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Tesi en modalitat de cotutela: Universitat Politècnica de Catalunya i Katholieke Universiteit Leuven Internet access is still unavailable to one-third of the world population due to the lack of infrastructure, high cost, and the digital divide. Many access-limited communities opt for shared Internet access where they build common network infrastructures to mitigate the cost. Internet connectivity in such infrastructures is typically provided by several limited, sometimes non-dedicated, gateways. Client nodes, i.e., the end-user hosts, use one gateway and switch to another when the first fails. In this scheme, the gateway configuration is done manually on the end-user side. This form of Internet connectivity is widespread and has the advantage that no central control is required, but it is also unreliable and inefficient due to several factors, such as unbalanced traffic load across the gateways. There is no doubt that the network would benefit from a gateway selection mechanism that can provide good connectivity to the client node as well as balanced load distribution and a dynamic adaptation to the current network state. However, providing such a dynamic gateway selection is complicated: since the perceived performance of the gateways changes frequently and might depend on the location of the client node in the network, and optimal selection would require the continuous monitoring of the gateway performance by the client node. The cost of such network-wide performance monitoring is high in large-scale networks and can outweigh the benefits of the dynamic gateway selection. The thesis's goal is to design a low-cost, distributed mechanism that provides an efficient and dynamic gateway selection while considering the overall balanced gateway selection distribution. To this end, we have split the problem of gateway selection into different sub-problems. First, we focus on reducing the cost of gateway performance monitoring. We propose an approach to reduce the number of monitoring requests generated by each node and analyze its effect on the gateway selection. Then, we present a collaborative monitoring method that allows neighbor nodes to share the load of the gateway monitoring. We show that every node can carry out the necessary tasks: performance monitoring, collaboration with its neighbors, and fault tolerance measures, with little computation and communication overhead. Second, to improve the gateway selection, we focus on making a selection decision that fulfills the individual performance requirements of the client nodes as well as global load balancing requirements. The solutions developed by us for the different sub-problems are embedded into a general and extensible, layered framework for gateway selection that we have called the Sense-Share-Select framework. Experimental validation and comparison with existing methods show that our framework provides accurate collaborative performance monitoring, improves the QoE for the nodes, and distributes the client nodes over the gateways in a balanced manner. The simplicity and flexibility of the framework make it adaptable to other network domains such as IoT networks and other scenarios where resource monitoring and load balancing are required. El acceso a Internet aún no está disponible para un tercio de la población mundial debido a la falta de infraestructuras, el alto costo y la brecha digital. Muchas comunidades con acceso limitado optan por el acceso compartido a Internet donde construyen infraestructuras de red comunitaria para mitigar el costo. La conectividad a Internet en dichas infraestructuras suele estar a cargo de varias puerta de enlaces limitadas en recursos, y a veces no dedicadas. Los nodos de cliente, es decir, los hosts de usuario final, utilizan una puerta de enlace y cambian a otra cuando falla la primera. En este esquema, la configuración de la puerta de enlace se realiza manualmente en el lado del usuario final. Esta forma de conectividad a Internet está muy extendida y tiene la ventaja de que no se requiere un control central, pero tampoco es confiable y eficiente debido a varios factores, como una carga desequilibrada de tráfico a través de las puertas de enlace. No hay duda de que la red se beneficiaría de un mecanismo de selección de pasarela que pueda proporcionar una buena conectividad al nodo cliente, así como una distribución equilibrada de la carga y una adaptación dinámica al estado actual de la red. Sin embargo, proporcionar una selección de puerta de enlace tan dinámica es complicado: dado que el rendimiento percibido de las puertas de enlace cambia con frecuencia y podría depender de la ubicación del nodo cliente en la red, y la selección óptima requeriría la supervisión continua del rendimiento de la puerta de enlace por parte del nodo cliente. El costo de dicha supervisión del rendimiento en toda la red es muy alto en redes de gran escala y puede superar los beneficios de la selección de puerta de enlace dinámica. El objetivo de la tesis es diseñar un mecanismo distribuido de bajo costo que proporcione una selección de puerta de enlace dinámica y eficiente al tiempo que considera la distribución general de selección de puerta de enlace equilibrada. Con este fin, hemos dividido el problema de la selección de la puerta de enlace en diferentes subproblemas. Primero, nos enfocamos en reducir el coste del monitoreo del rendimiento de la puerta de enlace. Proponemos un enfoque para reducir la cantidad de solicitudes de monitoreo generadas por cada nodo y analizar su efecto en la selección de la puerta de enlace. Luego, presentamos un método de monitoreo colaborativo que permite a los nodos vecinos compartir la carga del monitoreo de la puerta de enlace. Demostramos que cada nodo puede realizar las tareas necesarias: monitoreo del rendimiento, colaboración con sus vecinos y medidas de tolerancia a fallas, con poca sobrecarga de cómputo y comunicación. En segundo lugar, para mejorar la selección de la puerta de enlace, nos centramos en tomar una decisión de selección que cumpla con los requisitos de rendimiento individuales de los nodos del cliente, así como con los requisitos de equilibrio de carga global. Las soluciones desarrolladas por nosotros para los diferentes subproblemas están integradas en un marco general y extensible en capas para la selección de puertas de enlace que hemos llamado el marco Sense-Share-Select. La validación experimental y la comparación con los métodos existentes muestran que nuestro marco proporciona un monitoreo de rendimiento colaborativo preciso, mejora la QoE para los nodos y distribuye los nodos del cliente a través de las puertas de enlace de manera equilibrada. La simplicidad y flexibilidad del marco lo hacen adaptable a otros dominios de red, como las redes de IoT y otros escenarios donde se requiere monitoreo de recursos y equilibrio de carga.

