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Background and aims Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. Methods Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. Results Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. Conclusions These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.

Citizenship Reimagined is an important book that arrives at a crucial time in the life of American federalism and immigration policy and politics. The book is a major empirical contribution to the ...

With the support of the Climate Technology Centre and Network (CTCN), the first phase of defining a road map for targeted research in Jamaica began in September 2020. During the development process, an effort was made to identify and analyse existing capacities in universities, research centres, and the private sector, whose lines of work support climate change priorities and the development of technological capacities in productive activities. This document presents an agenda for research and technology development (RT&D), the result of a co-creation process with academia, R&TD centres, and the private sector, to support climate change targets in the key sectors identified for the first phase: agriculture and fisheries, water, human settlement and infrastructure, waste, and energy. The sectors were prioritised using a multicriteria analysis that took account of the need for new knowledge to address climate change impact-related issues, as well as the importance of each sector in terms of economic impact, climate, environmental, and social impact.

The Eoarchean Isua supracrustal belt (ISB) has been interpreted as one of the earliest records of subduction processes, leading to the conclusion that a plate tectonic geodynamic system was likely operating since the early Archean. However, proposed tectonic models remain difficult to evaluate as our understanding of the metamorphic and structural evolution remains fragmentary. Here, we present a metamorphic study of the supracrustal rocks of the ISB. We used petrographic and microstructural observations, phase equilibria, isopleth geothermobarometry, and conventional thermometry to explore the prograde, peak, and retrograde metamorphic evolution of the northeastern ISB. Our results show that the ISB records a syn‐tectonic, amphibolite facies metamorphic event (M1) with peak conditions of 550°C–600°C and 0.5–0.7 GPa. M1 was followed by a static, lower amphibolite facies metamorphic event (M2; 3.5 Ga) and the Neoarchean (

Gladson Muthian,1 Veronica Mackey,1 Kedar Prasad,2 Clivel Charlton1 1Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, USA; 2Research and Development, Antioxidant Research Institute, Premier Micronutrient Corporation, Novato, CA, USA Background: Degeneration of nigrostriatal (NS) dopamine (DA) neurons is the major neuropathological marker of Parkinson’s disease (PD). The cause for the disorder is unknown, but a prenatal sensitization stage and a postnatal precipitating stage may be involved. The sensitization stage is based on studies showing that prenatal exposure to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) during the birth of substantia nigra (SN) DA neurons reduced DA, its metabolites, tyrosine hydroxylase (TH), the number of NS neurons as well as locomotor activities of the offspring. The observation that motor activities of the toxin-exposed animals deteriorated during aging, produced the condition equated to the precipitating stage. Other studies suggest that curcumin may offer protection.Purpose: For this project, we studied the protection offered by curcumin and an antioxidant formulation from MPTP-induced toxicity. Methods: Four groups of adult mice were pretreated, every other day for 27 days, with curcumin, 25 μg or 50 μg per mice of 25 g average body weight (equated to 1 mg/kg or 2 mg/kg) or with 25 mg/kg or 50 mg/kg of the antioxidant formulation. A control group received saline. MPTP was administer at the 20th day of pretreatment and all treatments continued for 7 days, then the animals were studied for changes in motor activities, striatal DA and DA metabolites as well as striatal and midbrain TH. The changes are indicative of PD-like NS damage. Results: The data showed that MPTP markedly reduced movements, as well as DA, its metabolites and TH. Curcumin and the antioxidant formulation blocked and ameliorated the toxic effects of MPTP. MPTP reduced DA to 49.1%. Curcumin restored DA to 87.3% and 84.8%, and the antioxidants restored and elevated DA to 132.1% and 121.2%. MPTP reduced striatal TH to 45.1%. The doses of curcumin restored TH to 60.9% and 75.1% and the antioxidants restored TH to 90.7% and 94.7%. Curcumin and the antioxidants reduced MPTP-induced death. Conclusion: The results demonstrated that curcumin and the antioxidants blocked the PD-like toxic effects of MPTP, indicative of the potentials as preventative measure for PD. Keywords: antioxidants, curcumin, dopamine, tyrosine hydroxylase, Parkinson’s disease

Background and objectives Endothelial dysfunction is common among patients with CKD. We tested the efficacy and safety of combination treatment with sodium nitrite and isoquercetin on biomarkers of endothelial dysfunction in patients with CKD. Design, setting, participants, & measurements This randomized, double-blind, placebo-controlled phase 2 pilot trial enrolled 70 patients with predialysis CKD. Thirty-five were randomly assigned to combination treatment with sodium nitrite (40 mg twice daily) and isoquercetin (225 mg once daily) for 12 weeks, and 35 were randomly assigned to placebo. The primary outcome was mean change in flow-mediated vasodilation over the 12-week intervention. Secondary and safety outcomes included biomarkers of endothelial dysfunction, inflammation, and oxidative stress as well as kidney function, methemoglobin, and adverse events. Intention-to-treat analysis was conducted. Results Baseline characteristics, including age, sex, race, cigarette smoking, history of hypertension and diabetes, use of renin-angiotensin system blockers, BP, fasting glucose, lipid profile, kidney function, urine albumin-creatinine ratio, and endothelial biomarkers, were comparable between groups. Over the 12-week intervention, flow-mediated vasodilation increased 1.1% (95% confidence interval, −0.1 to 2.3) in the treatment group and 0.3% (95% confidence interval, −0.9 to 1.5) in the placebo group, and net change was 0.8% (95% confidence interval, −0.9 to 2.5). In addition, changes in biomarkers of endothelial dysfunction (vascular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, vWf, endostatin, and asymmetric dimethylarginine), inflammation (TNF-α, IL-6, C-reactive protein, IL-1 receptor antagonist, and monocyte chemoattractant protein-1), and oxidative stress (oxidized LDL and nitrotyrosines) were not significantly different between the two groups. Furthermore, changes in eGFR, urine albumin-creatinine ratio, methemoglobin, and adverse events were not significantly different between groups. Conclusions This randomized phase 2 pilot trial suggests that combination treatment with sodium nitrite and isoquercetin did not significantly improve flow-mediated vasodilation or other endothelial function biomarkers but also did not increase adverse events compared with placebo among patients with CKD. Clinical Trial registry name and registration number: Nitrite, Isoquercetin, and Endothelial Dysfunction (NICE), NCT02552888

OBJECTIVES: To measure the effectiveness, safety and use of anti-Tumour necrosis Factor (TNF) therapy in paediatric inflammatory bowel disease (PIBD) in the United Kingdom (UK). METHODS: Prospective UK audit of patients newly starting anti-TNF therapy. Disease severity was assessed using Physician Global Assessment (PGA) +/or the Paediatric Crohn's Disease Activity Index (PCDAI). RESULTS: 37 centres participated (23 of 25 specialist PIBD sites). 524 patients were included; 429 Crohn's disease (CD), 76 ulcerative colitis (UC), 19 IBD unclassified (IBDU). 87% (488/562) anti-TNF was infliximab; commonest indication was active luminal CD 77% (330/429) or chronic refractory UC/IBDU 56% (53/95); 79% (445/562) had concomitant co-immunosuppression. In CD (267/429 male), median time from diagnosis to treatment was 1.42 years (IQR 0.63-2.97). Disease (at initiation) was moderate or severe in 91% (156/171) by PGA compared to 41% (88/217) by PCDAI; Kappa (Κ) 0.28 = only 'fair agreement' (p