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Oil induced heart failure results within embryonic sheepshead minnows, Cyprinodon variegatus.
CONTEXT Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. OBJECTIVE To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency exposed to major stress. DESIGN AND PARTICIPANTS Cross-sectional study 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N=83], sepsis [N=100], and combat stress [N=105]). Longitudinal study 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study 10 patients with primary adrenal insufficiency undergoing administration of 200mg hydrocortisone over 24 hours in four different delivery modes (continuous intravenous infusion; six-hourly oral, intramuscular or intravenous bolus administration). MAIN OUTCOME MEASURE We measured total serum cortisol and cortisone, free serum cortisol and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modelling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. RESULTS Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modelling identified continuous intravenous infusion of 200mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. CONCLUSIONS Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress. © Endocrine Society 2020.The Dictyostelium Intermediate Repeat Sequence 1 (DIRS-1) is the name-giving member of the DIRS order of tyrosine recombinase retrotransposons. In Dictyostelium discoideum, DIRS-1 is highly amplified and enriched in heterochromatic centromers of the D. discoideum genome. We show here that DIRS-1 it tightly controlled by the D. discoideum RNA interference machinery and is only mobilized in mutants lacking either the RNA dependent RNA polymerase RrpC or the Argonaute protein AgnA. DIRS retrotransposons contain an internal complementary region (ICR) that is thought to be required to reconstitute a full-length element from incomplete RNA transcripts. Using different versions of D. discoideum DIRS-1 equipped with retrotransposition marker genes, we show experimentally that the ICR is in fact essential to complete retrotransposition. We further show that DIRS-1 produces a mixture of single-stranded, mostly linear extrachromosomal cDNA intermediates. If this cDNA is isolated and transformed into D. discoideum cells, it can be used by DIRS-1 proteins to complete productive retrotransposition. https://www.selleckchem.com/products/ag-1478-tyrphostin-ag-1478.html This work provides the first experimental evidence to propose a general retrotransposition mechanism of the class of DIRS like tyrosine recombinase retrotransposons. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.CONTEXT Major advances have been made in the genetics and classification of congenital hyperinsulinism (CHI). OBJECTIVE To examine the genetics and clinical characteristics of patients with persistent and transient CHI. DESIGN A cross-sectional study with the register data and targeted sequencing of 104 genes affecting glucose metabolism. PATIENTS Genetic and phenotypic data were collected from 153 patients with persistent (n = 95) and transient (n = 58) CHI diagnosed between 1972 and 2015. Of these, 86 patients with persistent and 58 with transient CHI participated in the analysis of the selected 104 genes affecting glucose metabolism, including 10 CHI-associated genes, and 9 patients with persistent CHI were included because of their previously confirmed genetic diagnosis. MAIN OUTCOME MEASURES Targeted next-generation sequencing results and genotype-phenotype associations. RESULTS Five novel and 21 previously reported pathogenic or likely pathogenic variants in ABCC8, KCNJ11, GLUD1, GCK, HNF4A, and SLC16A1 genes were found in 68% (n = 65) and 0% of the patients with persistent and transient CHI, respectively. KATP channel mutations explained 82% of the mutation positive cases. CONCLUSIONS The genetic variants found in this nationwide CHI cohort are in agreement with previous studies, mutations in the KATP channel genes being the major causes of the disease. Pathogenic CHI-associated variants were not identified in patients who were both diazoxide responsive and able to discontinue medication within the first 4 months. Therefore, our results support the notion that genetic testing should be focused on patients with inadequate response or prolonged need for medication. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail [email protected] polypyrimidine tract binding protein (PTB) is a multi-domain protein involved in alternative splicing, mRNA localization, stabilization, polyadenylation and translation initiation from internal ribosome entry sites (IRES). In this latter process, PTB promotes viral translation by interacting extensively with complex structured regions in the 5'-untranslated regions of viral RNAs at pyrimidine-rich targets located in single strand and hairpin regions. To better understand how PTB recognizes structured elements in RNA targets, we solved the solution structure of the N-terminal RNA recognition motif (RRM) in complex with an RNA hairpin embedding the loop sequence UCUUU, which is frequently found in IRESs of the picornovirus family. Surprisingly, a new three-turn α3 helix C-terminal to the RRM, folds upon binding the RNA hairpin. Although α3 does not mediate any contacts to the RNA, it acts as a sensor of RNA secondary structure, suggesting a role for RRM1 in detecting pyrimidine tracts in the context of structured RNA. Moreover, the degree of helix formation depends on the RNA loop sequence. Finally, we show that the α3 helix region, which is highly conserved in vertebrates, is crucial for PTB function in enhancing Encephalomyocarditis virus IRES activity. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.DNA methylation and demethylation play a key role in the epigenetic regulation of gene expression; however, a series of oxidation reactions of 5-methyl cytosine (5mC) mediated by ten-eleven translocation (TET) enzymes driving demethylation process are yet to be uncovered. To elucidate the relationship between the oxidative processes and structural factors of DNA, we analysed the behavior of TET-mediated 5mC-oxidation by incorporating structural stress onto a substrate double-stranded DNA (dsDNA) using a DNA origami nanochip. The reactions and behaviors of TET enzymes were systematically monitored by biochemical analysis and single-molecule observation using atomic force microscopy (AFM). A reformative frame-like DNA origami was established to allow the incorporation of dsDNAs as 5mC-containing substrates in parallel orientations. We tested the potential effect of dsDNAs present in the tense and relaxed states within a DNA nanochip on TET oxidation. Based on enzyme binding and the detection of oxidation reactions within the DNA nanochip, it was revealed that TET preferred a relaxed substrate regardless of the modification types of 5-oxidated-methyl cytosine. Strikingly, when a multi-5mCG sites model was deployed to further characterize substrate preferences of TET, TET preferred the fully methylated site over the hemi-methylated site. This analytical modality also permits the direct observations of dynamic movements of TET such as sliding and interstrand transfer by high-speed AFM. In addition, the thymine DNA glycosylase-mediated base excision repair process was characterized in the DNA nanochip. Thus, we have convincingly established the system's ability to physically regulate enzymatic reactions, which could prove useful for the observation and characterization of coordinated DNA demethylation processes at the nanoscale. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.The brain's relationship to essential hypertension is primarily understood to be that of an end-organ, damaged late in life by stroke or dementia. Emerging evidence, however, shows that heightened blood pressure (BP) early in life and prior to traditionally defined hypertension, relates to altered brain structure, cerebrovascular function, and cognitive processing. Deficits in cognitive function, cerebral blood flow (CBF) responsivity, volumes of brain areas, and white matter integrity all relate to increased but pre-hypertensive levels of BP. Such relationships may be observed as early as childhood. In this review, we consider the basis of these relationships by examining the emergence of putative causative factors for hypertension that would impact or involve brain function/structure, e.g., sympathetic nervous system activation and related endocrine and inflammatory activation. Currently, however, available evidence is not sufficient to fully explain the specific pattern of brain deficits related to heightened BP. Despite this uncertainty, the evidence reviewed suggests the value that early intervention may have, not only for reducing BP, but also for maintaining brain function. © American Journal of Hypertension, Ltd 2020. All rights reserved. For Permissions, please email [email protected] hypothesized that digestibility of a zinc polysaccharide complex is greater than zinc sulfate when sows consume high fiber diets containing corn dried distillers grains with solubles (DDGS). Gilts and sows (n = 32) were blocked according to parity and assigned randomly to one of four dietary treatments (n = 8 sows/treatments). Dietary treatments consisted of 1) Control (ConZnSO4) - corn-soybean meal based diet + 100 ppm supplemental Zn from ZnSO4; 2) Control PSZn (ConPSZn) - corn-soybean meal based diet + 100 ppm supplemental Zn from Zn polysaccharide complex; 3) DDGS/ZnSO4 - corn-soybean meal-40% DDGS gestation diet and a 30% DDGS lactation diet, with each containing 100 ppm supplemental Zn from ZnSO4; 4) DDGS/PSZn - corn-soybean meal-40% DDGS gestation diet and a 30% DDGS lactation diet, with each containing 100 ppm supplemental Zn from Zn polysaccharide complex. A fifth dietary treatment was imposed using a subset of sows (n = 20) to determine basal Zn losses in gestating and lactating sows fed corn-soy had the greatest (P less then 0.05) ATTD, TTTD, and retention of Zn, which were opposite to responses observed in gestation. Furthermore, ATTD, TTTD, and Zn retention for lactating sows consuming DDGS/PSZn were less (P less then 0.05) than all other treatments. Overall, zinc digestibility of ZnSO4 and PSZn appears to be differentially influenced by stage of the reproductive cycle and presence of dietary fiber from DDGS. © The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail [email protected].
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