente a ser beneficioso en la mayoría de sus aspectos. Mirar la manera como nos alimentamos desde una visión crítica, analizando los potenciales de los que dispone el territorio puede servir como herramienta para reterritorialitzarlo y recuperar un modelo agroalimentario complejo, que aporte beneficios a las personas que producen la comida y a las que lo consumen, pero también en el territorio. En este proceso de investigación, basura una revisión de cuál es el impacto ambiental de la alimentación a través de todas sus etapas para detectar cuáles son los puntos críticos desde donde se puede intervenir como arquitectos y urbanistas. A partir de la revisión de varios teóricos urbanistas y geógrafos sensibles con el metabolismo del territorio, se escoge la cuenca hidrográfica del río Tordera como elemento de análisis y se investiga la relación con el impacto territorial de la producción alimentaria desde una visión histórica. Finalmente, se explora la posibilidad de reducir el impacto ambiental del consumo de alimentos a la c, The current agri-food model, centered on the global market, is a very well-calibrated but fragile mechanism that depends mainly on two significant elements. The first is long-distance transport, since only a part of the products (mainly fresh) are produced within a short distance (less than 100 km). But ultimately the entire agri-food system depends on the second element: the energy model’s access to (fossil) energy at low prices. From the moment of production to consumption and processing, fossil energy is omnipresent. From fertilizers, to fuel for transportation, maintenance in industrial and private refrigerators and finally with an industrialized collection system that also requires high amounts of energy. This fragile and polluting model, if revised, can go from being harmful to the environment globally and locally to being beneficial in most aspects. Looking at the way we feed ourselves from a critical point of view, analyzing the potentials of the territory can serve as a tool to reterritorialize it and recover a complex agri-food model, which brings benefits to the people who produce the food and to those who consume it, but also to the territory. In this research process, we have reviewed the environmental impact of food through all its stages in order to detect the critical points from which we can intervene as architects and urban planners. From the review of several urban theorists and geographers sensitive to the metabolism of the territory, the Tordera river basin is chosen as an element of analysis and the relationship with the territorial impact of food production is investigated from a historical perspective. Finally, the possibility of reducing the environmental impact of food consumption in the basin by increasing the agricultural area of the basin is explored.

Aquest estudi ofereix una exploració integral sobre l'orientació d'hipergràfs dins de les vies metabòliques. El nostre focus va estar en la formulació d'un model AMPL, permetent als investigadors obtenir solucions efectives mitjançant l'optimització de ILP. Les principals contribucions del nostre treball inclouen: - Desenvolupament d'un model lògicament robust per resoldre el problema de l'orientació d'hiperarestes en vies metabòliques. - Avaluació comparativa del model respecte alternatives, identificant punts forts, punts febles i escenaris d'aplicació òptims. - Introducció de restriccions addicionals considerades significatives en el camp de les vies metabòliques, incloentí: - La prevenció de la inversió en reaccions específiques. - La identificació de certs vèrtexs com interns. - La identificació de certs vèrtexs com externs. A més, aquest article presenta una eina d'interfície gràfica d'usuari (GUI) amigable que facilita l'exploració del model, l'anàlisi de resultats, l'addició de restriccions i l'orientació de vies metabòliques en escenaris del món real., This study offers a comprehensive exploration into the orientation of hypergraphs within metabolistic pathways. Our focus was on formulating an AMPL model, enabling researchers to attain effective solutions through ILP optimization. Key contributions of our work encompass: - Development of a logically robust model for solving hyperedge orientation in metabolistic pathways. - Benchmarking the model against alternatives, identifying strengths, weaknesses, and optimal application scenarios. - Introduction of additional constraints deemed significant in metabolistic pathways, including: - Prevention of inversion in specific reactions. - Identification of certain vertices as internal. - Identification of certain vertices as external. Additionally, this paper introduces a user-friendly GUI tool that facilitates model exploration, result analysis, constraint addition, and pathway orientation in real-world scenarios.

The liver is the major organ involved in the biotransformation of drugs and other chemicals. Disturbance of this process can lead to accumulation of toxic compounds and is therefore a key determinant in liver toxicity. Currently drug safety evaluations are mainly based on animal testing, however differences in drug metabolism between species hamper accurate prediction of the human situation. A shift towards human-based cell models to screen for drug-induced liver toxicity is ongoing. This thesis is focused on the use of intrahepatic cholangiocyte organoids (liver organoids) in the development of a human-based in vitro models for liver toxicity. These organoids can be applied in disease modeling and regenerative medicine approaches. We have shown the biotransformation capacity of liver organoids and their sensitivity to well-known drugs, which showed their potential as novel model for liver toxicity although a further improvement of the hepatic functionality is desired to accurately predict drug-induced liver toxicity. The addition of microphysiological relevant features, e.g., co-culture and/or flow, in in vitro systems is known to improve hepatic functionality of (stem cell-derived) hepatic cells. We added such features using bioprinting techniques combined with media perfusion in a tailor-made bioreactor. The techniques described in this these provide tools to aid in creating more complex in vivo-like models with increased cellular functionality. Bioengineered microphysiologically relevant tissue analogs can help to decrease the gap between animal models and simplistic in vitro models, which leads to a safer and more effective drug development.

