20,510 research outputs found

    Unraveling the effect of sex on human genetic architecture

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    Sex is arguably the most important differentiating characteristic in most mammalian species, separating populations into different groups, with varying behaviors, morphologies, and physiologies based on their complement of sex chromosomes, amongst other factors. In humans, despite males and females sharing nearly identical genomes, there are differences between the sexes in complex traits and in the risk of a wide array of diseases. Sex provides the genome with a distinct hormonal milieu, differential gene expression, and environmental pressures arising from gender societal roles. This thus poses the possibility of observing gene by sex (GxS) interactions between the sexes that may contribute to some of the phenotypic differences observed. In recent years, there has been growing evidence of GxS, with common genetic variation presenting different effects on males and females. These studies have however been limited in regards to the number of traits studied and/or statistical power. Understanding sex differences in genetic architecture is of great importance as this could lead to improved understanding of potential differences in underlying biological pathways and disease etiology between the sexes and in turn help inform personalised treatments and precision medicine. In this thesis we provide insights into both the scope and mechanism of GxS across the genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits through the calculation of sex-specific heritability, genetic correlations, and sex-stratified genome-wide association studies (GWAS). We further investigated whether sex-agnostic (non-stratified) efforts could potentially be missing information of interest, including sex-specific trait-relevant loci and increased phenotype prediction accuracies. Finally, we studied the potential functional role of sex differences in genetic architecture through sex biased expression quantitative trait loci (eQTL) and gene-level analyses. Overall, this study marks a broad examination of the genetics of sex differences. Our findings parallel previous reports, suggesting the presence of sexual genetic heterogeneity across complex traits of generally modest magnitude. Furthermore, our results suggest the need to consider sex-stratified analyses in future studies in order to shed light into possible sex-specific molecular mechanisms

    Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

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    Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases

    In search of 'The people of La Manche': A comparative study of funerary practices in the Transmanche region during the late Neolithic and Early Bronze Age (250BC-1500BC)

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    This research project sets out to discover whether archaeological evidence dating between 2500 BC - 1500 BC from supposed funerary contexts in Kent, flanders and north-eastern Transmanche France is sufficient to make valid comparisons between social and cultural structures on either side of the short-sea Channel region. Evidence from the beginning of the period primarily comes in the form of the widespread Beaker phenomenon. Chapter 5 shows that this class of data is abundant in Kent but quite sparse in the Continental zones - most probably because it has not survived well. This problem also affects the human depositional evidence catalogued in Chapter 6, particularly in Fanders but also in north-eastern Transmanche France. This constricts comparative analysis, however, the abundant data from Kent means that general trends are still discernible. The quality and volume of data relating to the distribution, location, morphology and use of circular monuments in all three zones is far better - as demonstrated in Chapter 7 -mostly due to extensive aerial surveying over several decades. When the datasets are taken as a whole, it becomes possible to successfully apply various forms of comparative analyses. Most remarkably, this has revealed that some monuments apparently have encoded within them a sophisticated and potentially symbolically charged geometric shape. This, along with other less contentious evidence, demonstrates a level of conformity that strongly suggests a stratum of cultural homogeneity existed throughout the Transmanche region during the period 2500 BC - 1500 BC. The fact that such changes as are apparent seem to have developed simultaneously in each of the zones adds additional weight to the theory that contact throughout the Transmanche region was endemic. Even so, it may not have been continuous; there may actually have been times of relative isolation - the data is simply too course to eliminate such a possibility

    Identification of new regenerative therapies in reproductive medicine and their application as a future therapeutic approach for endometrial regeneration