Internet access is still unavailable to one-third of the world population due to the lack of infrastructure, high cost, and the digital divide. Many access-limited communities opt for shared Internet access to build common network infrastructures to mitigate the cost. Internet connectivity in such infrastructures is typically provided by several limited, sometimes non-dedicated, gateways. Client nodes, i.e., the end-user hosts, use one gateway and switch to another when the first fails. In this scheme, the gateway configuration is done manually on the end-user side. This form of Internet connectivity is widespread and has the advantage that no central control is required, but it is also unreliable and inefficient due to several factors, such as unbalanced traffic load across the gateways. The thesis proposes that the network would benefit from a gateway selection mechanism that can provide good connectivity to the client nodes, balanced load distribution, and a dynamic adaptation to the current network state. However, providing such a dynamic gateway selection is complicated: since the performance of the gateways as perceived by the client nodes changes frequently and might depend on the location of the latter in the network, and optimal selection would require the continuous monitoring of the gateway performance by the client node. The cost of such network-wide performance monitoring is high in large-scale networks and would outweigh the benefits of the dynamic gateway selection. The thesis aims to design a low-cost distributed mechanism that provides an efficient and dynamic gateway selection while considering the overall balanced gateway selection distribution. ​ We presented the Sense-Share-Select framework, a distributed, collaborative Internet gateway selection framework designed for large-scale networks. We integrated the Power of Two Choices randomized load balancing algorithm with our close neighbors' collaborative performance monitoring algorithm to reduce and distribute the gateway performance monitoring overhead. The selection algorithm utilizes the capacity-based selection algorithm to avoid selecting the unstable gateways and provide a suitable gateway selection for each node. The result shows the framework provides over 90% accurate collaborative performance monitoring with minimal overhead and equally distributes the clients over the good, stable performing gateways. The framework is implemented in the guifi.net community network testing environment with production gateways to demonstrate the efficiency of the proposed framework in the large-scale, heterogeneous network. The Sense-Share-Select framework improves the current manual gateway selection of the guifi.net by improving the QoE of all client nodes and provides better QoE than the other state-of-the-art gateway selection algorithms. ​ (SC - Sciences) -- UCL, 2022

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

Glucocorticoids are widely used in threatened preterm labor to promote maturation in many organ systems in preterm babies and have significant beneficial effects on morbidity and mortality. We performed transcriptional profiling in fetal liver in a rat model of prenatal glucocorticoid exposure and identified marked gene expression changes in heme biosynthesis, utilization, and degradation pathways in late gestation. These changes in gene expression associated with alterations in DNA methylation and with a reduction in hepatic heme concentration. There were no persistent differences in gene expression, DNA methylation, or heme concentrations at 4 weeks of age, suggesting that these are transient effects. Our findings are consistent with glucocorticoid-induced accelerated maturation of the haematopoietic system and support the hypothesis that glucocorticoids can drive changes in gene expression in association with alterations in DNA methylation.

