398 research outputs found

    Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea

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    ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (β2 = 0.18, p-value = 0.07; β3 = −0.10, p-value = 0.02). SHS exposure at home (β2 = 0.10, p-value = 0.09; β3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (β2 = 0.03, p-value = 0.10; β3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK

    The Omics basis of human health: investigating plasma proteins and their genetic effects on complex traits

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    Over the past decade, the advancements in technology and the growing amount of identified genetic variants have led to a high number of important discoveries in the field of precision medicine concerning human biology and pathophysiology. However, it became evident that genomics alone could not properly explain the onset and regulation of the specific molecular mechanisms of certain phenotypes. Studying omics helped complement this gap in genetic research, providing detailed information on the quantification of molecules that are involved in structural and functional processes in the organism. Specifically, protein production, levels, and regulation are dynamic and change during the course of one’s lifetime. This information has proven fundamental to understanding how certain proteins affect complex phenotypes such as neurological and psychiatric disorders. In this thesis, I describe the three groups of analyses I conducted over the course of my doctoral programme on different sets of blood plasma proteins and over a broad range of neurological, psychiatric, cardiovascular, and electrophysiology phenotypes. The underlying mechanisms that trigger the onset of psychiatric and neurological conditions are often not limited to the nervous system, but rather stem from multi-system molecular triggers. The first part of the work I carried out aims at investigating the frequent co-occurrence and comorbidity of neurological and cardiovascular phenotypes by conducting a genome-wide association (GWA) meta-analysis of 183 neurology-related blood proteins on data from over 12000 individuals. The second part concerns the bivariate and multivariate analyses conducted on 276 cardiology and inflammatory proteins, while the third illustrates the contribution to consortia focussed on heart rate and electrophysiology. Results from the second and third parts of the work provided information that played an important role in understanding a part of the genetic mechanisms of the complex traits of interest. Overall, the results presented in this thesis strongly support the notion that proteomics is an important tool to be used to study complex traits and drug discovery and development should focus on targeting protein synthesis and regulation. Furthermore, the results also support the notion that complex diseases involve more than one biological system, and in order to gain a better understanding of human pathology, it is fundamental to study the causes and effects across the entire organism

    Evaluating wild and commercial populations of Bombus terrestris ssp. audax (Harris, 1780): from genotype to phenotype.

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    Bees, including bumblebees, are highly valued for the pollination services they provide to natural ecosystems and agricultural crops. However, many bee species are facing declines, likely a result of habitat loss, pesticide use and climate change. Additionally, the use of imported commercial bumblebee colonies for crop pollination poses several risks to wild pollinators, including competition, hybridisation and pathogen spillover. A stock-take is needed of wild bees on both genetic and functional levels to identify vulnerable populations, detect local adaptations and to prevent further pollinator losses. We examine wild Irish B. terrestris ssp. audax on genomic, proteomic, and behavioural levels with reference to British and commercial populations to deepen our understanding of the selective processes acting on wild and domesticated bumblebee populations. We find that wild Irish and British populations of B. t. audax are distinctive on genomic levels and exhibit differential signatures of selection. We also find putative evidence for genetic distinctions between wild and commercial populations. A genomic examination of canonical immune genes in wild, Irish bumblebees highlighted several genes undergoing positive, purifying and possibly balancing selection, possibly reflecting their functional diversity and indicating recent adaptation. We uncover distinctions in the proteomes of wild and commercial lineages of lab-reared worker bee fat bodies and brains, as well as in the proteomic responses of these organs to pesticide exposure and infection. Finally, distinctions in the growth dynamics of wild and commercial lineages of B. t. audax colonies were identified alongside differences in the bacterial and fungal gut microbiomes of lab-reared wild and commercial workers. Overall, the findings of this thesis provide novel insights into the genetic, physiological, and behavioural distinctions between wild and domesticated populations of B. t. audax which will likely have major implications for how we conserve valuable genetic resources and manage commercial bumblebee imports

    The genetic interactions of PKHD1 and ATMIN in autosomal recessive polycystic kidney disease (ARPKD)

