2,123 research outputs found

    About Women And Men:The relevance of sex differences In cardiovascular diseases

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    Undergraduate Catalog of Studies, 2023-2024

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    Undergraduate Catalog of Studies, 2023-2024

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    From TgO/GABA-AT, GABA, and T-263 Mutant to Conception of Toxoplasma

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    Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat's oocyst shedding. Increased sporozoite/merozoite TgO/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with “Rosetta stone”-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in TgO/GABA-AT-related-pathways. These candidates potentially influence merozoite's capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease

    It doesn't end with closure:Optimizing health care throughout life after esophageal atresia repair

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    Elucidating How MLH1 Loss Regulates a Metabolic Phenotype in Endometrial Cancer

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    Endometrial cancer is the fourth most common cancer in women and the most common gynaecological malignancy in the developed world. No new systemic treatments for endometrial cancer have been developed in recent years and its incidence is expected to double over the next decade. As such, there is a need to better understand key molecular pathways that are altered in the disease and could be targeted by novel treatments. The DNA MMR pathway is lost in approximately 30% of endometrial cancers. A small proportion of these are caused by germline mutations in one of the four MMR genes, however, the majority result from the epigenetic silencing of MLH1. Recently, our lab has shown that MLH1-deficient cells demonstrate a mitochondrial phenotype characterised by reduced OXPHOS, reduced mtDNA copy number and Complex I inhibition. OXPHOS-deficient cells must adapt their metabolism to compensate for energy defects and the inability to efficiently use the tricarboxylic acid cycle to generate energy. We hypothesise that this altered metabolism is driving tumourigenesis by increasing the tumour cells' metastatic potential. In this PhD we aimed to further investigate the influence MLH1 loss has on cellular metabolism using MLH1 positive and negative paired endometrial cell lines. Ultimately, we aim to understand whether altered metabolism in MLH1-deficient endometrial cancer may be therapeutically targeted

    It doesn't end with closure:Optimizing health care throughout life after esophageal atresia repair

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    About Women And Men:The relevance of sex differences In cardiovascular diseases

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    Phage therapy for Escherichia coli urinary tract infections: selecting therapeutic phages and understanding resistance mechanisms in urine

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    Urinary tract infections (UTIs) affect a large proportion of the human and canine population. Due to rising levels of antibiotic resistance, empirical treatment with conventional antibiotics may fail, which can increase the probabilities of recurrence and severe complications. The most common species causing UTIs is uropathogenic Escherichia coli (UPEC), from which a clonal complex of particular concern is the O25:H4-ST131 as it is associated with the global emergence of multidrug-resistant and highly pathogenic urinary tract and bloodstream infections. Phage therapy is regarded as a promising alternative to antibiotics and could be especially useful to treat multidrug- resistant bacteria such as ST131 strains. This work aimed to find phages that could target strain EC958: a well characterised member of the ST131 group; and to dissect the causes of resistance that could lead to unsuccessful treatment. First, the optimisation of an artificial urine (AU) that could be used to study the phage-bacterium interaction was carried out, with the intention of obtaining results that could be translated to human and veterinary medicine. Then, different phages and phage combinations were screened against EC958 in the AU and standard lab media (LB). Finding a phage cocktail that could inhibit EC958 in LB was relatively easy, whereas none of the combinations tested in AU could prevent its growth for more than 8 hours. To understand what was causing the resistance, the infection assays were analysed by media and by timepoint using the phage LUC4. For this, individual colonies were isolated from the surviving population after phage exposure and re-challenged with the phage. The majority of the resistant variants recovered from LB assays were insensitive to the phage in the subsequent infections, which indicated that they had a fixed resistance to the phage. In AU, two different phenotypes were found in the resistant population. Some of the single colonies gave rise to a fixed phage-resistant culture, and others were still susceptible to the phage, despite having survived the initial challenge. Analysis of short and long read sequencing data indicated that mutations led to loss of expression of the primary phage receptor—OmpC—in the fixed resistant variants. The transient resistance, which is also observed in pooled canine urine but not in LB, was accelerated when the bacteria were cultured in the supernatant of an EC958 culture, and this was not due to significant changes in the phage adsorption rate. It was concluded that the productive phage infection was highly dependent on the culture conditions and the physiological state of the bacterial culture, which validated the effort to develop the AU for E. coli-phage interaction studies. The mechanism underlying the transient resistance could not be fully deciphered in the time available, but various hypotheses are discussed in the thesis and are currently being tested. Towards testing phage therapy for E. coli ST131 UTIs, three pilot studies were carried out in pigs: the first one with the aim of testing the safety of therapeutic phages produced from a detoxified E. coli strain; the second to establish a porcine model of UTI with ST131, and the third one used the UTI model to observe the efficacy of the phage. This study was also useful to analyse a phage treatment of EC958 infection in vivo, and ex vivo, by challenging the infected urine samples with phage. Preliminary data from these pilot studies suggested that pigs can be a good model to study E. coli UTIs and phage therapy. The phage preparations did not cause any significant inflammatory response in the pigs. E. coli ST131 strain EC958 was able to colonise and establish a UTI after intravesical instillation, with some evidence of macroscopical lesions in the bladder mucosa such as petechias. However, it is speculated that the infection was starting to self-resolve after a week. Phage LUC4 showed little impact to treat the UTI in vivo, with only a very short-lived reduction in bacterial counts in the urine of one of two animals. In line with the in vitro studies using AU and pooled urine, analysis of the surviving bacteria showed that they retained sensitivity to phage LUC4 when tested under laboratory conditions. This indicated that transient resistance was also the main issue preventing an effective intervention in vivo, for which it is important to understand the mechanism behind this resistance in order to achieve a safe and effective phage therapy for a multidrug-resistant UPEC such as ST131 EC958

    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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