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    El útero es uno de los principales órganos internos del sistema reproductor femenino. Está compuesto de tres capas tisulares: perimetrio, miometrio y endometrio. Esta última capa recubre la cavidad intrauterina y es responsable directa de la implantación embrionaria (para la cual necesita un grosor endometrial mínimo). Entre las patologías que afectan al endometrio pueden distinguirse, entre otras, la atrofia endometrial (insuficiente grosor endometrial) y el síndrome de Asherman (presencia de adhesiones intrauterinas y tejido fibrótico), las cuales conforman el hilo conductor de esta tesis, compuesta de 4 artículos científicos. En ambos casos, el tejido endometrial se encuentra degenerado, lo que dificulta la implantación embrionaria, ocasionando problemas de fertilidad. A día de hoy, ninguna de estas patologías cuenta con una cura totalmente efectiva. Hasta el momento, una de las opciones terapéuticas más prometedora es la inyección de células madre. Por ello, el primer objetivo de esta tesis fue evaluar como la inyección de células madre derivadas de la médula ósea (aisladas con la detección del antígeno CD133), que había resultado ser efectiva tanto en un modelo humano como en uno animal, estaba modificando el endometrio molecularmente. Para así, intentar entender cuáles son los mecanismos paracrinos a través de los cuales llevan a cabo su acción terapéutica. Este primer estudio reveló que estas células madre parecían estar promoviendo la regeneración endometrial mediante la creación de un escenario inmunomodulador (sub-expresión del gen CXCL8), que daría paso a la sobreexpresión de genes involucrados en la regeneración tisular, como SERPINE1, IL4, y JUN. Otro tratamiento que ha ido ganando acepción con los años es el plasma rico en plaquetas, eje central del manuscrito 2. Este manuscrito evidencia como este plasma, especialmente si proviene de sangre de cordón umbilical, es capaz de promover procesos celulares, como la migración y la proliferación de las células endometriales, así como eventos regenerativos en un modelo animal con daño endometrial inducido. Sea cual sea la aproximación terapéutica de elección, se ha hipotetizado que esta regeneración tisular podría surgir de la estimulación del nicho de células madre presente en el endometrio. Es por ello que el objetivo 3 supuso el estudio de los trabajos publicados, tanto de modelos murinos como humanos, relativos a esta población de células madre endometriales. Esta búsqueda permitió concluir que aún quedan lagunas de conocimiento, bien sea en la definición de marcadores celulares específicos o en de la contribución de la médula ósea a este nicho de células madre endometriales. Finalmente, dada la mencionada falta actual de una terapia definitiva para las pacientes con atrofia endometrial o síndrome de Asherman, el cuarto y último objetivo de esta tesis supuso el estudio de todas aquellas aproximaciones que se han llevado a cabo en modelos animales que simulan este tipo de patologías humanas. Este trabajo concluyó que si bien están emergiendo nuevas terapias muy prometedoras, como son aquellas derivadas de la bioingeniería (por ejemplo, uso de hidrogeles o biomoldes), todavía falta perfeccionar y estandarizar los modelos tanto animales como in vitro que permitan una mejor traslación clínica de las mismas.The uterus is one of the main internal organs of the female reproductive system. It is composed of three different tissue layers: perimetrium, myometrium, and endometrium. This last layer covers the intrauterine cavity and is directly responsible for embryo implantation (for which it needs a certain minimum endometrial thickness). Among the pathologies affecting the endometrium, we can distinguish, among others, endometrial atrophy (characterized by an insufficient endometrial thickness) and Asherman's syndrome (a rare disease characterized by the presence of intrauterine adhesions and fibrotic tissue), which form the common thread of this thesis, composed of four original manuscripts. In both cases, the endometrial tissue is degenerated, which hinders the correct embryo implantation, causing then fertility problems. To date, none of these pathologies has a totally effective cure. So far, one of the most promising therapeutic options is the injection of stem cells. Therefore, the first objective was to evaluate how the infusion of bone marrow-derived stem cells (isolated with the antigen CD133), which had proven effective in both a human and an animal model, was modifying the endometrium at the molecular level. Then, this work aimed to understand the paracrine mechanisms through which these cells were carrying out their therapeutic and regenerative action over the endometrial tissue. This first study revealed that these stem cells appeared to be promoting endometrial regeneration by creating an immunomodulatory scenario (down-regulation of the CXCL8 gene), which would give way to the over-expression of genes (SERPINE1, IL4, and JUN) involved in tissue regeneration. Another treatment gaining acceptance over the years is a blood derivate, platelet-rich plasma, which was the focus of the second manuscript. This work shows how this plasma, mainly derived from umbilical cord blood rather than adult peripheral blood, can promote cellular processes, such as cell migration and proliferation of different types of endometrial cells (from primary culture and from stem cell lines). These plasmas also revealed how they triggered the over-expression of certain proteins involved in regenerative events in a mouse model with induced endometrial damage. Whatever the therapeutic approach of choice, it has been hypothesized that regeneration could arise from stimulation of the stem cell niche present in the endometrium. That is why objective three involved studying those works, both murine and human models, concerning this population of endometrial stem cells. This search concluded that there are still gaps in knowledge, either in the definition of specific endometrial stem cell markers or in the contribution of the bone marrow to this endogenous endometrial stem cell niche. Finally, given the aforementioned current lack of definitive therapy for patients with endometrial atrophy or Asherman's syndrome, the last objective involved studying all those approaches that have been carried out in animal models that simulate this type of human pathology. This work concluded that although new therapies are emerging, such as those derived from bioengineering (e.g. use of decellularized scaffolds or hydrogels), there is still a need to perfect and standardize both animal and in vitro models to allow a better clinical translation of these therapies

