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| 11. |
- Berger, J. S., et al.
(författare)
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Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial
- 2016
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703. ; 175, s. 86-93
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Tidskriftsartikel (refereegranskat)abstract
- Background Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y(12) receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events. Study design EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1: 1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction-defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur. Conclusions The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.
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| 12. |
- Arnlund, David, et al.
(författare)
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Visualizing a protein quake with time-resolved X-ray scattering at a free-electron laser
- 2014
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Ingår i: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 11:9, s. 923-926
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Tidskriftsartikel (refereegranskat)abstract
- We describe a method to measure ultrafast protein structural changes using time-resolved wide-angle X-ray scattering at an X-ray free-electron laser. We demonstrated this approach using multiphoton excitation of the Blastochloris viridis photosynthetic reaction center, observing an ultrafast global conformational change that arises within picoseconds and precedes the propagation of heat through the protein. This provides direct structural evidence for a 'protein quake': the hypothesis that proteins rapidly dissipate energy through quake-like structural motions.
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| 13. |
- Boutet, S., et al.
(författare)
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High-Resolution Protein Structure Determination by Serial Femtosecond Crystallography
- 2012
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 337:6092, s. 362-364
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Tidskriftsartikel (refereegranskat)abstract
- Structure determination of proteins and other macromolecules has historically required the growth of high-quality crystals sufficiently large to diffract x-rays efficiently while withstanding radiation damage. We applied serial femtosecond crystallography (SFX) using an x-ray free-electron laser (XFEL) to obtain high-resolution structural information from microcrystals (less than 1 micrometer by 1 micrometer by 3 micrometers) of the well-characterized model protein lysozyme. The agreement with synchrotron data demonstrates the immediate relevance of SFX for analyzing the structure of the large group of difficult-to-crystallize molecules.
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| 14. |
- Gutierrez, J. A., et al.
(författare)
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Polyvascular Disease and Risk of Major Adverse Cardiovascular Events in Peripheral Artery Disease A Secondary Analysis of the EUCLID Trial
- 2018
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Ingår i: Jama Network Open. - : American Medical Association (AMA). - 2574-3805. ; 1:7
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The effect of polyvascular disease on cardiovascular outcomes in the background of peripheral artery disease (PAD) is unclear. OBJECTIVE To determine the risk of ischemic events (both cardiac and limb) among patients with PAD and polyvascular disease. DESIGN, SETTING, AND PARTICIPANTS In this post hoc secondary analysis of the international Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, outcomes were compared among 13 885 enrolled patients with PAD alone, PAD + coronary artery disease (CAD), PAD + cerebrovascular disease (CVD), and PAD + CAD + CVD. Adjusted Cox proportional hazards regression models were implemented to determine the risk associated with polyvascular disease and outcomes, and intention-to-treat analysis was performed. The EUCLID trial was conducted from December 31, 2012, to March 7, 2014; the present post hoc analysis was performed from June 1, 2017, to February 5, 2018. INTERVENTIONS EUCLID evaluated ticagrelor vs clopidogrel in preventing major adverse cardiac events (cardiovascular death, myocardial infarction [MI], or ischemic stroke) and major bleeding in patients with PAD. MAIN OUTCOMES AND MEASURES The primary end point was a composite of cardiovascular death, MI, or ischemic stroke. Key secondary end points included the individual components of the primary end point and acute limb ischemia leading to hospitalization, major amputation, and lower-extremity revascularization. The primary end point of Thrombolysis in Myocardial Infarction (TIMI) major bleeding was also evaluated. RESULTS The EUCLID trial randomized 13 885 patients with a median age of 66 years (interquartile range, 60-73 years), of whom 3888 (28.0%) were women. At baseline, 7804 patients (56.2%) had PAD alone; 2639 (19.0%) had PAD + CAD; 2049 (14.8%) had PAD + CVD; and 1393 (10.0%) had PAD + CAD + CVD. Compared with patients with isolated PAD, the adjusted hazard ratios (aHRs) for major adverse cardiac events were 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CVD, 1.65 (95% CI, 1.43491; P < .001) for PAD + CAD, and 1.99 (95% CI, 1.69-2.34; P < .001)for PAD + CAD + CVD. The aHRs for lower-extremity revascularization were 1.17 (95% CI, 1.03-1.34; P = .01) for PAD + CAD, 1.17 (95% CI, 1.02-1.35; P = .02) for PAD + CVD. and 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CAD + CVD. Polyvascular disease was not associated with an increased risk of acute limb ischemia (aHR for PAD + CVD, 0.91; 95% CI, 0.62-1.34, P = .63; PAD + CAD, 0.93; 95% CI, 0.64-1.34. P = .69; and PAD + CAD + CVD, 0.98; 95% CI, 0.63-1.53, P = .93), major amputation (aHR for PAD + CVD, 0.83; 95% CI, 0.541.27, P = .40; PAD + CAD, 0.74; 95% CI, 0.47-1.16, P = .19; and PAD + CAD + CVD, 1.12; 95% CI, 0.691.80, P = .65), or TI MI major bleeding (PAD + CVD, 0.98; 0.66-1.44, P = .91; PAD + CAD, 1.04; 0.741.48, P = .81; and PAD + CAD + CVD, 0.96; 95% CI, 0.62-1.51, P = .88). CONCLUSIONS AND RELEVANCE Compared with patients with PAD alone, the risk of major adverse cardiac events and lower-extremity revascularization increased with multiple vascular bed involvement. There was no clear increased risk of bleeding associated with polyvascular disease.
