Evolução molecular do receptor serotoninérgico 5-HT3 em primatas do novo mundo e outros cordados

A serotonina (5-hidroxitriptamina, 5-HT) é uma molécula evolutivamente antiga, ubíqua e multifacetada, profundamente envolvida na regulação de muitos processos fisiológicos e comportamentais em animais, plantas, fungos e outros organismos. Esses processos incluem desenvolvimento, funções cardiovasculares e endócrinas, percepção sensorial, apetite, comportamento sexual, sono, cognição e memória. As funções da 5-HT são mediadas por seus receptores; em humanos, eles compõem um conjunto de 13 receptores ligados a proteína G (GPCR) e um receptor pentamérico de canal iónico (pLGIC): 5-HT3 (codificado por até cinco genes: HTR3A, HTR3B, HTR3C, HTR3D, e HTR3E). O receptor 5-HT3 forma um poro seletivo de íons que abre após ativação do receptor por 5-HT, permitindo a entrada de cátions na célula, e a despolarização neuronal, produzindo uma resposta excitatória rápida. Estabelecer relações entre variações genéticas e fenotípicas entre organismos durante a evolução é um dos maiores objetivos da biologia atual. Nesta Tese o receptor 5-HT3 é o objeto de estudo, para a melhor compreensão de sua evolução molecular, em pequena (Primatas do novo mundo ou NWM, primatas e mamíferos próximos, Capítulo 3) e grande escala (Cordados, Capítulo 4). No Capítulo 3 são apresentadas evidências de seleção positiva com possível importância funcional no gene HTR3A nos primatas do novo mundo, dentro do contexto dos primatas e mamíferos. Específicamente, quatro (4) sítios foram identificados (398, 403, 432 e 416) na região desordenada do domínio intracelular M3-M4, usando análises moleculares. Além disso, foram encontradas associações estatísticas desses sítios com traços reprodutivos e de comportamento social (tais como dispersão feminina do grupo natal e monogamia social), usando abordagens estatísticas clássicas e bayesianas, e foram identificados motivos lineares com potencial importância na interação com enzimas regulatórias (por ex. GSK3). Esses resultados sugerem que as variáveis achadas podem ter um papel importante na aquisição e manutenção de comportamentos adaptativos nos primatas do novo mundo. O Capítulo 4 foca na emergência e evolução dos diferentes membros da família gênica do receptor 5-HT3 nos cordados. Nele propomos que todos os membros da família 5-HT3 surgiram a partir dum único gene, que foi duplicado durante os dois grandes eventos de duplicação genômica que aconteceram cedo na evolução dos vertebrados, e que posteriormente experimentou sucessivas duplicações em tandem e perdas nas diferentes linhagens dos cordados, sugerindo um cenário complexo. Assim, HTR3A aparece em todas as linhagens investigadas, sob forte seleção purificadora, enquanto outras subunidades (HTR3C, HTR3D e HTR3E) foram perdidas e/ou duplicadas durante a evolução dos vertebrados, e experimentaram relaxamentos nas pressões seletivas. Esses achados sugerem um cenário no qual subunidades essenciais (como HTR3A) foram conservadas nas espécies devido à sua condição essencial para a formação e função do receptor, e somente variantes pontuais (como as descritas no Capítulo 3) foram permitidas e selecionadas em taxa e contextos evolutivos específicos. No entanto, subunidades “não essenciais” puderam acumular mais mutações, chegando inclusive a pseudogenizar, permitindo também a emergência de novas propriedades estruturais, assim como um maior repertório de receptores. Nossos resultados fornecem uma primeira visão da complexa história evolutiva do receptor 5-HT3, e nos permitem especular que a diversidade observada constitui um exemplo de evolvabilidade do sistema, que permitiu a regulação fina de uma ampla quantidade de processos fisiológicos e comportamentais nos vertebrados.Serotonin (5-hydroxytryptamine, 5-HT) is an evolutionary old, widespread, and multifaceted molecule, with profound involvements in the regulation of many behavioral and physiological processes in animals, plants, fungi, and other organisms. These processes include development, cardiovascular and endocrine function, sensory perception, appetite, sexual behaviour, sleep, cognition, and memory. Most serotonergic functions are mediated through its receptors, which in humans comprise a set of 13 G protein-coupled receptors, and a single ligand-gated ion channel: the 5-HT3 receptor. 5HT3 receptor (encoded by up to five genes HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E) forms a pentameric ion-selective pore that opens upon activation by 5-HT, allowing cation influx into the cell and membrane depolarization, and leading to a rapid, excitatory response. Establishing relationships between genetic and phenotypic variation across organisms along the course of evolution is one of the major goals in biology. In this Thesis, the 5-HT3 receptor is the study subject, in order to better understand its evolution at a molecular level on a small (New World monkeys, primates and related mammals, Chapter 3) and a bigger scale (all major Chordata lineages, Chapter 4). In Chapter 3, I present evidences for positive selection with putative functional importance in HTR3A variability in New World Monkeys, within a primate and mammalian context. Specifically, I identified four sites (398, 403, 432 and 416) located at disordered regions of the intracellular (M3-M4) domain, by using molecular analyses. In addition, I found statistical associations with reproductive and social behaviours (such as female-biased dispersal and social monogamy), using two different approaches (classical and Bayesian), and I searched for linear motifs that arose from the variants under positive selection, which that might potentially mediate protein-protein interaction with regulatory enzymes (e.g. GSK3). Our results suggest that the variants we found may play a role in mediating the acquisition and maintenance of adaptive behaviours in NWMs. In Chapter 4, I focused on the emergence and evolution of the members of the 5-HT3 receptor family in Chordata. I postulate that all 5-HT3 members arose from a single gene that underwent subsequent expansions during the two events of whole genome duplications (WGD) that occurred early in vertebrate evolution, followed by multiple events of tandem duplication and loss across lineages. This work shows a striking variability in number of subunits among chordate groups, revealing a more complex scenario than previously expected. Thus, HTR3A is found in all species surveyed, and it under strong purifying selection, while other subunits (e.g. HTR3C, HTR3D and HTR3E) are lost and/or duplicated in many diverse lineages, and experimented a relaxation in selective pressure. These findings are compatible with a scenario in which essential subunits (such as HTR3A) are conserved across species due to their essentiality for receptor formation and function, and only punctual variants (such as those we described in Chapter 3) are allowed and selected in specific taxa and contexts. On the other hand, non-essential subunits (e.g. CDE subunits) can accumulate more mutations (and even pseudogenize), thus allowing the emergence of novel structural properties, and thus a larger array of possible receptors. Altogether, the results presented in this Thesis provide a first glimpse at the complex evolutionary history of the 5-HT3 receptor family, and allow us to speculate that the observed diversity at the genic level constitute an example of system evolvability. Such flexibility, likely allowed fine-tuned regulation of a broad array of physiological and behavioral functions across vertebrates living under different ecological niches and selective pressures

