| 191. |
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| 192. |
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| 193. |
- Tsiantoulas, D., et al.
(författare)
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APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 597
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide(1). The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs)(2) and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall(2). A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs(3), but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis.
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| 194. |
- Binder, J., et al.
(författare)
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Machine learning prediction and tau-based screening identifies potential Alzheimer's disease genes relevant to immunity
- 2022
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- With increased research funding for Alzheimer's disease (AD) and related disorders across the globe, large amounts of data are being generated. Several studies employed machine learning methods to understand the ever-growing omics data to enhance early diagnosis, map complex disease networks, or uncover potential drug targets. We describe results based on a Target Central Resource Database protein knowledge graph and evidence paths transformed into vectors by metapath matching. We extracted features between specific genes and diseases, then trained and optimized our model using XGBoost, termed MPxgb(AD). To determine our MPxgb(AD) prediction performance, we examined the top twenty predicted genes through an experimental screening pipeline. Our analysis identified potential AD risk genes: FRRS1, CTRAM, SCGB3A1, FAM92B/CIBAR2, and TMEFF2. FRRS1 and FAM92B are considered dark genes, while CTRAM, SCGB3A1, and TMEFF2 are connected to TREM2-TYROBP, IL-1 beta-TNF alpha, and MTOR-APP AD-risk nodes, suggesting relevance to the pathogenesis of AD. Jessica Binder et al. developed a machine learning model to discover potential drug targets for Alzheimer's disease. They validated their 20 top candidates in several in vitro models, and highlight FRRS1, CTRAM, SCGB3A1, FAM92B/CIBAR2, and TMEFF2 as potential AD risk genes.
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| 195. |
- Hegele, R. A., et al.
(författare)
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Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement
- 2020
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Ingår i: Lancet Diabetes & Endocrinology. - : Elsevier BV. - 2213-8587. ; 8:1, s. 50-67
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Tidskriftsartikel (refereegranskat)abstract
- Genome sequencing and gene-based therapies appear poised to advance the management of rare lipoprotein disorders and associated dyslipidaemias. However, in practice, underdiagnosis and undertreatment of these disorders are common, in large part due to interindividual variability in the genetic causes and phenotypic presentation of these conditions. To address these challenges, the European Atherosclerosis Society formed a task force to provide practical dinical guidance focusing on patients with extreme concentrations (either low or high) of plasma low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol. The task force also recognises the scarcity of quality information regarding the prevalence and outcomes of these conditions. Collaborative registries are needed to improve health policy for the care of patients with rare dyslipidaemias.
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| 196. |
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| 197. |
- Olsson, Anders, 1940-, et al.
(författare)
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Can LDL cholesterol be too low? Possible risks of extremely low levels
- 2017
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Ingår i: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796. ; 281:6, s. 534-553
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Forskningsöversikt (refereegranskat)abstract
- Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important. This is an article from the symposium: Risks and benefits of Extremely Low LDL Cholesterol.
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| 198. |
- Schumann, G, et al.
(författare)
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Stratified medicine for mental disorders
- 2014
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Ingår i: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. - : Elsevier BV. - 1873-7862. ; 24:1, s. 5-50
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Tidskriftsartikel (refereegranskat)
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| 199. |
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| 200. |
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