Mangumzamora4205

How genetic defects trigger the molecular changes that cause late-onset disease is important for understanding disease progression and therapeutic development. Fuchs' endothelial corneal dystrophy (FECD) is an RNA-mediated disease caused by a trinucleotide CTG expansion in an intron within the TCF4 gene. The mutant intronic CUG RNA is present at one-two copies per cell, posing a challenge to understand how a rare RNA can cause disease. Late-onset FECD is a uniquely advantageous model for studying how RNA triggers disease because (i) Affected tissue is routinely removed during surgery; (ii) The expanded CTG mutation is one of the most prevalent disease-causing mutations, making it possible to obtain pre-symptomatic tissue from eye bank donors to probe how gene expression changes precede disease; and (iii) The affected tissue is a homogeneous single cell monolayer, facilitating accurate transcriptome analysis. Here, we use RNA sequencing (RNAseq) to compare tissue from individuals who are pre-symptomatic (Pre_S) to tissue from patients with late stage FECD (FECD_REP). The abundance of mutant repeat intronic RNA in Pre_S and FECD_REP tissue is elevated due to increased half-life in a corneal cells. In Pre_S tissue, changes in splicing and extracellular matrix gene expression foreshadow the changes observed in advanced disease and predict the activation of the fibrosis pathway and immune system seen in late-stage patients. The absolute magnitude of splicing changes is similar in pre-symptomatic and late stage tissue. Our data identify gene candidates for early drivers of disease and biomarkers that may represent diagnostic and therapeutic targets for FECD. We conclude that changes in alternative splicing and gene expression are observable decades prior to the diagnosis of late-onset trinucleotide repeat disease.Background Respiratory syncytial virus (RSV) is a leading cause of viral pneumonia and bronchiolitis during the first six months of life. Placentally-transferred antibodies can prevent severe RSV illness, and maternal immunization may reduce illness in young infants. Identifying protective antibody levels will facilitate the advancement of vaccine candidates and maternal immunization. Methods We conducted a nested case-control study involving 587 Malian mother-infant pairs, followed from birth to 6 months of age. RSV cases were infants who developed influenza-like-illness (ILI) or pneumonia and were RSV positive by PCR. Cases were matched to healthy controls and RSV-negative ILI controls. RSV-A and RSV-B neutralizing antibodies were measured in maternal, cord blood, and infant sera at 3 and 6 months of age. Results Maternal antibodies were efficiently transferred to infants. Maternal and infant RSV titers were strongly correlated. Infant antibody titers against RSV-A were 3X higher compared to those against RSV B. At birth, infants who remained healthy had significantly higher RSV-A and RSV-B titers compared to infants that subsequently contracted RSV. RSV-A IC80 titer >239 or RSV-B IC80 titer >60 at birth was significantly associated with being a healthy control compared to an RSV case within the first three months of life. RSV-A IC80 titers in cord blood were associated with decreased episodes of pneumonia. Conclusions Maternally acquired RSV antibodies were associated with protection of infants against community-detected cases of RSV-ILI and pneumonia. RSV antibody levels in cord blood can predict whether an infant will be infected with RSV or remain uninfected.Basaltic rocks play a significant role in CO2 sequestration from the atmosphere during their weathering. Moreover, the primary microorganisms that colonize them, by providing mineral elements and nutrients, are shown to promote growth of diverse heterotrophic communities and plants, therefore positively impacting Earth's long-term climate balance. However, the first steps of microbial colonization and subsequent rock weathering remain poorly understood, especially regarding microbial communities over a chronological sequence. Here, we analyzed the microbial communities inhabiting the soil developed in crevices on lava flows derived from different eruptions on Fogo Island. Investigated soils show typically low carbon and nitrogen content and are relatively similar to one another regarding their phylogenetic composition, and similar to what was recorded in large soil surveys with dominance of Actinobacteria and Proteobacteria. Moreover, our results suggest a stronger effect of the organic carbon than the lava flow age in shaping microbial communities as well as the possibility of exogenous sources of bacteria as important colonizers. Furthermore, archaea reach up to 8.4% of the total microbial community, dominated by the Soil Crenarchaeotic Group, including the ammonium-oxidizer Candidatus Nitrososphaera sp. Therefore, this group might be largely responsible for ammonia oxidation under the environmental conditions found on Fogo.Objectives to establish and quantify any observable association between the exposure to community prescriptions for quinine and acute kidney injury (AKI) events in a population of older adults. Design two observational studies using the same dataset, a retrospective longitudinal cohort study and a self-controlled case series (SCCS). Setting NHS health board in Scotland. Participants older adults (60+ years) who received quinine prescriptions in Tayside, Scotland, between January 2004 and December 2015. The first study included 12,744 individuals. The SCCS cohort included 5,907 people with quinine exposure and more than or equal to one AKI event. Main outcome measured in the first study, multivariable logistic regression was used to calculate odds ratios (ORs) for AKI comparing between episodes with and without recent quinine exposure after adjustment for demographics, comorbidities and concomitant medications. The SCCS study divided follow-up for each individual into periods 'on' and 'off' quinine, calculating incidence rate ratios (IRRs) for AKI adjusting for age. Results during the study period, 273,596 prescriptions for quinine were dispensed in Tayside. A total of 13,616 AKI events occurred during follow-up (crude incidence 12.5 per 100 person-years). In the first study, exposure to quinine before an episode of care was significantly associated with an increased probability of AKI (adjusted OR = 1.27, 95% confidence interval (CI) 1.21-1.33). learn more In the SCCS study, exposure to quinine was associated with an increased relative incidence of AKI compared to unexposed periods (IRR = 1.20, 95% CI 1.15-1.26), with the greatest risk observed within 30 days following quinine initiation (IRR = 1.48, 95% CI 1.35-1.61). Conclusion community prescriptions for quinine in an older adult population are associated with an increased risk of AKI.