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  1. Article ; Online: DIPPER, a spatiotemporal proteomics atlas of human intervertebral discs for exploring ageing and degeneration dynamics

    Vivian Tam / Peikai Chen / Anita Yee / Nestor Solis / Theo Klein / Mateusz Kudelko / Rakesh Sharma / Wilson CW Chan / Christopher M Overall / Lisbet Haglund / Pak C Sham / Kathryn Song Eng Cheah / Danny Chan

    eLife, Vol

    2020  Volume 9

    Abstract: The spatiotemporal proteome of the intervertebral disc (IVD) underpins its integrity and function. We present DIPPER, a deep and comprehensive IVD proteomic resource comprising 94 genome-wide profiles from 17 individuals. To begin with, protein modules ... ...

    Abstract The spatiotemporal proteome of the intervertebral disc (IVD) underpins its integrity and function. We present DIPPER, a deep and comprehensive IVD proteomic resource comprising 94 genome-wide profiles from 17 individuals. To begin with, protein modules defining key directional trends spanning the lateral and anteroposterior axes were derived from high-resolution spatial proteomes of intact young cadaveric lumbar IVDs. They revealed novel region-specific profiles of regulatory activities and displayed potential paths of deconstruction in the level- and location-matched aged cadaveric discs. Machine learning methods predicted a ‘hydration matrisome’ that connects extracellular matrix with MRI intensity. Importantly, the static proteome used as point-references can be integrated with dynamic proteome (SILAC/degradome) and transcriptome data from multiple clinical samples, enhancing robustness and clinical relevance. The data, findings, and methodology, available on a web interface (http://www.sbms.hku.hk/dclab/DIPPER/), will be valuable references in the field of IVD biology and proteomic analytics.
    Keywords intervertebral disc ; nucleus pulposus ; proteomics ; SILAC ; degradome ; ageing ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-12-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Lower Plasma Melatonin Levels Predict Worse Long-Term Survival in Pulmonary Arterial Hypertension

    Zongye Cai / Theo Klein / Laurie W. Geenen / Ly Tu / Siyu Tian / Annemien E. van den Bosch / Yolanda B. de Rijke / Irwin K. M. Reiss / Eric Boersma / Dirk J. Duncker / Karin A. Boomars / Christophe Guignabert / Daphne Merkus

    Journal of Clinical Medicine, Vol 9, Iss 1248, p

    2020  Volume 1248

    Abstract: Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing ... ...

    Abstract : Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve patients with PH and their clinical significance are still unknown. Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in PH patients ( n = 64, 43 pulmonary arterial hypertension (PAH) and 21 chronic thromboembolic PH (CTEPH)) and healthy controls ( n = 111). Melatonin levels were higher in PH, PAH, and CTEPH patients when compared with controls (Median 118.7 (IQR 108.2–139.9), 118.9 (109.3–147.7), 118.3 (106.8–130.1) versus 108.0 (102.3–115.2) pM, respectively, p all < 0.001). The mortality was 26% (11/43) in the PAH subgroup during a long-term follow-up of 42 (IQR: 32–58) months. Kaplan–Meier analysis showed that, in the PAH subgroup, patients with melatonin levels in the 1st quartile (<109.3 pM) had a worse survival than those in quartile 2–4 (Mean survival times were 46 (95% CI: 30–65) versus 68 (58–77) months, Log-rank, p = 0.026) with an increased hazard ratio of 3.5 (95% CI: 1.1–11.6, p = 0.038). Endogenous melatonin was increased in treatment-naïve patients with PH, and lower levels of melatonin were associated with worse long-term survival in patient with PAH.
    Keywords melatonin ; pulmonary hypertension ; survival ; clinical outcome ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Lipid signature of advanced human carotid atherosclerosis assessed by mass spectrometry imaging

    Astrid M. Moerman / Mirjam Visscher / Nuria Slijkhuis / Kim Van Gaalen / Bram Heijs / Theo Klein / Peter C. Burgers / Yolanda B. De Rijke / Heleen M.M. Van Beusekom / Theo M. Luider / Hence J.M. Verhagen / Antonius F.W. Van der Steen / Frank J.H. Gijsen / Kim Van der Heiden / Gijs Van Soest

    Journal of Lipid Research, Vol 62, Iss , Pp 100020- (2021)

    2021  

    Abstract: Abstract: Carotid atherosclerosis is a risk factor for ischemic stroke, one of the main causes of mortality and disability worldwide. The disease is characterized by plaques, heterogeneous deposits of lipids, and necrotic debris in the vascular wall, ... ...

    Abstract Abstract: Carotid atherosclerosis is a risk factor for ischemic stroke, one of the main causes of mortality and disability worldwide. The disease is characterized by plaques, heterogeneous deposits of lipids, and necrotic debris in the vascular wall, which grow gradually and may remain asymptomatic for decades. However, at some point a plaque can evolve to a high-risk plaque phenotype, which may trigger a cerebrovascular event. Lipids play a key role in the development and progression of atherosclerosis, but the nature of their involvement is not fully understood. Using matrix-assisted laser desorption/ionization mass spectrometry imaging, we visualized the distribution of approximately 200 different lipid signals, originating of >90 uniquely assigned species, in 106 tissue sections of 12 human carotid atherosclerotic plaques. We performed unsupervised classification of the mass spectrometry dataset, as well as a histology-directed multivariate analysis. These data allowed us to extract the spatial lipid patterns associated with morphological plaque features in advanced plaques from a symptomatic population, revealing spatial lipid patterns in atherosclerosis and their relation to histological tissue type. The abundances of sphingomyelin and oxidized cholesteryl ester species were elevated specifically in necrotic intima areas, whereas diacylglycerols and triacylglycerols were spatially correlated to areas containing the coagulation protein fibrin. These results demonstrate a clear colocalization between plaque features and specific lipid classes, as well as individual lipid species in high-risk atherosclerotic plaques.
    Keywords atherosclerosis ; mass spectrometry ; lipidomics ; lipids ; sphingolipids ; Vascular Biology ; Biochemistry ; QD415-436
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease

    Antoine Dufour / Caroline L. Bellac / Ulrich Eckhard / Nestor Solis / Theo Klein / Reinhild Kappelhoff / Nikolaus Fortelny / Parker Jobin / Jacob Rozmus / Jennifer Mark / Paul Pavlidis / Vincent Dive / Sean J. Barbour / Christopher M. Overall

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 18

    Abstract: IFN-γ is central in inflammatory pathogenesis, response to infection and autoimmune diseases. Here the authors show that MMP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and ... ...

    Abstract IFN-γ is central in inflammatory pathogenesis, response to infection and autoimmune diseases. Here the authors show that MMP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and affecting pathogenesis of mouse models of peritonitis, SLE and rheumatoid arthritis.
    Keywords Science ; Q
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease

    Antoine Dufour / Caroline L. Bellac / Ulrich Eckhard / Nestor Solis / Theo Klein / Reinhild Kappelhoff / Nikolaus Fortelny / Parker Jobin / Jacob Rozmus / Jennifer Mark / Paul Pavlidis / Vincent Dive / Sean J. Barbour / Christopher M. Overall

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 18

    Abstract: IFN-γ is central in inflammatory pathogenesis, response to infection and autoimmune diseases. Here the authors show that MMP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and ... ...

    Abstract IFN-γ is central in inflammatory pathogenesis, response to infection and autoimmune diseases. Here the authors show that MMP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and affecting pathogenesis of mouse models of peritonitis, SLE and rheumatoid arthritis.
    Keywords Science ; Q
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction

    Valerio Russo / Theo Klein / Darielle J. Lim / Nestor Solis / Yoan Machado / Sho Hiroyasu / Layla Nabai / Yue Shen / Matthew R. Zeglinski / Hongyan Zhao / Cameron P. Oram / Peter A. Lennox / Nancy Van Laeken / Nick J. Carr / Richard I. Crawford / Claus-Werner Franzke / Christopher M. Overall / David J. Granville

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    2018  Volume 11

    Abstract: Abstract In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the ... ...

    Abstract Abstract In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the disruption and separation of this junction and sub-epidermal blistering. Granzyme B (GzmB) is a serine protease secreted by immune cells. Dysregulated inflammation may lead to increased GzmB accumulation and proteolysis in the extracellular milieu. Although elevated GzmB is observed at the level of the DEJ in inflammatory and blistering skin conditions, the present study is the first to explore GzmB in the context of DEJ degradation in autoimmune sub-epidermal blistering. In the present study, GzmB induced separation of the DEJ in healthy human skin. Subsequently, α6/β4 integrin, collagen VII, and collagen XVII were identified as extracellular substrates for GzmB through western blot, and specific cleavage sites were identified by mass spectrometry. In human bullous pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita, GzmB was elevated at the DEJ when compared to healthy samples, while α6/β4 integrin, collagen VII, and collagen XVII were reduced or absent in the area of blistering. In summary, our results suggest that regardless of the initial causation of sub-epidermal blistering, GzmB activity is a common final pathway that could be amenable to a single targeted treatment approach.
    Keywords Medicine ; R ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Active site specificity profiling datasets of matrix metalloproteinases (MMPs) 1, 2, 3, 7, 8, 9, 12, 13 and 14

    Ulrich Eckhard / Pitter F. Huesgen / Oliver Schilling / Caroline L. Bellac / Georgina S. Butler / Jennifer H. Cox / Antoine Dufour / Verena Goebeler / Reinhild Kappelhoff / Ulrich auf dem Keller / Theo Klein / Philipp F. Lange / Giada Marino / Charlotte J. Morrison / Anna Prudova / David Rodriguez / Amanda E. Starr / Yili Wang / Christopher M. Overall

    Data in Brief, Vol 7, Iss , Pp 299-

    2016  Volume 310

    Abstract: The data described provide a comprehensive resource for the family-wide active site specificity portrayal of the human matrix metalloproteinase family. We used the high-throughput proteomic technique PICS (Proteomic Identification of protease Cleavage ... ...

    Abstract The data described provide a comprehensive resource for the family-wide active site specificity portrayal of the human matrix metalloproteinase family. We used the high-throughput proteomic technique PICS (Proteomic Identification of protease Cleavage Sites) to comprehensively assay 9 different MMPs. We identified more than 4300 peptide cleavage sites, spanning both the prime and non-prime sides of the scissile peptide bond allowing detailed subsite cooperativity analysis. The proteomic cleavage data were expanded by kinetic analysis using a set of 6 quenched-fluorescent peptide substrates designed using these results. These datasets represent one of the largest specificity profiling efforts with subsequent structural follow up for any protease family and put the spotlight on the specificity similarities and differences of the MMP family. A detailed analysis of this data may be found in Eckhard et al. (2015) [1]. The raw mass spectrometry data and the corresponding metadata have been deposited in PRIDE/ProteomeXchange with the accession number http://www.ebi.ac.uk/pride/archive/projects/PXD002265. Keywords: Matrix metalloproteinases, MMPs, PICS, Proteomics, Quenched fluorescence, Specificity profiling, Cleavage sites
    Keywords Computer applications to medicine. Medical informatics ; R858-859.7 ; Science (General) ; Q1-390
    Subject code 540
    Language English
    Publishing date 2016-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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