    Studies on the insecticidal mechanism of Bacillus thuringiensis Vip3A and Cry proteins

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    El control de plagas y patógenos ha tenido un efecto importante en la mejora del rendimiento de los sistemas agrícolas a nivel mundial. Diferentes tipos de insecticidas químicos se han usado extensivamente durante mucho tiempo para el control de plagas de insectos. Debido a la aparición de resistencias, problemas de contaminación de aguas y problemas de salud humana causados por dichos insecticidas de síntesis, la agricultura moderna necesita una estrategia de gestión integrada de plagas más saludable, respetuosa con el medio ambiente y sostenible. El uso de Bacillus thuringiensis (Bt) y sus proteínas insecticidas para el control de plagas es una de las estrategias biotecnológicas más importantes hasta la fecha. Además, los genes que codifican sus proteínas insecticidas han sido transferidos a plantas, las cuales están siendo utilizadas comercialmente, desde 1996 en gran parte del mundo para el control eficiente de numerosas plagas de insectos. En los últimos años, una nueva subclase de proteínas insecticidas secretables (Vip3) producida durante el crecimiento vegetativo de Bt se ha considerado para la aplicación combinada con las convencionalmente empleadas proteínas Cry, cuya aplicación se ve amenazada por la aparición de poblaciones de insectos resistentes. Las proteínas Vip3 no tienen homología de secuencia con las proteínas Cry y son tóxicas para insectos lepidópteros, sin embargo, su modo de acción todavía no se conoce completamente. En este proyecto de tesis, con el objetivo de mejorar su aplicación en el control biotecnológico de plagas y la comprensión del modo de acción de las proteínas Vip3, se estudiaron diversos aspectos de su actividad insecticida (espectro de acción, resistencia cruzada e interacción con otras proteínas), y se realizó un estudio de los residuos clave para el mantenimiento de la estructura tridimensional y la toxicidad de la proteína Vip3Af mediante mutagénesis dirigida. También analizamos la posible implicación de la unión a receptores en la aparición de resistencia utilizando una cepa resistente que había sido seleccionada con Vip3Aa. En primer lugar, se investigó la toxicidad de 10 toxinas Bt (Cry1Ab, Cry1Ac, Cry1Ah, Cry1Fa, Cry2Aa, Cry2b, Cry1Ie, Vip3Aa19, Vip3Aa16 y Vip3Ca) frente a Mythimna separata (plaga agrícola muy destructiva en Asia y Australia), así como su aplicación combinada mediante bioensayos llevados a cabo en laboratorio. Los resultados mostraron que la concentración letal media LC50 (Cry1Ac/Vip3Aa19/Vip3Ca 3061 veces) se obtuvo rápidamente después de 8 o 9 generaciones de selección en laboratorio. Sin embargo, no se obtuvo resistencia notable seleccionando con Cry1Ab o Cry1F en la misma población y durante el mismo número de generaciones. En un estudio realizado por otros investigadores, también se encontró una respuesta rápida similar a la selección de Vip3Aa en H. virescens, alcanzando un nivel de resistencia > 2300 veces mayor en la décima generación. Es importante hacer notar que esta rápida evolución de la selección en condiciones de laboratorio contrasta con los resultados obtenidos con las proteínas Cry1, tanto en nuestro trabajo como por otros autores: una la población de O. furnacalis adquirió un nivel de resistencia a Cry1Ab de alrededor de 100 veces sólo después de 35 generaciones de selección; de manera similar, una población de O. nubilalis desarrolló una resistencia de más de 3000 veces a Cry1F después de 35 generaciones de selección. Esta diferencia en respuesta a la selección, además de reflejar una frecuencia mucho mayor de alelos de resistencia para Vip3Aa, puede sugerir diferencias en los mecanismos de resistencia a las proteínas Vip3Aa y Cry1, lo cual queda en evidencia cuando se estudia la unión de Vip3A a BBMV de insectos resistentes El análisis de la unión de 125I-Vip3Aa a BBMV de larvas de M. separata tanto de insectos susceptibles y resistentes no reveló ninguna diferencia de unión, ya sea cualitativa o cuantitativa. Los resultados sugieren que la unión alterada a los receptores de la membrana del intestino medio no es el principal mecanismo de resistencia a la proteína Vip3Aa. Numerosos estudios han demostrado que la alteración de los receptores de membrana es un mecanismo evolutivo común que confiere altos niveles de resistencia a las proteínas Cry, pero nunca se ha establecido su relación con la resistencia a Vip3A. Las diferencias de unión cualitativas o c