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- Andersson, KM, et al.
(författare)
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SURVIVIN INHIBITS TRANSCRIPTION OF PBX1 AND SUPPORTS THE EFFECTOR PHENOTYPE OF THE MEMORY CD4 T CELLS IN RHEUMATOID ARTHRITIS
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 227-228
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The oncogenic protein survivin is a marker of severe rheumatoid arthritis (RA). High serum levels of Survivin predict progressive joint damage1and poor treatment response2.Objectives:To study the role of survivin in the transcriptional regulation of phenotype in CD4+T cells.Methods:CD4+T cells of RA female patients were isolated from the perpheral blood. Activated CD4+cells were treated with survivin inhibitor YM155. Transcriptional analysis was done by RNAseq (Illumina) and conventional qPCR. Chromatin of CD4 cells was immunoprecipitated using polyclonal antibodies to survivin and subjected to deep sequencing (survivin ChIPseq, Hiseq2000, Illumina) and aligned to GRCh38. Statistical analysis of differentially expressed genes (DEG) was done in R-studio using Benjamini-Hochberg adjustment for multiple testing (Bioconductor, DESeq2 package).Results:Survivin ChIPseq of the activated CD4+T cells was enriched with the genes engaged in regulatory transcription factor specific DNA binding (GO:0000987, adj p=0.0005) and RNA polymerase II regulatory transcription (GO:0000978, adj p = 0.0004). Among survivin targets were the genes of HOX-B cluster and TALE family proteins MEIS, PKNOX and PBX1 controlling early leukopoesis and T cell maturation. Inhibition of survivin in PBMC resulted in significant upregulation of PBX1 (p=0.023), MEIS3 (p=0.0036), similar tendency was observed for HOXB6 and HOXC4 genes. RNAseq analysis CD4 cells of RA patients with different transcription of PBX1, identified 1636 genes (adj p<10-5). BIRC5, coding for survivin, was 8.3 folds higher in CD4+cells with low PBX1 (p=0.0005). Among the core transcription factors of T helper cell differentiation, we identifed NF-kB1 and NF-kB2, TBX21, IRF4, IRF8 and STAT3, BATF and BATF3. This followed by significantly higher TNF, IFNg and IL17A and IL17F in PBX1lo CD4 T cells. The pathway enrichment analysis of DEG identified strong over-representation of cytokine-specific genes (GO:005125, GO:0005126, GO:0048018, GO:0030545, FDR q-values 10-12-10-9). The genes of IL4, IL5, IL13, IL9, IL3 and CSF2 located within the chromosome 5 were common for all GO-lists, and were higher in PBX1lo, but none of those genes was identified by survivin-ChIPseq or PBX1-ChIPseq. Analysis of ChIPseq data identified the genes of STAT3, IRF4, IRF8 and BATF as common targets for PBX1 and survivin.Conclusion:This genome-wide analysis indicates that survivin regulates transcription of the TALE family protein PBX1 in CD4+ T cells, which has essential effect for differentiation and phenotype of Th subsets. Low PBX1 in RA patients is associated with terminally differentiated effector CD4+ T cells.References:[1]Svensson, B.et.al.Smoking in combination with antibodies to cyclic citrullinated peptides is associated with persistently high levels of survivin in early rheumatoid arthritis: a prospective cohort study.Arthritis Res Ther16, R12 (2014).[2]Levitsky, A.et.al.Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial.BMC Med13, 247 (2015).Disclosure of Interests:None declared
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| 19. |
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| 20. |
- Beck, S., et al.
(författare)
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Experimenting with Open Innovation in Science (OIS) practices: A novel approach to co-developing research proposals
- 2021
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Ingår i: CERN IdeaSquare Journal of Experimental Innovation. - 2413-9505. ; 5:2, s. 28-49
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Tidskriftsartikel (refereegranskat)abstract
- Co-producing scientific research with those who are affected by it is an emerging phenomenon in contemporary science. This article summarizes and reflects on both the process and outcome of a novel experiment to co-develop scientific research proposals in the field of Open Innovation in Science (OIS), wherein scholars engaged in the study of open and collaborative practices collaborated with the “users” of their research, i.e., scientists who apply such practices in their own research. The resulting co-developed research proposals focus on scientific collaboration, open data, and knowledge sharing and are available as an appendix to this article.
