Towards disentangling the genetic complexity and clinical heterogeneity of psychotic disorders: from family-based approaches to gene-environment studies

[eng] Psychotic disorders are psychiatric conditions with a worldwide prevalence of around 4% and a tremendous personal, economic and social burden. As complex phenotypes, psychotic disorders are caused by multiple genetic variants, environmental factors and their interaction. According to this, a better understanding of the genetic and environmental influences underlying these disorders may provide a way to dissect the biology of psychosis and, ultimately, allow developing novel therapies. However, the study of the aetiological basis of schizophrenia and other psychotic disorders, though, has a serious limitation in the high biological heterogeneity underlying these pathologies. The heterogeneity of clinical profiles and the high phenotypic variability, in turn, causes uncertainty on the genetic results related to these disorders. Thus, the reduction of phenotypic complexity has become an essential step to contribute to the genetic dissection of brain complex phenotypes. The present dissertation aimed to contribute disentangling the heterogeneity of psychotic disorders by means of different approaches: the use of family-based studies, the use of psychosis-associated intermediate phenotypes and the use of gene-environment interaction studies. Three specific hypotheses related to these approaches have been tested, giving rise to six manuscripts submitted to international peer reviewed journals. The results of the present thesis reveal that the combined use of family-based designs and intermediate phenotypes related to psychosis may facilitate the identification of more homogeneous forms of psychotic disorders in terms of genetic aetiology. Thus, by means of this strategy, two different subclinical phenotypes such as schizotypy (a set of personality traits) and the cognitive dimension of attention and working memory have been identified as familial vulnerability markers for psychosis in samples of families affected with schizophrenia and bipolar disorder, respectively. The study of the familial aggregation pattern of these phenotypes have lead to the identification of subgroups of families with similar phenotypic –and, therefore also genotypic– profiles. Moreover, by using family-based association designs, different genes involved in the modulation of synaptic plasticity (DAOA, ZNF804A, AKT1) have been associated with the risk for psychosis, as measured with the expression of intermediate phenotypes, including schizotypy and cognitive performance. Also, results from this thesis provide evidence of the role genetic variability on cognitive performance and also as a modulator of the effect of cannabis use on the variance of other intermediate phenotypes. Particularly, it has been revealed the effect of AKT1 gene on attentional processes and, also, the effect of ZNF804A gene on the expression of schizotypy conditional to the cannabis use. Despite the last advances in the comprehension of the aetiology of psychosis, the identification of the involved genetic factors has still a long way to go. Thus, it is necessary to continue making efforts towards understanding the aetiopathogenic basis of psychotic disorders, taking into account both genetic and environmental factors. The present dissertation has intended to provide our grain of sand to the collective construction of knowledge on the aetiology of psychosis by means of using different strategies that have proven to contribute to elucidating the heterogeneity underlying these disorders, which in turn might lead to an improvement of the identification of the underlying causal genetic variants.[cat] Els trastorns psicòtics són trastorns mentals amb una prevalença mundial del 4% i amb una gran càrrega personal, econòmica i social associada, que estan causats per factors genètics, factors ambientals i la interacció d’ambdós durant diferents etapes del desenvolupament cerebral. Si volem disposar de noves teràpies que ajudin a millorar la qualitat de vida de les persones amb algun diagnòstic psicòtic, és evident que abans ens cal entendre millor les contribucions que la càrrega genètica i la càrrega ambiental de cada individu tenen en el desenvolupament d’aquests trastorns. Malauradament, l’estudi de les bases etiològiques de l’esquizofrènia i d’altres trastorns psicòtics està condicionada per la gran heterogeneïtat clínica que presenten aquests fenotips. Per tant, per tal de seguir avançant en la identificació dels factors genètics associats al risc per a psicosi, és necessari conèixer i abordar els factors relacionats amb aquesta heterogeneïtat. En aquest sentit, aquesta tesi pretén contribuir a abordar aquesta heterogeneïtat intrínseca als trastorns psicòtics a través de diferents estratègies: l’ús de mostres de famílies, l’ús de fenotips intermedis associats al risc per a psicosi i l’estudi de la interacció gen-ambient en l’etiologia d’aquests trastorns. En aquesta tesi s’han plantejat tres hipòtesis diferents, que han donat lloc a 6 articles publicats en revistes científiques internacionals. Els resultats inclosos en la tesi revelen que l’anàlisi de fenotips intermedis associats al risc per psicosi en mostres de famílies facilita la identificació de formes més homogènies de psicosi, en relació a la seva etiologia genètica. Així doncs, mitjançant aquesta estratègia s’han identificat dos fenotips subclínics, com són la esquizotípia (trets de personalitat) i la dimensió cognitiva de l’atenció i la memòria de treball, com a marcadors de vulnerabilitat familiar per a psicosi en una mostra de famílies afectades amb esquizofrènia i en una de famílies afectades amb trastorn bipolar, respectivament. L’estudi del patró d’agregació familiar d’aquests fenotips ha permès la identificació de subgrups de famílies amb perfils fenotípics –i, per tant, també genotípics– similars. A més, en mostres clíniques i també no-clíniques, s’ha identificat la relació d’alguns gens relacionats amb la plasticitat sinàptica (DAOA, ZNF804A, AKT1) amb el risc de patir psicosi, mesurat a través de l’expressió de diferents fenotips intermedis com els nivells d’esquizotípia o el rendiment cognitiu. Els resultats inclosos en aquesta tesi també evidencien el paper que la variabilitat genètica té sobre el rendiment cognitiu i, alhora, com a modulador de l’efecte que el consum de cannabis té sobre l’expressió de diferents fenotips intermedis. En particular, s’ha descrit l’efecte del gent AKT1 en l’atenció i també l’efecte del gen ZNF804A sobre l’expressió de l’esquizotípia condicionat al consum de cannabis. Tot i els últims avenços en la comprensió de la etiologia de la psicosi, la investigació dels factors genètics causants de la psicosi i la seva interacció amb els factors ambientals encara té un llarg camí per recórrer. Aquesta tesi ha pretès aportar un granet de sorra a la construcció col·lectiva d’aquest coneixement mitjançant l’ús de diferents estratègies, les quals han demostrat que poden ser molt útils per tal d’abordar d’una manera més eficaç l’heterogeneïtat clínica inherent als trastorns psicòtics i poder millorar la identificació de les variants genètiques i ambientals implicades

