HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease.

Fructose is a major component of dietary sugar and its overconsumption exacerbates key pathological features of metabolic syndrome. The central fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose compared with KHK-A and is produced primarily in the liver, thus restricting fructose metabolism almost exclusively to this organ. Here we show that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathological cardiac hypertrophy through hypoxia-inducible factor 1α (HIF1α) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. Heart-specific depletion of SF3B1 or genetic ablation of Khk, but not Khk-A alone, in mice, suppresses pathological stress-induced fructose metabolism, growth and contractile dysfunction, thus defining signalling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathological growth

DO SOCCER ASSOCIATIONS REALLY SPEND ON A GOOD THING? EMPIRICAL EVIDENCE ON HETEROGENEITY IN THE CONSUMER RESPONSE TO MATCH UNCERTAINTY OF OUTCOME

"The purpose of this study is to analyze whether previous results describing the effect of uncertainty of outcome on match attendance in team sports have been driven by heterogeneity in fan demand. We apply censored quantile regression methods and place particular emphasis on the relationship between match uncertainty and attendance demand, as previous results are highly ambiguous. This is more surprising, as each season association and league officials continue to spend millions on enhancing this uncertainty. We also control for season ticket holders, who are unlikely to be influenced by match specificities. Based on data from German soccer, our results indicate that fan demand shows heterogeneity across quantiles and that increasing match uncertainty of outcome exclusively benefits teams who already face strong attendance demand. "("JEL "D12, C14, C24, L83) Copyright (c) 2008 Western Economic Association International.

Blinding Eye Disease and Associated Genetic and Epidemiological Factors in a Mayan Population of Guatemala

Purpose : The Mayan population in Guatemala is understudied within vision research. This observational cohort of individuals seeking eye care may help identify unique clinical, demographic, environmental, and genetic factors for blinding eye disease. This study will serve to (a) identify the ocular health needs within this population and (b) any possible modifiable risk factors. Methods : We conducted a cross-sectional study with 126 participants. Each received an eye exam, provided a blood sample, and were administered a standardized epidemiological questionnaire at the Lion\u27s Eye Hospital in Salama, Guatemala. Interpreters were available for translation to the patients\u27 native dialect. We also performed a genome-wide association study using Illumina\u27s HumanOmni2.5-8 chip to examine SNPs. We used quality control measures and performed a logistic regression analysis to determine which genetic components were associated with eye disease. Results : The population was 46% male, and the average age was 65.2. We found that the most prevalent eye conditions were cataracts (54.8%), followed by pseudoexfoliation syndrome (PXF) (24.6%). The population with both conditions was 22.2%. We conducted multivariate analyses to determine which epidemiological factors were significantly associated with the population\u27s eye conditions at p\u3c.05. In our epidemiological analysis, including 121 participants for completeness, we found that eye disease was significantly more likely with advanced age. Cataracts were significantly more common among those living in the 10 districts with the least resources. Furthermore, having cataracts was associated with a greater likelihood of PXF after adjusting for age and sex. In our genetic analysis, the SNP most significantly associated with PXF is within the gene KSR2 (p\u3c1 x 10-5). Several SNP\u27s were associated with Cataracts at Genome-Wide significance adjusting for covariates (p\u3c5 x 10-8). Almost three-quarters of these SNPs lie within 13 genes, with the majority of genes having only one significant SNP. Conclusions : To the best of our knowledge utilizing PhenGenI, these SNP\u27s and genes have not been previously associated with cataracts, glaucoma, or PXF. This study can aid in understanding the prevalence of eye conditions in this population but may also inform public health planning and delivering of quality, accessible and relevant health and preventative care within Guatemala

Systemic Disease and Ocular Comorbidity Analysis of Geographically Isolated Federally Recognized American Indian Tribes of the Intermountain West