Leveraging auxiliary data from arbitrary distributions to boost GWAS discovery with Flexible cFDR.

Funder: GlaxoSmithKlineGenome-wide association studies (GWAS) have identified thousands of genetic variants that are associated with complex traits. However, a stringent significance threshold is required to identify robust genetic associations. Leveraging relevant auxiliary covariates has the potential to boost statistical power to exceed the significance threshold. Particularly, abundant pleiotropy and the non-random distribution of SNPs across various functional categories suggests that leveraging GWAS test statistics from related traits and/or functional genomic data may boost GWAS discovery. While type 1 error rate control has become standard in GWAS, control of the false discovery rate can be a more powerful approach. The conditional false discovery rate (cFDR) extends the standard FDR framework by conditioning on auxiliary data to call significant associations, but current implementations are restricted to auxiliary data satisfying specific parametric distributions, typically GWAS p-values for related traits. We relax these distributional assumptions, enabling an extension of the cFDR framework that supports auxiliary covariates from arbitrary continuous distributions ("Flexible cFDR"). Our method can be applied iteratively, thereby supporting multi-dimensional covariate data. Through simulations we show that Flexible cFDR increases sensitivity whilst controlling FDR after one or several iterations. We further demonstrate its practical potential through application to an asthma GWAS, leveraging various functional genomic data to find additional genetic associations for asthma, which we validate in the larger, independent, UK Biobank data resource