En l'absence de traitements ou de vaccins, les infections par les virus de la dengue (VDEN) et Zika (VZIK), constituent un enjeu majeur de santé publique dans le monde. Lors de l’infection, les VDEN et VZIK remodèlent le réticulum endoplasmique (ER) pour former des usines de réplication virale (URv) qui incluent les convolutions de membrane (CM). De plus, ils induisent l'élongation des mitochondries (par NS4B pour VDEN) en faveur de la réplication virale suggérant une modulation des fonctions mitochondriales. Des observations antérieures ont identifié des contacts physiques entre les mitochondries et les CM en même temps qu'une diminution des contacts de l’interface réticulo-mitochondriale (IRM). Par conséquent, nous avons étendu nos recherches au niveau moléculaire, par comment les VDEN et VZIK exploitent l’IRM pour leur réplication, et si cela modifie le métabolisme respiratoire mitochondriale et l'apoptose. Des analyses en microscopie électronique à transmission démontrent que les VDEN et VZIK altèrent l’IRM. Celle-ci repose sur plusieurs interactions entre des protéines situées à la surface des deux organites, telles que PTPIP51-VAPB, SYNJ2BP-RRBP1 ou VDAC1-IP3R1. L'infection par les VDEN et VZIK induit une altération globale de ces interactions. Simultanément, l'infection virale altère le profil d'expression de RRBP1 et SYNJ2BP, suggérant qu'ils ciblent spécifiquement cette interaction protéine-protéine. Par ailleurs, l'inhibition de l'expression des protéines de l’IRM augmente la réplication virale, ce qui soutient que l’IRM est altérée au bénéfice de la réplication virale. De plus, l'infection par VDEN/VZIK et l'expression de NS4B modulent de manière significative la phosphorylation oxydative mitochondriale. Nos analyses métabolomiques et mitoprotéomiques révèle que cela est corrélé à une diminution de l'abondance de plusieurs métabolites du cycle de Krebs et à des changements dans la stoechiométrie des protéines de la chaîne de transport d'électrons. Par

info:eu-repo/semantics/published

The gastrointestinal epithelium constitutes a chemosensory system for microbiota-derived metabolites such as short-chain fatty acids (SCFA). Here, we investigate the spatial distribution of Olfr78, one of the SCFA receptors, in the mouse intestine and study the transcriptome of colon enteroendocrine cells expressing Olfr78. The receptor is predominantly detected in the enterochromaffin and L subtypes in the proximal and distal colon, respectively. Using the Olfr78-GFP and VilCre/Olfr78flox transgenic mouse lines, we show that loss of epithelial Olfr78 results in impaired enterochromaffin cell differentiation, blocking cells in an undefined secretory lineage state. This is accompanied by a reduced defense response to bacteria in colon crypts and slight dysbiosis. Using organoid cultures, we further show that maintenance of enterochromaffin cells involves activation of the Olfr78 receptor via the SCFA ligand acetate. Taken together, our work provides evidence that Olfr78 contributes to colon homeostasis by promoting enterochromaffin cell differentiation., SCOPUS: ar.j, info:eu-repo/semantics/published

Most phytophagous insect species exhibit a limited diet breadth and specialize on a few or a single host plant. In contrast, some species display a remarkably large diet breadth, with host plants spanning several families and many species. It is unclear, however, whether this phylogenetic generalism is supported by a generic metabolic use of common host chemical compounds ('metabolic generalism') or alternatively by distinct uses of diet-specific compounds ('multi-host metabolic specialism')? Here, we simultaneously investigated the metabolomes of fruit diets and of individuals of a generalist phytophagous species, Drosophila suzukii, that developed on them. The direct comparison of metabolomes of diets and consumers enabled us to disentangle the metabolic fate of common and rarer dietary compounds. We showed that the consumption of biochemically dissimilar diets resulted in a canalized, generic response from generalist individuals, consistent with the metabolic generalism hypothesis. We also showed that many diet-specific metabolites, such as those related to the particular color, odor, or taste of diets, were not metabolized, and rather accumulated in consumer individuals, even when probably detrimental to fitness. As a result, while individuals were mostly similar across diets, the detection of their particular diet was straightforward. Our study thus supports the view that dietary generalism may emerge from a passive, opportunistic use of various resources, contrary to more widespread views of an active role of adaptation in this process. Such a passive stance towards dietary chemicals, probably costly in the short term, might favor the later evolution of new diet specializations.

Als catalans ens agrada barrejar coses, fins i tot a la gastronomia. Un exemple evident d’aquest costum és el mar i muntanya. Els plats de mar i muntanya, com el seu nom indica, combinen ingredients típics de la cuina de muntanya amb els marins. Tot degustant aquests plats, a pocs se’ls acut pensar en les similituds i diferències entre els organismes marins i els terrestres. Per què una gamba i un pollastre són tan diferents? Més enllà que uns respiren amb brànquies i els altres amb pulmons, les diferències entre tots dos estan arrelades a la base del mateix ecosistema