Background: The American Indian Navajo and Goshute peoples are underserved patient populations residing in the Four Corners area of the United States and Ibupah, Utah, respectively. Methods: We conducted a cross-sectional study of epidemiological factors and lipid biomarkers that may be associated with type II diabetes, hypertension and retinal manifestations in tribal and non-tribal members in the study areas (n = 146 participants). We performed multivariate analyses to determine which, if any, risk factors were unique at the tribal level. Fundus photos and epidemiological data through standardized questionnaires were collected. Blood samples were collected to analyze lipid biomarkers. Univariate analyses were conducted and statistically significant factors at p < 0.10 were entered into a multivariate regression. Results: Of 51 participants for whom phenotyping was available, from the Four Corners region, 31 had type II diabetes (DM), 26 had hypertension and 6 had diabetic retinopathy (DR). Of the 64 participants from Ibupah with phenotyping available, 20 had diabetes, 19 had hypertension and 6 had DR. Navajo participants were less likely to have any type of retinopathy as compared to Goshute participants (odds ratio (OR) = 0.059; 95% confidence interval (CI) = 0.016–0.223; p < 0.001). Associations were found between diabetes and hypertension in both populations. Older age was associated with hypertension in the Four Corners, and the Navajo that reside there on the reservation, but not within the Goshute and Ibupah populations. Combining both the Ibupah, Utah and Four Corners study populations, being American Indian (p = 0.022), residing in the Four Corners (p = 0.027) and having hypertension (p < 0.001) increased the risk of DM. DM (p < 0.001) and age (p = 0.002) were significantly associated with hypertension in both populations examined. When retinopathy was evaluated for both populations combined, hypertension (p = 0.037) and living in Ibupah (p < 0.001) were associated with greater risk of retinopathy. When combining both American Indian populations from the Four Corners and Ibupah, those with hypertension were more likely to have DM (p < 0.001). No lipid biomarkers were found to be significantly associated with any disease state. Conclusions: We found different comorbid factors with retinal disease outcome between the two tribes that reside within the Intermountain West. This is indicated by the association of tribe and with the type of retinopathy outcome when we combined the populations of American Indians. Overall, the Navajo peoples and the Four Corners had a higher prevalence of chronic disease that included diabetes and hypertension than the Goshutes and Ibupah. To the best of our knowledge, this is the first study to conduct an analysis for disease outcomes exclusively including the Navajo and Goshute tribe of the Intermountain West

Systemic Disease and Ocular Comorbidity Analysis of Geographically Isolated Federally Recognized American Indian Tribes of the Intermountain West

BACKGROUND: The American Indian Navajo and Goshute peoples are underserved patient populations residing in the Four Corners area of the United States and Ibupah, Utah, respectively. METHODS: We conducted a cross-sectional study of epidemiological factors and lipid biomarkers that may be associated with type II diabetes, hypertension and retinal manifestations in tribal and non-tribal members in the study areas (n = 146 participants). We performed multivariate analyses to determine which, if any, risk factors were unique at the tribal level. Fundus photos and epidemiological data through standardized questionnaires were collected. Blood samples were collected to analyze lipid biomarkers. Univariate analyses were conducted and statistically significant factors at RESULTS: Of 51 participants for whom phenotyping was available, from the Four Corners region, 31 had type II diabetes (DM), 26 had hypertension and 6 had diabetic retinopathy (DR). Of the 64 participants from Ibupah with phenotyping available, 20 had diabetes, 19 had hypertension and 6 had DR. Navajo participants were less likely to have any type of retinopathy as compared to Goshute participants (odds ratio (OR) = 0.059; 95% confidence interval (CI) = 0.016-0.223; CONCLUSIONS: We found different comorbid factors with retinal disease outcome between the two tribes that reside within the Intermountain West. This is indicated by the association of tribe and with the type of retinopathy outcome when we combined the populations of American Indians. Overall, the Navajo peoples and the Four Corners had a higher prevalence of chronic disease that included diabetes and hypertension than the Goshutes and Ibupah. To the best of our knowledge, this is the first study to conduct an analysis for disease outcomes exclusively including the Navajo and Goshute tribe of the Intermountain West