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| 21. |
- Burgess, Selena G, et al.
(författare)
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Probing the dynamic interface between trimethylamine dehydrogenase (TMADH) and electron transferring flavoprotein (ETF) in the TMADH—2ETF complex: role of the Arg-alpha237 (ETF) and Tyr-442 (TMADH) residue pair.
- 2008
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 47:18, s. 5168-5181
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Tidskriftsartikel (refereegranskat)abstract
- We have used multiple solution state techniques and crystallographic analysis to investigate the importance of a putative transient interaction formed between Arg-alpha237 in electron transferring flavoprotein (ETF) and Tyr-442 in trimethylamine dehydrogenase (TMADH) in complex assembly, electron transfer, and structural imprinting of ETF by TMADH. We have isolated four mutant forms of ETF altered in the identity of the residue at position 237 (alphaR237A, alphaR237K, alphaR237C, and alphaR237E) and with each form studied electron transfer from TMADH to ETF, investigated the reduction potentials of the bound ETF cofactor, and analyzed complex formation. We show that mutation of Arg-alpha237 substantially destabilizes the semiquinone couple of the bound FAD and impedes electron transfer from TMADH to ETF. Crystallographic structures of the mutant ETF proteins indicate that mutation does not perturb the overall structure of ETF, but leads to disruption of an electrostatic network at an ETF domain boundary that likely affects the dynamic properties of ETF in the crystal and in solution. We show that Arg-alpha237 is required for TMADH to structurally imprint the as-purified semiquinone form of wild-type ETF and that the ability of TMADH to facilitate this structural reorganization is lost following (i) redox cycling of ETF, or simple conversion to the oxidized form, and (ii) mutagenesis of Arg-alpha237. We discuss this result in light of recent apparent conflict in the literature relating to the structural imprinting of wild-type ETF. Our studies support a mechanism of electron transfer by conformational sampling as advanced from our previous analysis of the crystal structure of the TMADH-2ETF complex [Leys, D. , Basran, J. , Sutcliffe, M. J., and Scrutton, N. S. (2003) Nature Struct. Biol. 10, 219-225] and point to a key role for the Tyr-442 (TMADH) and Arg-alpha237 (ETF) residue pair in transiently stabilizing productive electron transfer configurations. Our work also points to the importance of Arg-alpha237 in controlling the thermodynamics of electron transfer, the dynamics of ETF, and the protection of reducing equivalents following disassembly of the TMADH-2ETF complex.
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| 22. |
- Chandrasekaran, V, et al.
(författare)
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AGGREGATED SURVIVIN BINDING AROUND HISTONE H3 EPIGENETIC MODIFICATIONS IN RISK LOCI ASSOCIATED WITH RHEUMATOID ARTHRITIS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 428-428
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Survivin is an integral part of the Chromosomal Passenger Complex (CPC) which plays a vital role in mitosis. Experiments have demonstrated that survivin can physically bind to DNA. Crystallographic studies show that survivin binds to Threonine-3 of histone H3. In patients with autoimmune diseases, increased survivin expression contributes to an aggravated disease phenotype. Thus, functional, and mechanistic data point to a potential chromatin regulatory role for survivin, possibly in combination with the established gene regulatory function carried out by histone epigenetic modifications (EM).Objectives:The objective of the study was to analyse the co-localization of chromatin bound survivin with three histone H3 epigenetic modifications – acetylated lysine 27 (K27ac) and trimethylated lysine 4 (K4me3) and lysine-27 (K27me3). The second objective was to analyse if survivin-bound DNA sequences overlapped with sequences in the vicinity of 106 GWAS SNPs that are associated with a risk of developing rheumatoid arthritis (RA).Methods:Chromatin from CD4 T cells of 14 female subjects was immunoprecipitated with survivin antibodies and each of the histone H3 antibodies, and coupled with sequencing (ChIPseq, Hiseq2000, Illumina). After mapping the annotations of sequenced regions to the human reference genome hg38, enriched peaks were identified through Homer software. The identified survivin ChIP peaks were analysed for colocalization with peaks of the three histone H3 EMs and with RA risk loci, using the Bioconductor package ‘ChIPPeakAnno’ through RStudio.Results:Among the total of ~13,000 individual survivin ChIP-peaks, 33% colocalized with histone H3 EM peaks. The overlapping peaks show a linear increase in average peak size compared with the peaks showing no colocalization with any H3 EM peak. A maximum of 5.5-fold increase in average peak size was observed when survivin bound peaks overlap with peaks of all three H3 EMs. A major proportion (86%) of top RA risk SNPs was associated with either binding of survivin or H3 EMs. In this subset, 63% of RA risk SNPs were found within an area of 100 kilobases from survivin ChIP-peaks, with preferential enrichment of high-scoring peaks when survivin colocalizes with all 3 H3 EMs. Survivin was bound to risk SNPs annotated to, among others, the major immunological genes CD83, IRF4, CD28, ICOS and IL2RAConclusion:This study presents experimental evidence that survivin binding to DNA preferentially occurred in regions with high density of histone EMs. The increased aggregation of survivin around histone H3 EMs point to its potential regulatory function in gene transcription. Since regions around RA risk SNPs overlap with survivin peaks, survivin’s nuclear function could have immunologically important effects in mechanisms of autoimmune diseases.Disclosure of Interests:None declared
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| 23. |
- Chandrasekaran, V, et al.
