8,464 research outputs found

    Inter-individual variation of the human epigenome & applications

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    Roles of the ubiquitin ligase complex CRL5Ozz and its substrate Alix in skeletal muscle

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    Exploring missing heritability in neurodevelopmental disorders:Learning from regulatory elements

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    In this thesis, I aimed to solve part of the missing heritability in neurodevelopmental disorders, using computational approaches. Next to the investigations of a novel epilepsy syndrome and investigations aiming to elucidate the regulation of the gene involved, I investigated and prioritized genomic sequences that have implications in gene regulation during the developmental stages of human brain, with the goal to create an atlas of high confidence non-coding regulatory elements that future studies can assess for genetic variants in genetically unexplained individuals suffering from neurodevelopmental disorders that are of suspected genetic origin

    Lasting mesothalamic dopamine imbalance and altered exploratory behavior in rats after a mild neonatal hypoxic event

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    IntroductionAdversities during the perinatal period can decrease oxygen supply to the fetal brain, leading to various hypoxic brain injuries, which can compromise the regularity of brain development in different aspects. To examine the catecholaminergic contribution to the link between an early-life hypoxic insult and adolescent behavioral aberrations, we used a previously established rat model of perinatal hypoxia but altered the hypobaric to normobaric conditions.MethodsExploratory and social behavior and learning abilities were tested in 70 rats of both sexes at adolescent age. Inherent vertical locomotion, sensory-motor functions and spatial learning abilities were explored in a subset of animals to clarify the background of altered exploratory behavior. Finally, the concentrations of dopamine (DA) and noradrenaline in midbrain and pons, and the relative expression of genes for DA receptors D1 and D2, and their down-stream targets (DA- and cAMP-regulated phosphoprotein, Mr 32 kDa, the regulatory subunit of protein kinase A, and inhibitor-5 of protein phosphatase 1) in the hippocampus and thalamus were investigated in 31 rats.ResultsA lesser extent of alterations in exploratory and cognitive aspects of behavior in the present study suggests that normobaric conditions mitigate the hypoxic injury compared to the one obtained under hypobaric conditions. Increased exploratory rearing was the most prominent consequence, with impaired spatial learning in the background. In affected rats, increased midbrain/pons DA content, as well as mRNA levels for DA receptors and their down-stream elements in the thalamus, but not the hippocampus, were found.ConclusionWe can conclude that a mild hypoxic event induced long-lasting disbalances in mesothalamic DA signaling, contributing to the observed behavioral alterations. The thalamus was thereby indicated as another structure, besides the well-established striatum, involved in mediating hypoxic effects on behavior through DA signaling

    Roles of the ubiquitin ligase complex CRL5Ozz and its substrate Alix in skeletal muscle

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    Netrin-1 isoforms and macrophage phenotype: role in the pathophysiology of atherosclerosis

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    Atherosclerosis is a chronic inflammatory disease and is the main cause of ischaemic heart disease, stroke, and other cardiovascular diseases. The development of atherosclerotic plaques incidence has been increasing significantly during the last few decades and is due to different factors, such as the increased consumption of high fat food, smoking and increased incidence of diabetes mellitus. This is currently a major burden on health systems, which require new therapeutic targets to address this challenge. The involvement of netrin-1 in inflammation and atherosclerosis has been studied during the last two decades. Different groups have established that netrin-1 plays a prominent role in these contexts and has different effects depending on where it is produced, and which cells are targeted by it. While endothelial-derived netrin-1 secreted into the circulation gives rise to a protective effect against atherosclerosis, macrophage-derived netrin-1 within the plaque has a pro-atherogenic effect, promoting the trapping and survivability of foam cells. More recently, a truncated isoform of netrin-1 was found in the nuclei of different types of cancer cells. This form of netrin-1 has also been studied in endothelial cells, but so far, no relationship between the expression of truncated netrin-1 and macrophages has been established. The link between cytokine stimulation, macrophage phenotype and netrin-1 isoforms has until now been unclear. The work described in this thesis looked at the expression and function of netrin-1 on monocytes and different macrophage phenotypes. Gene expression analysis revealed that macrophages express both full-length and truncated netrin-1. Classical activated is the macrophage phenotype that presents higher expression of netrin-1, and the expression of both isoforms is at least partially dependent on NF-κB activation pathway. Netrin-1 inhibits monocyte migration by inhibiting chemokines’ chemoattractant effect. CCL2 and netrin-1 individually showed an attractant effect towards THP-1-derived macrophages, but the signals were inhibited when the two were combined. The apoptotic agent selected to study netrin-1 anti-apoptotic effect was not UNC5b-dependent and, therefore, limited our ability to acquire relevant data regarding this process. Administration of exogenous netrin-1 to mice, increasing its systemic levels, showed an acute and chronic protective effect against inflammation. Mice treated with netrin-1 showed less macrophages within the tissue after the induction of local inflammation. Furthermore, increasing the netrin-1 systemic levels of mice prevented the enlargement of the aortic sinus and development of plaque after feeding them 60% HFD over a 6-week period. This thesis provides relevant insights into the role of macrophage phenotypes in the expression of netrin-1 isoforms within atherosclerotic plaques, and how netrin-1 affects these immune cells. The findings highlight the significance of netrin-1 as a potential therapeutic target for treating not only cardiovascular disease but also other inflammatory conditions. Therefore, this research sheds light on the promising future of netrin-1 as a treatment option for a range of diseases