Pensar, fer i entendre ciència a través de l'error

El procés de construcció del coneixement científic és complex, dinàmic i col·lectiu a partir de l'argumentació basada en evidències, on l'error hi té un paper fonamental. La identificació d'errors i la reflexió al voltant d'aquest element són pràctiques científiques habituals, i sovint actuen com a motor d'aprenentatge, fent que les recerques avancin. Tanmateix, la ciència escolar sovint encara fomenta una visió de la ciència massa simple, linear i centrada en el producte final, on l'error no hi té cabuda. En aquest article es descriuen algunes experiències d'aula basades en un enfocament indagatiu on l'error s'aprofita per a desenvolupar la competència científica de l'alumnat.The process of construction of scientific knowledge is complex, dynamic, collective and built on evidence-based argumentation, in which error plays a fundamental role. The identification of errors and the subsequent reflection are common scientific practices, and often act as a learning engine, moving research fordward. However, school science often continues to foster a vision of science that is too simple, linear and focused on the final product, where there is no room for error. This article describes some classroom experiences based on an inquiry approach in which error is used to develop students' scientific competence.El proceso de construcción del conocimiento científico es complejo, dinámico y colectivo a partir de la argumentación basada en evidencias, donde el error tiene un papel fundamental. La identificación de errores y la reflexión alrededor de este elemento son prácticas científicas habituales, y a menudo actúan como motor de aprendizaje, haciendo que las investigaciones avancen. Sin embargo, la ciencia escolar a menudo todavía fundamenta una visión de la ciencia demasiado simple, linear y centrada en el producto final, donde no cabe el error. En este artículo se describen algunas experiencias de aula basadas en un enfoque indagativo donde el error se aprovecha para desarrollar la competencia científica del alumnado

Experiencia docente en diseño de bases de datos con la ayuda de herramientas de e-learning

Una de las competencias básicas en torno a la materia de bases de datos consiste en realizar el diseño conceptual y lógico de una base de datos relacional. En este artículo se presenta la experiencia realizada en el diseño de una base de datos con un número considerable de tablas y en relación a la organización y gestión de una empresa real. Para facilitar las tareas de corrección y evaluación a los profesores implicados se ha utilizado una plataforma de e-learning que corrige diagramas entidad/relación y los esquemas de bases de datos generados.Peer Reviewe

Stereodivergent addition of 4-Silyloxy-1,2-Allenes to aldehydes by hydroboration

We have established a new stereodivergent approach to 2-vinyl-1,3-diols based on a hydroboration of allene/addition of aldehyde tandem process. The stereocenter present next to the allenyl moiety (C1) in the starting allene effectively determines the configuration of the new formed carbinol (C3) whereas the relative configuration of C2 and C3 is determined by the configuration (E/Z) of the transient 2- alkenylborane intermediate. It should be noted that the order of mixing of the reagents and the kind of aldehyde used allowed us to obtain three out of the four possible diastereomers of the 1,3- diol