(författare)
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FUNCTIONAL ROLE OF SURVIVIN IN ORGANIZATION OF BIVALENT CHROMATIN REGIONS AND CONSEQUENCE FOR ARTHRITIS-RELEVANT GENE EXPRESSION
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 231-231
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Bivalent chromatin (BvCR) is characterized by the presence of simultaneous active and repressive modifications on histone H3 proteins. Influencing expression of the genes, BvCR determine cell fate and direct differentiation and lineage commitment in primary T cells and contribute to autoimmunity. Survivin is highly expressed during cell division and in effector Th1 cells contributing to aggravation of autoimmune inflammation. Survivin can physically bind to DNA, specifically to Threonine-3 of histone H3 (1). Thus, functional, and mechanistic data point to a potential chromatin regulatory role for survivin, potentially acting in combination with histone epigenetic modifications (EMs).ObjectivesThe goal of our study is to establish the colocalization of survivin with BvCRs and to deduce functional effects of this collaboration on chromatin organization and gene expression.MethodsChromatin from CD4+ T cells of 14 female subjects was immunoprecipitated with survivin antibodies and histone H3K27ac, H3K27me3, H3K4me3 antibodies, and coupled with DNA sequencing (ChIPseq, Hiseq2000, Illumina). BvCR were identified as exact overlaps of the three histone EM peaks and the overlapping regions were searched for co-localization with survivin using the ‘ChIPPeakAnno’ Bioconductor package. Tag counts K27me3>K27ac were defined as inactive/poised BvCR, while tag count K27me3<K27ac were identified asactive BvCR. Motif search was done through the MEME tool, and high/moderate complexity motifs with E-value >10e-5 were selected and scanned through the HOCOMOCO database to identify consensus transcription factor (TF) motifs. TFs co-localized with the BvCD were identified through ReMap database. To identify survivin sensitive genes, CD4+ T cells were treated with survivin inhibitor YM155 and a list of reproducible DEG (log2FC>[0.4], >1 experiment) was mapped and analysed for clustering with BvCR.ResultsCo-localization of survivin ChIP peaks with individual H3-peaks was significantly less frequent compared to overlap with all three (a3)-H3 BvCR (7.1 vs 29.8%, p=8.9e-13). Overlap of a3-H3 peaks not containing survivin was less frequent (34%) compared to those which contained survivin (66%). Notably, survivin peak size was 5.5-fold higher when colocalized with a3-H3 peaks, compared to no, or any single H3 (p<2.2e-16). In contrast, no size difference for any of the H3 EM peaks was found.Further analysis of two non-redundant groups of BvCR that contain (survivin-a3H3, n=4085), and not containing survivin (a3H3noSurv, n = 2131) demonstrated that survivin was mostly associated with inactive BvCR (OR1.29, p=6.6e-6), while no such specificity was found for BvCR with no survivin. Additionally, survivin containing BvCR contained abundant binding sites matching known consensus TF motifs. No sequence-specific motifs were identified in BvCR with no survivin. Comparison of results obtained through HOCOMOCO and ReMap databases resulted in a list of 68 unique TFs. Many of those are key regulators of adaptive immune responses, cellular metabolism, and pluripotency. Differentially expressed genes mapped to BvCR demonstrated enrichment for cellular hormone metabolic processes, regeneration and DNA biosynthesis.ConclusionThis study provides experimental evidence that survivin defines binding specificity in bivalent chromatin regions being associated with regulation of cellular metabolism and renewal of CD4+ T cells that are functionally important to resist autoimmunity.References[1]Kelly AE, Ghenoiu C, Xue JZ, Zierhut C, Kimura H, Funabiki H. Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B Science. 2010 Oct 8; 330(6001): 235–239.Disclosure of InterestsNone declared
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