    Adaptive task selection using threshold-based techniques in dynamic sensor networks

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    Sensor nodes, like many social insect species, exist in harsh environments in large groups, yet possess very limited amount of resources. Lasting for as long as possible, and fulfilling the network purposes are the ultimate goals of sensor networks. However, these goals are inherently contradictory. Nature can be a great source of inspiration for mankind to find methods to achieve both extended survival, and effective operation. This work aims at applying the threshold-based action selection mechanisms inspired from insect societies to perform action selection within sensor nodes. The effect of this micro-model on the macro-behaviour of the network is studied in terms of durability and task performance quality. Generally, this is an example of using bio-inspiration to achieve adaptivity in sensor networks

    Patterns of subspecies diversity in the giraffe, Giraffa camelopardalis (L. 1758): comparison of systematic methods and their implications for conservation policy

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    This thesis examines the subspecific taxonomic status of the giraffe and considers the role of formal taxonomy in the formulation of conservation policy. Where species show consistent. geographically structured phenotypic variation such geographic patterns may indicate selective forces (or other population-level effects) acting. upon local populations. These consistent geographic patterns may be recognised formally as subspecies and may be of interest in single or multi-species biodiversity or biogeography studies for delimiting areas of conservation priority. Subspecies may also be used in the formulation of management policies and legislation. Subspecies are, by definition, allopatric. This thesis explicitly uses methodology of systematic biology and phylogenetic reconstruction to investigate patterns of variation between geographic groups. The taxonomic status of the giraffe is apposite for review. The species provides three independent data sets that may be analysed quantitatively for geographic structure; pelage patterns, morphology and genetics. Museum specimens. grouped according to geographic origin, were favoured for study as more than one type of data was often available for an individual. Population aggregation analysis of forty pelage pattern characters maintained six separate subspecies, while agglomerating some neighbouring populations into a subspecies. A 'traditional' morphometric approach, using multivariate statistical analysis of adult skull measurements, was complemented by a geometric morphometric approach; landmarkrestricted eigenshape analysis. Four morphologically distinct groups were recognised by both morphological analyses. Phylogenetic analysis of mitochondrial DNA control region sequences indicates five major cIades. Nested cIade analysis identifies population fragmentation, range expansion and genetic isolation by distance as contributing to the genetic structure of the giraffe. The results of the analyses show remarkable congruence. These results are discussed in terms of the formulation of conservation policy and the differing requirements of'blological and legal classification systems. The value of a formal taxonomic framework to the recognition, and subsequent conservation, of biodiversity is emphasised
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