Estudio del clima organizacional en una empresa prestadora de servicio de vigilancia y seguridad privada

Abstract The Organizational Climate (OC) is a basic factor in the appraisals that workers have of the structures and processes that occur in the workplace, its importance lies in the fact that an employee’s behavior is the result of perceptions that he/she has from the organizational factors , which will depend in large part , from the activities , interactions, and another set of experiences that each member has with the organization. Hence the CO reflects the interaction between personal The Organizational Climate (OC) is a basic factor in the findings that workers have the structures and processes that occur in the workplace, its importance lies in the fact that an employee’s behavior is the result of perceptions that the organizational factors, which will depend , in large part , activities , interactions, and another set of experiences that each member has with the organization. Hence the CO reflects the interaction between personal and organizational characteristics ones. The type of design was transverse descriptive. The sample consisted on 81 subjects of operational level, consisting of the Guards who perform the service of Surveillance and Private Security and 11 subjects performing administrative functions. We concluded that the current satisfactory climate perception by employees of this organization is closely linked to the commitment that is currently assumed by them from all the hierarchical levels.            El Clima Organizacional (CO) es un factor básico en las apreciaciones que los trabajadores tienen de las estructuras y procesos que ocurren en el medio laboral, su importancia radica en el hecho de que la conducta de un empleado es el resultado de las percepciones que tenga de la organización; las cuales van a depender, en gran medida, de las actividades, interacciones y otra serie de experiencias que cada miembro tenga. De ahí que el CO refleje la interacción entre características personales y organizacionales. El tipo de diseño fue descriptivo transversal. La muestra estuvo conformada por 92 miembros de la organización, de los cuales 81 son empleados del nivel operativo, quienes prestan el servicio de Vigilancia y Seguridad Privada, y 11 son funcionarios administrativos. Se utilizó un diseño transversal. Los resultados permitieron concluir la percepción de un CO satisfactorio por parte de los empleados de esta organización, en ambos niveles jerárquicos, lo cual está estrechamente ligado al compromiso que actualmente asumen los mismos sin distingo del cargo ocupado. El objetivo de la presente investigación fue determinar el clima organizacional imperante en una empresa de servicio de vigilancia en la ciudad de Santa Marta.   &nbsp

Evaluation physicochemical oil guts viscera bocachico (prochilodus magdalenae) and tilapia plateada (oreochromis niloticus)

El objetivo del presente trabajo fue evaluar las características fisicoquímicas del aceite crudo y refinado obtenido de las vísceras de bocachico (Prochilodus magdalenae) y la tilapia plateada (Oreochromis niloticus), capturadas en la Ciénaga de Zapatosa. Se tuvieron en cuenta las épocas de invierno y verano para determinar diferencias significativas entre los aceites obtenidos de cada especie. Se tomaron muestras de cuatro poblaciones pesqueras aledañas a la ciénaga, y se conformó con éstas una sola unidad muestral. El aceite crudo extraído de las vísceras fue sometido a un proceso de refinación (desgomado, neutralización, lavado, secado y blanqueo). A ambos aceites se les determinó rendimiento, acidez, índice de yodo, índice de saponificación, índice de peróxido, materia insaponificable, densidad, índice de refracción y perfil lipídico.The aim of this study was to evaluate the characteristics physicochemical of crude and refined oil obtained from the guts of bocachico (Prochilodus magdalenae) and silver tilapia (Oreochromis niloticus), caught in the Zapatosa swamp. The winter and summer periods were taken into account to determine significant differences in the oils obtained from each species. Samples of four neighboring fishing villages were taken from the swamp, and settled for these one sample unit. Crude oil extracted from the offal was then subjected to a refining process (degumming, neutralization, washing, drying and bleaching). Both oils were tested for returns, acidity, iodine, saponification index, peroxide, unsaponifiable matter, density, refractive index and lipid profile

