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- Araujo, I. M., et al.
(författare)
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Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons
- 2007
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Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 14:9, s. 1635-1646
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Tidskriftsartikel (refereegranskat)abstract
- Proteolytic cleavage of the Na+/Ca2+ exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca2+ dynamics, calpain activation and cell viability, in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. Selective overactivation of AMPA receptors caused the reversal of the NCX, which accounted for approximately 30% of the rise in intracellular free calcium concentration ([Ca2+](i)). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl] isothiourea (KB-R7943), partially inhibited the initial increase in [Ca2+](i), and prevented a delayed increase in [Ca2+](i). In parallel, overactivation of AMPA receptors strongly activated calpains and led to the proteolysis of NCX3. KB-R7943 prevented calpain activation, cleavage of NCX3 and was neuroprotective. Silencing of NCX3 reduced Ca2+ uptake, calpain activation and was neuroprotective. Our data show for the first time that NCX reversal is an early event following AMPA receptor stimulation and is linked to the activation of calpains. Since calpain activation subsequently inactivates NCX, causing a secondary Ca2+ entry, NCX may be viewed as a new suicide substrate operating in a Ca2+-dependent loop that triggers cell death and as a target for neuroprotection.
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| 2. |
- Matos-Semedo, F., et al.
(författare)
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House dust mite (HDM) and storage mite (SM) molecular sensitisation profiles and association with clinical outcomes in allergic asthma and rhinitis: Protocol for a systematic review
- 2021
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Identification and characterisation of single allergens at molecular level is important. Component-resolved diagnosis offers the possibility of higher diagnostic precision, thereby allowing better patient management. House dust mites (HDM) have a worldwide distribution. Studies from different countries have shown that IgE-mediated allergy to storage mites (SM) is important in rural and urban populations. With the availability of HDM and SM molecular allergen components, studies have investigated whether different molecular sensitisation profiles are associated with clinical disease outcomes. However, no previous systematic review has synthesised the underlying evidence. Methods and analysis We will search Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register), MEDLINE, EMBASE, CINAHL, AMED, ISI Web of Science (Science and Social Science Index) from inception to March 2020. Unpublished and ongoing work, as well as research in progress will be searched in www.ClinicalTrials.gov; www.controlledtrials.com and wwwanzctrorgau. We will contact an international panel of experts in this field. No language restrictions will apply; translations will be undertaken where necessary. The Critical Appraisal Skills Programme quality assessment tool will be used to appraise the methodological quality of included studies. A descriptive summary with data tables will be constructed, and if adequate, meta-analysis using random effects will be performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist will be followed for reporting. Ethics and dissemination Since this systematic review will be only based on published and retrievable literature, no ethics approval is required. We will publish the systematic review in an international peer-reviewed journal. Trial registration number reviewregistry959. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| 6. |
- Frampton, Matthew, et al.
(författare)
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Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin's lymphoma
- 2013
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- In addition to HLA, recent genome-wide association studies (GWASs) of Hodgkin's lymphoma (HL) have identified susceptibility loci for HL at 2p16.1, 8q24.21 and 10p14. In this study, we perform a GWAS meta-analysis with published GWAS (totalling 1,465 cases and 6,417 controls of European background), and follow-up the most significant association signals in 2,024 cases and 1,853 controls. A combined analysis identifies new HL susceptibility loci mapping to 3p24.1 (rs3806624; P = 1.14 x 10(-12), odds ratio (OR) = 1.26) and 6q23.3 (rs7745098; P = 3.42 x 10(-9), OR = 1.21). rs3806624 localizes 5' to the EOMES (eomesodermin) gene within a p53 response element affecting p53 binding. rs7745098 maps intergenic to HBS1L and MYB, a region previously associated with haematopoiesis. These findings provide further insight into the genetic and biological basis of inherited susceptibility to HL.
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| 7. |
- Mitchell, Jonathan S., et al.
(författare)
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Genome-wide association study identifies multiple susceptibility loci for multiple myeloma
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P = 1.31 x 10(-8)), 6q21 (rs9372120, P = 9.09 x 10(-15)), 7q36.1 (rs7781265, P = 9.71 x 10(-9)), 8q24.21 (rs1948915, P = 4.20 x 10(-11)), 9p21.3 (rs2811710, P = 1.72 x 10(-13)), 10p12.1 (rs2790457, P = 1.77 x 10(-8)), 16q23.1 (rs7193541, P = 5.00 x 10(-12)) and 20q13.13 (rs6066835, P = 1.36 x 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
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| 8. |
- Sud, Amit, et al.
(författare)
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Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1, s. 1892-1892
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Tidskriftsartikel (refereegranskat)abstract
- Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10-17), 6q23.3 (rs6928977, P = 4.62 × 10-11), 10p14 (rs3781093, P = 9.49 × 10-13), 13q34 (rs112998813, P = 4.58 × 10-8) and 16p13.13 (rs34972832, P = 2.12 × 10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.
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