In wireless community access networks, clients tend to reach the Internet through multiple gateway nodes instead of a single default gateway. The mapping of gateways to clients should take into account the perception of network performance from each client node. Network conditions and traffic load can fluctuate and make repeated client-gateway measurements necessary. However, frequent measurements would result in a high communication overhead as well as high processing overhead in gateways and clients. We propose a lightweight client-side gateway selection algorithm by crowd-sourcing monitoring information from neighbor clients, without requiring explicit topology information or a detailed view of the network, while providing an accurate selection as compared to an ideal omniscient approach. Our collaborative gateway selection algorithm achieves good end-to-end performance, such as low latency perceived at client nodes, and fair distribution of the measurements over the gateway nodes. The number of performance measurements triggered by clients are reduced drastically, from n down to 2 measurements per node in each period. An experimental evaluation of our approach shows more than 80% similarity estimation of the gateway performance in the majority of the considered cases. We propose two variants of the gateway selection algorithm, collaborative-best and collaborative-fair, which yield near optimal gateway selection while utilizing partial information.

In wireless community access networks, clients tend to reach the Internet through multiple gateway nodes instead of a single default gateway. The mapping of gateways to clients should take into account the perception of network performance from each client node. Network conditions and traffic load can fluctuate and make repeated client-gateway measurements necessary. However, frequent measurements would result in a high communication overhead as well as high processing overhead in gateways and clients. We propose a lightweight client-side gateway selection algorithm by crowd-sourcing monitoring information from neighbor clients, without requiring explicit topology information or a detailed view of the network, while providing an accurate selection as compared to an ideal omniscient approach. Our collaborative gateway selection algorithm achieves good end-to-end performance, such as low latency perceived at client nodes, and fair distribution of the measurements over the gateway nodes. The number of performance measurements triggered by clients are reduced drastically, from n down to 2 measurements per node in each period. An experimental evaluation of our approach shows more than 80% similarity estimation of the gateway performance in the majority of the considered cases. We propose two variants of the gateway selection algorithm, collaborative-best and collaborative-fair, which yield near optimal gateway selection while utilizing partial information.

Supplementary methods. ERRBS on germ cells. Figure S1. 5mC profiling in sperm. Figure S2. DNA methylation in the developing germline is unaffected by Dex treatment across the genome. Figure S3. DNA methylation in the developing germline is unaffected by Dex treatment: reproducibility and power calculations. Figure S4. sRNA-Seq analysis is sufficiently powered to detect differential expression. Figure S5. F1-sperm sRNA expression shows consistent lack of affect for Dex treatment for two quantification methods. Figure S6. Fold changes between Dex and Veh sRNA expression and histone methylation and are not correlated. (PDF 1566 kb)

Epidemiological evidence suggests that exposure to an adverse environment in early life is associated with an increased risk of cardio-metabolic and behavioral disorders in adulthood, a phenomenon termed 'early life programming'. One major hypothesis for early life programming is fetal glucocorticoid overexposure. In animal studies, prenatal glucocorticoid excess as a consequence of maternal stress or through exogenous administration to the mother or fetus is associated with programming effects on cardiovascular and metabolic systems and on the brain. These effects can be transmitted to subsequent generations. Studies in humans provide some evidence that prenatal glucocorticoid exposure may exert similar programming effects on glucose/insulin homeostasis, blood pressure and neurodevelopment. The mechanisms by which glucocorticoids mediate these effects are unclear but may include a role for epigenetic modifications. This review discusses the evidence for glucocorticoid programming in animal models and in humans.