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    A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.The main gene associated with Autosomal Recessive Polycystic Kidney Disease (ARPKD) is PKHD1 which encodes a ciliary protein associated with planar cell polarity. In mice, mutations in the transcription factor Atmin can present with an ARPKD-like phenotype with kidney disease similar to an early manifestation of ARPKD. Like the mouse gene Pkhd1, mutations in Atmin are associated with altered WNT/PCP expression. Previous work has suggested that Atmin and Pkhd1 do not physically interact, but Atmin may modulate Pkhd1 expression. However, the mechanisms governing this relationship are unknown. ARPKD is a rare disorder typically associated with severe kidney and liver disease in children. The disease has considerable clinical and familial variability, but little is known regarding genotype-phenotype relationships. It has been proposed that genetic modifiers may influence disease severity. Next-generation sequencing (NGS) using ChIP-Seq and RNA-Seq techniques in mouse kidneys and intermedullary collecting duct (mIMCD3) cells identified new transcriptional targets of Atmin, which did not include Pkhd1 but included genes associated with cystic kidneys in animal models (Camk2g and G6pc). NGS in Atmin and Pkhd1 KDs identified a common transcriptional network between the two genes. Gene enrichment analysis suggests this common network is associated with immune system processes. Dysregulated genes associated with double KDs showed greater enrichment of processes associated with the actin cytoskeleton, cell cycle and energy metabolism. Loss of Atmin expression negatively impacts the ciliary localisation of Fibrocystin, suggesting that Atmin may be needed for the proper localisation of Fibrocystin to the cilium. NGS in ARPKD kidneys highlights mutations in ATMIN as a potential regulator of disease severity, associated with reduced ARPKD severity. Expression differences in WNT genes may be present between severe and moderate ARPKD and transcriptomic profiling identified candidate diagnostic markers in ARPKD which included MSC, FGA, WNT4, WNT9B and KIF26B. This work indicates that Atmin and Pkhd1 interact in a similar transcriptional network in mice. Atmin is not a transcription factor of Pkhd1 but may modulate its function by governing its ciliary localisation by a yet unknown mechanism. Additionally, ATMIN mutations may modulate ARPKD disease severity, and the amount of differential expression in WNT/PCP genes may be a marker of disease severity.PKD Charity, Arran Brown Rainbow Foundation, and the University of Wolverhampton

    Using genomic approaches to characterise the immune response to biologicals

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    Biologic therapies are effective treatments for inflammatory bowel disease (IBD). Successful treatment leads to reduced hospitalisation and surgeries, and an improvement in quality of life for patients. Unfortunately, the use of these treatments are associated with challenges such as treatment failure, an increased risk of infections, and suboptimal vaccine responses. An understanding of the molecular mechanisms underlying the challenges of existing IBD therapies, such as anti-tumour necrosis factor (anti-TNF), will allow strategies to be developed to overcome these challenges and aid drug sequencing. Technological advances in genomics has enabled a deeper understanding of these molecular mechanisms. The primary aim of this thesis was to utilise genomic approaches to understand the molecular mechanisms underlying the effects of anti-TNF therapies in the setting of treatment failure and attenuated vaccine response. In this thesis, I demonstrated that DNA methylation profiles might potentially be used as a predictor for anti-TNF drug concentration at week 14, which is the only modifiable factor associated with primary non-response to anti-TNF at week 14. In the setting of the COVID-19 pandemic, I demonstrated that antibody response following SARS-CoV-2 vaccine was attenuated in patients treated with infliximab compared to vedolizumab. Using genomic approaches including DNA methylation and single-cell RNA profiling, I identified acute but non-persistent changes in immune cell proportions following a third dose of SARS-CoV-2 vaccine, and identified baseline DNA methylation signatures that were associated with vaccine antibody response. Further, I optimised a pipeline for profiling single cell gene expression in human PBMC samples from an observational cohort study. The findings from my thesis have improved understanding of the molecular mechanisms underlying the challenges of IBD therapies using genomic approaches. Overall, it has changed clinical practice, influenced government policies, and brings us one step closer to implementing personalised treatments for patients with IBD.Wellcome GW4-CAT Doctoral Fellowship, grant number 222850/Z/21/

