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- Walters, R G, et al.
(författare)
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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 463:7281, s. 671-5
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Tidskriftsartikel (refereegranskat)abstract
- Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
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| 2. |
- Ardura-Fabregat, A., et al.
(författare)
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Targeting Neuroinflammation to Treat Alzheimer’s Disease
- 2017
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Ingår i: CNS Drugs. - : Springer Science and Business Media LLC. - 1172-7047 .- 1179-1934. ; 31:12, s. 1-26
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Forskningsöversikt (refereegranskat)abstract
- Over the past few decades, research on Alzheimer’s disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that—upon engagement of pattern recognition receptors—induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.
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| 7. |
- Mariani, A., et al.
(författare)
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First-principle based predictions of the effects of negative triangularity on DTT scenarios
- 2024
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 64:4
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Tidskriftsartikel (refereegranskat)abstract
- Plasmas with negative triangularity (NT) shape have been recently shown to be able to achieve H-mode levels of confinement in L-mode, avoiding detrimental edge localised modes. Therefore, this plasma geometry is now studied as a possible viable option for a future fusion reactor. Within this framework, an NT option is under investigation for the full power scenario of the Divertor Tokamak Test (DTT) facility, under construction in Italy, with δ t o p = − 0.32 / δ b o t t o m ≃ 0.02 top/bottom triangularity values at the separatrix. The transport properties of this scenario are studied in this work. Gyrokinetic GENE simulations and integrated modelling using ASTRA with the quasi-linear trapped gyro-Landau fluid (TGLF) model have been performed. The emerging picture from the ASTRA-TGLF runs with boundary conditions at ρ t o r = 0.94 is that, in the L-mode NT option, the larger peaking of the kinetic profiles in the edge region is not sufficient to recover the loss of the PT H-mode pedestal, and reach similar central temperature values. Two additional shapes are also considered, obtained by flipping the triangularity of the scenarios, to single out the effect of the triangularity sign. A negligible ‘direct’ effect of the triangularity is found for the L-mode, while a small beneficial effect is observed for the H-mode. The ASTRA-TGLF results are validated by GENE and TGLF stand-alone at two selected radii. GENE shows ITG dominant micro-instability and explains the small beneficial effect of the NT for the H-mode as due to a strong reduction of the heat fluxes, when reversing the triangularity, with a relatively high T i stiffness. An improvement of the predicted performances of the NT DTT scenario could come from ρ tor ≳ 0.9 , as indicated by some recent experiments at the tokamak à configuration variable (TCV) and ASDEX Upgrade.
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| 9. |
- Banfi, C, et al.
(författare)
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Prenylcysteine oxidase 1, an emerging player in atherosclerosis
- 2021
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4:1, s. 1109-
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Tidskriftsartikel (refereegranskat)abstract
- The research into the pathophysiology of atherosclerosis has considerably increased our understanding of the disease complexity, but still many questions remain unanswered, both mechanistically and pharmacologically. Here, we provided evidence that the pro-oxidant enzyme Prenylcysteine Oxidase 1 (PCYOX1), in the human atherosclerotic lesions, is both synthesized locally and transported within the subintimal space by proatherogenic lipoproteins accumulating in the arterial wall during atherogenesis. Further, Pcyox1 deficiency in Apoe-/- mice retards atheroprogression, is associated with decreased features of lesion vulnerability and lower levels of lipid peroxidation, reduces plasma lipid levels and inflammation. PCYOX1 silencing in vitro affects the cellular proteome by influencing multiple functions related to inflammation, oxidative stress, and platelet adhesion. Collectively, these findings identify the pro-oxidant enzyme PCYOX1 as an emerging player in atherogenesis and, therefore, understanding the biology and mechanisms of all functions of this unique enzyme is likely to provide additional therapeutic opportunities in addressing atherosclerosis.
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