In addition to the genetic constitution inherited by an organism, the developmental trajectory and resulting mature phenotype are also determined by mechanisms acting during critical windows in early life that influence and establish stable patterns of gene expression. This is the crux of the developmental origins of health and disease hypothesis that suggests undernutrition during gestation and infancy predisposes to ill health in later life. The hypothesis that periconceptional maternal micronutrient supplementation might affect fetal genome-wide methylation within gene promoters was explored in cord blood samples from offspring of Gambian women enrolled into a unique randomized, double blind controlled trial. Significant changes in the epigenome in cord blood DNA samples were further explored in a subset of offspring at 9 months. Gender-specific changes related to periconceptional nutritional supplementation were identified in cord blood DNA samples, some of which showed persistent changes in infant blood DNA samples. Significant effects of periconceptional micronutrient supplementation were also observed in postnatal samples which were not evident in cord blood. In this Gambian population, the increased death rate of individuals born in nutritionally poor seasons has been related to infection and it is of interest that we identified differential methylation at genes associated with defence against infection and immune response. Although the sample size was relatively small, these pilot data suggest that periconceptional nutrition in humans is an important determinant of newborn whole genome methylation patterns but may also influence postnatal developmental patterns of gene promoter methylation linking early with disease risk.

Intrauterine exposures mediated by maternal diet may affect risk of cardiovascular disease, obesity, and type 2 diabetes. Recent evidence, primarily from animal studies and observational data in humans, suggests that the epigenome can be altered by maternal diet during the periconceptional period and that these programming events may underlie later disease risk. A randomized controlled trial of periconceptional micronutrient supplementation in The Gambia, where seasonal nutritional variations affect fetal growth and postnatal outcomes, provided a unique opportunity to test this hypothesis. Specifically, we targeted imprinted genes, which play important roles in allocation of maternal resources while being epigenetically regulated. DNA methylation at 12 differentially methylated regions (DMRs) was analyzed in cord blood samples from 58 offspring of women participating in a double-blind randomized-controlled trial of pre- and periconceptional micronutrient supplementation (including folate, zinc, and vitamins A, B, C, and D). We observed sex-specific effects of micronutrient supplementation, reducing methylation levels at two of the DMRs analyzed, IGF2R in girls and GTL2-2 in boys. This pilot study is the first to analyze DNA methylation in the context of a randomized controlled trial, and it provides suggestive evidence that periconceptional maternal nutrition alters offspring methylation at imprinted loci.

Cytosines at cytosine-guanine (CG) dinucleotides are the near-exclusive target of DNA methyltransferases in mammalian genomes. Spontaneous deamination of methylcytosine to thymine makes methylated cytosines unusually susceptible to mutation and consequent depletion. The loci where CG dinucleotides remain relatively enriched, presumably due to their unmethylated status during the germ cell cycle, have been referred to as CpG islands. Currently, CpG islands are solely defined by base compositional criteria, allowing annotation of any sequenced genome. Using a novel bioinformatic approach, we show that CG clusters can be identified as an inherent property of genomic sequence without imposing a base compositional a priori assumption. We also show that the CG clusters co-localize in the human genome with hypomethylated loci and annotated transcription start sites to a greater extent than annotations produced by prior CpG island definitions. Moreover, this new approach allows CG clusters to be identified in a species-specific manner, revealing a degree of orthologous conservation that is not revealed by current base compositional approaches. Finally, our approach is able to identify methylating genomes (such as Takifugu rubripes) that lack CG clustering entirely, in which it is inappropriate to annotate CpG islands or CG clusters.

The distribution of cytosine methylation in 6.2 Mb of the mouse genome was tested using cohybridization of genomic representations from a methylation-sensitive restriction enzyme and its methylation-insensitive isoschizomer. This assay, termed HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR), allows both intragenomic profiling and intergenomic comparisons of cytosine methylation. The intragenomic profile shows most of the genome to be contiguous methylated sequence with occasional clusters of hypomethylated loci, usually but not exclusively at promoters and CpG islands. Intergenomic comparison found marked differences in cytosine methylation between spermatogenic and brain cells, identifying 223 new candidate tissue-specific differentially methylated regions (T-DMRs). Bisulfite pyrosequencing confirmed the four candidates tested to be T-DMRs, while quantitative RT-PCR for two genes with T-DMRs located at their promoters showed the HELP data to be correlated with gene activity at these loci. The HELP assay is robust, quantitative, and accurate and is providing new insights into the distribution and dynamic nature of cytosine methylation in the genome.