    The Structure and Function of the Retina in Multiple Sclerosis

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    Background: Multiple sclerosis (MS) is a complex heterogenous autoimmune inflammatory disease with a prolonged and variable time course. The visual system is frequently implicated, either as the presenting symptom, or, with advancement of the disease. This has been documented in the literature with changes in visual acuity (VA) that are accompanied by functional changes in the optic nerve, measured with the visual evoked potential (VEP) and possible retrograde degeneration involving the retinal ganglion cells in the retina, measured with the pattern reversal electroretinogram (PERG). However, inflammatory episodes may be clinical or subclinical in nature and may go unrecognised. Originating from the same embryological origins, the effect of inflammation in MS on the on the retina is less well known. The research hypothesis was that there is a measurable difference in the function of retinal cells in patients with newly diagnosed multiple sclerosis, suggestive of inflammatory retinopathy compared to healthy controls. The overall aim was to investigate any differences in the electrophysiological function of the visual pathway of patients newly diagnosed with MS compared to healthy controls. Methods: The visual system is explored with clinical (VA), electrophysiology (VEP and electroretinography (ERG – pattern and flash) and structural (OCT) measures, in patients presenting with symptoms suggestive of MS to a specialist service. This prospective case control study investigates the visual pathway at the earliest stage of the disease to look for differences in structure and function between patients and healthy volunteers that might serve as a biomarker in the future. Results: There were a number of variables that were significantly different between the two groups, logistic regression analysis found that VA (p 0.038) and VEP P100 peak-time (p 0.014) from the right eye as significant. Dividing the participants by prolongation of the VEP P100 peak-time as defined in clinical practice, found a number of ERG amplitude variables as well as VA that were consistently different between the groups regardless of symptoms. Conclusion: The study confirms optic nerve involvement in MS with VEP and VA abnormalities consistent with the literature in this cohort. Additionally, VA and some ERG amplitude variables were significantly reduced in participants with MS, when grouped according to VEP P100 peak-time, suggesting inner and outer retinal changes. Further work would be required to confirm these findings. No OCT structural changes were found in any of the analysis that included the macula thickness, ganglion cell layer or retinal nerve fibre layer. Keywords: multiple sclerosis (MS), visual evoked potential (VEP), pattern electroretinogram (PERG), electroretinogram (ERG), optical coherence tomography (OCT

    Biomedical and Pharmacological Applications of Marine Collagen

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    Biomimetic polymers and materials have been widely used in a variety of biomedical and pharmacological applications. Particularly, collagen-based biomaterials have been extensively applied in various biomedical fields, such as scaffolds in tissue engineering. However, there are many challenges associated with the use of mammalian collagen, including the issues of religious constrains, allergic or autoimmune reactions, and the spread of animal diseases. Over the past few decades, marine collagen (MC) has emerged as a promising biomaterial for biomedical and pharmacological applications. Marine organisms are a rich source of structurally novel and biologically active compounds, and to date, many biological components have been isolated from various marine resources. MC offers advantages over mammalian collagen due to its water solubility, low immunogenicity, safety, biocompatibility, antimicrobial activity, functionality, and low production costs. Due to its characteristics and physicobiochemical properties, it has tremendous potential for use as a scaffold biomaterial in tissue engineering and regenerative medicine, in drug delivery systems, and as a therapeutic. In this Special Issue, we encourage submissions related to the recent developments, advancements, trends, challenges, and future perspectives in this new research field. We expect to receive contributions from different areas of multidisciplinary research, including—but not restricted to—extraction, purification, characterization, fabrication, and experimentation of MC, with a particular focus on their biotechnological, biomedical and pharmacological uses

    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
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