Competency maps: An effective model to integrate professional competencies across a STEM curriculum

Curricula designed in the context of the European Higher Education Area need to be based on both domain-specific and professional competencies. Whereas universities have had extensive experience in developing students’ domain-specific competencies, fostering professional competencies poses a new challenge we need to face. This paper presents a model to globally develop professional competencies in a STEM degree program, and assesses the results of its implementation after four years. The model is based on the use of competency maps, in which each competency is defined in terms of competency units. Each competency unit is described by their expected learning outcomes at three domain levels. This model allows careful analysis, revision and iteration for an effective integration of professional competencies in domain-specific subjects. A global competency map is also designed, including all the professional-competency learning outcomes to be achieved throughout the degree. This map becomes a useful tool for curriculum designers and coordinators. The results were obtained from four sources: 1) students’ grades (classes graduated from 2013 to 2016, the first four years from the new Bachelor’s Degree in Informatics Engineering at the Barcelona School of Informatics); 2) students’ surveys (answered by students when they finished the degree); 3) the government employment survey, where former students evaluate the satisfaction of the received training in the light of their work experience; and 4) the Everis Foundation University-Enterprise Ranking, answered by over 2000 employers evaluating their satisfaction regarding their employees’ university training, where the Barcelona School of Informatics scores first in the national ranking. The results show that competency maps are a good tool for developing professional competencies in a STEM degree.Peer ReviewedPostprint (author's final draft

Control of Therapeutic Levels of Anticoagulation and Associated Factors: A Prospective Cohort Study

Teràpia anticoagulant; Vitamin K; Estudis de cohortsTerapia anticoagulante; Vitamin K; Estudios de cohortesAnticoagulant therapy; Vitamin K; Cohort StudiesMaintaining therapeutic levels of anticoagulation is essential to avoid health complications in people who take vitamin K antagonists. This study aimed to analyze the influence of people’s characteristics and the presence of changes in their lives in the control of therapeutic levels of anticoagulation. A longitudinal multicenter study with a 1-year follow-up of a cohort of 199 people receiving anticoagulant therapy was performed. The effect of biological, clinical, social, lifestyle, and changes in life on the international normalized ratio (INR) was analyzed. During the follow-up, 46.7% of participants presented good INR control. At baseline, a diagnosis of atrial fibrillation (P = .00), the lack of comorbidities (P = .03), absence of depression (P = .04), and not following a pharmacological treatment with hypoglycemia drugs (P = .01) were associated with good INR control. During the follow-up, the variable of making changes to the usual diet was associated with poor INR control (P = .05). In the binary multiple regression model, factors associated with poor control were taking hypoglycemia drugs (P = .02) and the presence of depression (P = .04), and only the diagnosis of atrial fibrillation was associated with good control (P = .03). People with a diagnosis of atrial fibrillation had good INR control. Having comorbidities, suffering depression, taking hypoglycemia drugs, and making changes to the diet have a negative effect on INR control

In situ investigation of the mechanochemically promoted Pd–Ce interaction under stoichiometric methane oxidation conditions

The optimization of the supported Pd phase for CH4 activation on Pd/CeO2 catalysts has been a matter of great interest in the recent literature, aiming at the design of efficient methane abatement catalysts for Natural Gas fueled Vehicles (NGVs). Under lean conditions, a mixed Pd0 /PdO combination has been indicated as exhibiting the best performance, while controversial results have been reported under stoichiometric conditions depending on the support oxide, where either Al2O3 or zeolite-based supports are usually considered. Here, by means of synchrotron-based in situ NAP-XPS and XRD measurements, we follow the evolution of Pd species on Pd/CeO2 samples prepared by dry mechanochemical synthesis (M) under stoichiometric CH4 oxidation feed, unravelling a stable Pd0 /Pd2+ arrangement in a close to 1 : 1 ratio as the most active palladium state for CH4 activation when excess oxygen is not available, in contrast to what was reported for Pd/alumina materials, where metallic Pd0 nanoparticles showed the highest activity. The combination of NAP-XPS analysis and activity test results highlights the promotional effect of the Pd–Ce interaction, resulting in enhanced oxygen transfer and improved activity and stability of the Pd/CeO2 catalyst prepared by a novel mechanochemical approach even under low O2 content, large excess of water vapor (10 vol%) and high temperature exposure (4700 1C)