Background and Aims Both low and high birthweight is associated with adverse health outcomes throughout life. Altered expression of imprinted genes which regulate fetal and placental growth may be one mechanism linking the environment and later disease risk. We have studied the expression of candidate imprinted genes in placenta with respect to anthropometric parameters at birth. Methods 58 term placentas (27 male) were obtained from the Edinburgh Reproductive Tissue BioBank. Pregnancies complicated by congenital abnormalities or diabetes were excluded. Gene expression was analysed using real-time PCR. Results Median birthweight was 3900g (interquartile range: 2949–4340g). Insulin-like growth factor 2 (IGF2) mRNA levels correlated positively with standard deviation scores for birthweight (Spearman’s rho=0.335, p =0.005), head circumference (Spearman’s rho=0.424, p =0.001) and length (Spearman’s rho=0.259, p =0.041). Growth factor receptor-bound protein 10 (GRB10) mRNA levels correlated negatively with birthweight standard deviation score (Spearman’s rho= –0.221, p =0.048). The expression of two other imprinted genes, PHLDA2 and ZIM2 showed no relation to size at birth. Conclusion Both IGF2 and GRB10 are imprinted in the placenta and impact on fetal and placental growth. IGF2 is paternally imprinted and increased expression is implicated in overgrowth disorders; in contrast, GRB10 is maternally imprinted in trophoblasts and disruption in mice leads to overgrowth. Additionally, GRB10 has recently been identified as having a role in insulin signaling. As genomic imprinting is under epigenetic regulation, these targets are strong candidates for exploration of environmentally influenced non-Mendelian effects on fetal size and developmental programming.

Preterm infants are at increased risk of cardiometabolic disease in later life. Extrauterine growth restriction, catch-up growth, altered adiposity, and abnormal hypothalamic-pituitary-adrenal axis activity could be predisposing factors. Altered DNA methylation (5-methylcytosine, 5mC) might be one underlying mechanism. We hypothesised that preterm infants have altered 5mC at the linked differentially methylated region 2 (DMR2) of IGF2 and the H19 imprinting control region (H19 ICR) compared with term infants over the first year of life.We recruited 46 preterm (range 25 weeks + 2 days' gestation to 31 + 5, mean 28 + 6) and 40 term infants (38 + 3 to 42 + 2 weeks' gestation, mean 40 + 2). Anthropometric variables including body composition were measured at term age and 3 months corrected age with air displacement plethysmography and at 1-year-corrected age with skin-fold thickness. Salivary cortisol was measured at 3 months corrected age after the physical examination. Percentage methylation (%5mC) was analysed with pyrosequencing on buccal DNA. Statistical analysis used Student's t test and multivariate linear regression.Preterm infants demonstrated growth deficit early in postnatal life but had greater percentage body fat at term age (β=5·73, p0·001), but not at 3 months (β=-0·28, p=0·82). Compared with term infants, preterm infants had a blunted cortisol response to physical examination (mean difference 0·38 μg/dL, p=0·024). At birth, preterm infants had a significant decrease in %5mC at DMR2 compared with term infants at birth (β=-11·48, p0·001) and compared with preterm infants at term-corrected age (t=3·13, p=0·01). By term-corrected age, preterm infants had decreased %5mC at both DMR2 (β=-2·84, p=0·013) and the H19 ICR (β=-2·31, p=0·048) compared with term infants at birth, although this difference disappeared at 1 year. Social deprivation was independently associated with decreased %5mC at DMR2 at birth (β=-1·73, p=0·006) and term-corrected age (β=-0·86, p=0·016) but not at 1 year (β=-0·89, p=0·07).Our results show that decreased %5mC accompanies the early growth deficit in preterm infants. The marked reduction in %5mC at IGF2 DMR2 in preterm infants at birth compared with term-age supports existing evidence that imprinting at secondary regions is established after fertilisation, whereas imprinting is established during gametogenesis at primary regions (H19 ICR). Both regions might be susceptible to early life stressors such as preterm birth and social deprivation.Chief Scientist Office of the Scottish Government.