Genetic feature engineering enables characterisation of shared risk factors in immune-mediated diseases

Abstract: Background: Genome-wide association studies (GWAS) have identified pervasive sharing of genetic architectures across multiple immune-mediated diseases (IMD). By learning the genetic basis of IMD risk from common diseases, this sharing can be exploited to enable analysis of less frequent IMD where, due to limited sample size, traditional GWAS techniques are challenging. Methods: Exploiting ideas from Bayesian genetic fine-mapping, we developed a disease-focused shrinkage approach to allow us to distill genetic risk components from GWAS summary statistics for a set of related diseases. We applied this technique to 13 larger GWAS of common IMD, deriving a reduced dimension “basis” that summarised the multidimensional components of genetic risk. We used independent datasets including the UK Biobank to assess the performance of the basis and characterise individual axes. Finally, we projected summary GWAS data for smaller IMD studies, with less than 1000 cases, to assess whether the approach was able to provide additional insights into genetic architecture of less common IMD or IMD subtypes, where cohort collection is challenging. Results: We identified 13 IMD genetic risk components. The projection of independent UK Biobank data demonstrated the IMD specificity and accuracy of the basis even for traits with very limited case-size (e.g. vitiligo, 150 cases). Projection of additional IMD-relevant studies allowed us to add biological interpretation to specific components, e.g. related to raised eosinophil counts in blood and serum concentration of the chemokine CXCL10 (IP-10). On application to 22 rare IMD and IMD subtypes, we were able to not only highlight subtype-discriminating axes (e.g. for juvenile idiopathic arthritis) but also suggest eight novel genetic associations. Conclusions: Requiring only summary-level data, our unsupervised approach allows the genetic architectures across any range of clinically related traits to be characterised in fewer dimensions. This facilitates the analysis of studies with modest sample size by matching shared axes of both genetic and biological risk across a wider disease domain, and provides an evidence base for possible therapeutic repurposing opportunities

Premio a la investigación e innovación educativa : experiencias 2020

Con el presente libro, la Secretaría de Educación del Distrito y el Instituto para la Investigación Educativa y el Desarrollo Pedagógico, ofrecen a la ciudadanía 10 textos que recogen el trabajo arduo y comprometido de los maestros y las maestras de la ciudad, ganadores de la XIV versión del Premio a la Investigación e Innovación Educativa. Las propuestas son muestra del buen camino que está recorriendo la educación de Bogotá, en las más variadas disciplinas y campos del conocimiento, como los relacionados con el medio ambiente, la inclusión, la tecnología, la ciudadanía y la convivencia, el arte, y los procesos de enseñanza-aprendizaje en distintas áreas, entre otros

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Probing effective field theory operators in the associated production of top quarks with a Z boson in multilepton final states at root s=13 TeV

Peer reviewe

Observation of tW production in the single-lepton channel in pp collisions at root s=13 TeV

A measurement of the cross section of the associated production of a single top quark and a W boson in final states with a muon or electron and jets in proton-proton collisions at root s = 13 TeV is presented. The data correspond to an integrated luminosity of 36 fb(-1) collected with the CMS detector at the CERN LHC in 2016. A boosted decision tree is used to separate the tW signal from the dominant t (t) over bar background, whilst the subleading W+jets and multijet backgrounds are constrained using data-based estimates. This result is the first observation of the tW process in final states containing a muon or electron and jets, with a significance exceeding 5 standard deviations. The cross section is determined to be 89 +/- 4 (stat) +/- 12 (syst) pb, consistent with the standard model.Peer reviewe