    Effective Utilization of Molecular Genetic Screening of Patients with Sickle Cell Disease and Beta Thalassemia Major in Saudi Arabia

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    Hereditary blood diseases are prevalent in the Kingdom of Saudi Arabia. The majority of these blood disorders are sickle cell disease and β-thalassemia with variants located on the beta globin gene (HBB). Aim: To determine the profile of novel or previously reported causative mutations in more than 150 transfusion dependent individuals using TaqMan genotyping and next-generation DNA sequencing. In addition, I explored the genomic variation in a family with transfusion dependency but without a definitive genetic diagnosis related to HBB. I also attempted to detect unknown genetic variations in functionally related genes and applied in-silico analysis of the detected variants to propose candidate genes that may contribute to the severe etiology of thalassemia within a family. Methods: To identify HBB variants, I conducted Taqman genotyping tests using SCD, c.92+5G>C, c.92+1G>A, c.93-21G>A, c.27dupG, and c.118C>T as the most frequently identified HBB variants within the Saudi population. After that, targeted next generation sequencing was performed on samples with either negative or only heterozygous results for these variants. The use of different molecular techniques including MLPA alpha thalassemia, whole exome sequencing, cytoscan HD array, and whole genome sequencing was undertaken on samples that needed further investigation. Implementation of different data filtering approaches and several in-silico techniques were utilized to investigate the detected variants. Results: After Taqman genotyping of the 154 DNA samples, 100 samples were either homozygous or compound heterozygous for the most frequently known HBB variants. The rest of these samples were sequenced using targeted NGS and 20 different common and rare HBB variants were identified. Three out of the 154 samples did not have any apparent HBB mutation and further investigation was applied using additional molecular techniques. This led to the identification of two gene candidates, SMC5 and TALDO1, with possible novel associations in increasing the severity of clinical manifestation in transfusion-dependent patients with heterozygous pathogenic variant of beta thalassemia. Conclusion: Beta thalassemia is a heterogenous disease with a wide range of clinical severity and the steps towards identification of the underlying genetic cause of the phenotype is different from case to case and may require a combination of several molecular techniques. Therefore, the interaction of illness-causing variations with the rest of an individual's genome is crucial to gaining a complete understanding of the condition. Excellent detection rates in less time may be achieved with a specialized filtering technique and strategy, making this an option for primary laboratory workflow

    COMPUTATIONAL MODELING OF GENE REGULATION, GAMETE FORMATION, AND EMBRYO IMPLANTATION

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    DNA located in genes is transcribed into RNA which is translated into protein. The regulation of transcription and translation is carried out by several factors including a gene’s primary sequence, cis-regulatory elements (CREs) in non-coding DNA regions, epigenetic marks on the histones which compact DNA, and trans-binding factors (or proteins). The differential expression of a gene is crucial for establishing lineage-specific cell identity and phenotypic variability. Mutation or dysregulation may lead to natural variation within a population or aberrant gene expression and disease; trait-associated variation is known to be enriched in putative CREs, supporting their role in the origins of disease. Understanding the mechanisms by which CREs interact with one another and their cellular environment to regulate transcription may inform knowledge of biological pathways and provide a crucial foundation for developing new treatments. Further, because all DNA is passed to an offspring from their parents, it is important to understand not just the outcomes on expression due to coding and non-coding variation, but also how genetic material is passed to future generations. These dissertation chapters apply modeling approaches to large amounts of genetic and gene expression data in order to 1) better understand how the sequence and epigenetic makeup of CREs impact gene expression within hematopoiesis; 2) scan for selfish genetic elements which are preferentially passed to offspring within human sperm samples; and 3) predict implantation success for euploid embryos given gene expression profiles. Our models within Chapters 2-4 describe the impact of CREs within the blood cell lineage, connecting CREs to putative target genes, and establishing that the hematopoietic CREs were enriched for blood-trait associated genetic variation. Within Chapter 5, we find no compelling evidence of selfish genetic elements within a large sample of human sperm. Finally, within Chapter 6, we identify some genes which seem to impact the success of IVF embryo implantation by acting through regulation of translation
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