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  1. Article ; Online: Analysis of Wild Type and Variant B Cystatin C Interactome in Retinal Pigment Epithelium Cells Reveals Variant B Interacting Mitochondrial Proteins

    Emil Carlsson / Umar Sharif / Wasu Supharattanasitthi / Luminita Paraoan

    Cells, Vol 12, Iss 713, p

    2023  Volume 713

    Abstract: Cystatin C, a secreted cysteine protease inhibitor, is abundantly expressed in retinal pigment epithelium (RPE) cells. A mutation in the protein’s leader sequence, corresponding to formation of an alternate variant B protein, has been linked with an ... ...

    Abstract Cystatin C, a secreted cysteine protease inhibitor, is abundantly expressed in retinal pigment epithelium (RPE) cells. A mutation in the protein’s leader sequence, corresponding to formation of an alternate variant B protein, has been linked with an increased risk for both age-related macular degeneration (AMD) and Alzheimer’s disease (AD). Variant B cystatin C displays intracellular mistrafficking with partial mitochondrial association. We hypothesized that variant B cystatin C interacts with mitochondrial proteins and impacts mitochondrial function. We sought to determine how the interactome of the disease-related variant B cystatin C differs from that of the wild-type (WT) form. For this purpose, we expressed cystatin C Halo-tag fusion constructs in RPE cells to pull down proteins interacting with either the WT or variant B form, followed by identification and quantification by mass spectrometry. We identified a total of 28 interacting proteins, of which 8 were exclusively pulled down by variant B cystatin C. These included 18 kDa translocator protein (TSPO) and cytochrome B5 type B, both of which are localized to the mitochondrial outer membrane. Variant B cystatin C expression also affected RPE mitochondrial function with increased membrane potential and susceptibility to damage-induced ROS production. The findings help us to understand how variant B cystatin C differs functionally from the WT form and provide leads to RPE processes adversely affected by the variant B genotype.
    Keywords cystatin C ; variant B ; mitochondria ; aging ; mistrafficking ; translocator protein ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A reinforcement-learning approach to efficient communication.

    Mikael Kågebäck / Emil Carlsson / Devdatt Dubhashi / Asad Sayeed

    PLoS ONE, Vol 15, Iss 7, p e

    2020  Volume 0234894

    Abstract: We present a multi-agent computational approach to partitioning semantic spaces using reinforcement-learning (RL). Two agents communicate using a finite linguistic vocabulary in order to convey a concept. This is tested in the color domain, and a natural ...

    Abstract We present a multi-agent computational approach to partitioning semantic spaces using reinforcement-learning (RL). Two agents communicate using a finite linguistic vocabulary in order to convey a concept. This is tested in the color domain, and a natural reinforcement learning mechanism is shown to converge to a scheme that achieves a near-optimal trade-off of simplicity versus communication efficiency. Results are presented both on the communication efficiency as well as on analyses of the resulting partitions of the color space. The effect of varying environmental factors such as noise is also studied. These results suggest that RL offers a powerful and flexible computational framework that can contribute to the development of communication schemes for color names that are near-optimal in an information-theoretic sense and may shape color-naming systems across languages. Our approach is not specific to color and can be used to explore cross-language variation in other semantic domains.
    Keywords Medicine ; R ; Science ; Q
    Subject code 401
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: CRISPR/Cas9-mediated one step bi-allelic change of genomic DNA in iPSCs and human RPE cells in vitro with dual antibiotic selection

    Wasu Supharattanasitthi / Emil Carlsson / Umar Sharif / Luminita Paraoan

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 7

    Abstract: Abstract CRISPR/Cas9 causes double-stranded DNA breaks that can undergo DNA repair either via non-homologous end joining (NHEJ) or, in the presence of a template, homology-directed repair (HDR). HDR is typically used to insert a specific genetic ... ...

    Abstract Abstract CRISPR/Cas9 causes double-stranded DNA breaks that can undergo DNA repair either via non-homologous end joining (NHEJ) or, in the presence of a template, homology-directed repair (HDR). HDR is typically used to insert a specific genetic modification into the genome but has low efficiency compared to NHEJ, which is lowered even further when trying to create a homozygous change. In this study we devised a novel approach for homozygous single base editing based on utilising simultaneously two donor DNA templates cloned in plasmids with different antibiotic resistant genes. The donor templates were co-transfected alongside the CRISPR/Cas9 machinery into cells and a double antibiotic selection was optimised and allowed the isolation of viable desired clones. We applied the method for obtaining isogenic cells homozygous for variant B cystatin C, a recessive risk factor for age-related macular degeneration and Alzheimer’s disease, in both induced Pluripotent Stem Cells (iPSCs) and a human RPE cell line. Bi-allelic gene edited clones were validated by sequencing, demonstrating that the double antibiotic templates approach worked efficiently for both iPSCs and human differentiated cells. We propose that this one step gene editing approach can be used to improve the specificity and frequency of introducing homozygous modifications in mammalian cells.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: DNA Methylation Patterns in CD8+ T Cells Discern Psoriasis From Psoriatic Arthritis and Correlate With Cutaneous Disease Activity

    Amandine Charras / Jessica Garau / Sigrun R. Hofmann / Emil Carlsson / Cristina Cereda / Susanne Russ / Susanne Abraham / Christian M. Hedrich

    Frontiers in Cell and Developmental Biology, Vol

    2021  Volume 9

    Abstract: Background: Psoriasis is a T cell-mediated chronic autoimmune/inflammatory disease. While some patients experience disease limited to the skin (skin psoriasis), others develop joint involvement (psoriatic arthritis; PsA). In the absence of disease- and/ ... ...

    Abstract Background: Psoriasis is a T cell-mediated chronic autoimmune/inflammatory disease. While some patients experience disease limited to the skin (skin psoriasis), others develop joint involvement (psoriatic arthritis; PsA). In the absence of disease- and/or outcome-specific biomarkers, and as arthritis can precede skin manifestations, diagnostic and therapeutic delays are common and contribute to disease burden and damage accrual.Objective: Altered epigenetic marks, including DNA methylation, contribute to effector T cell phenotypes and altered cytokine expression in autoimmune/inflammatory diseases. This project aimed at the identification of disease-/outcome-specific DNA methylation signatures in CD8+ T cells from patients with psoriasis and PsA as compared to healthy controls.Method: Peripheral blood CD8+ T cells from nine healthy controls, 10 psoriasis, and seven PsA patients were collected to analyze DNA methylation marks using Illumina Human Methylation EPIC BeadChips (>850,000 CpGs per sample). Bioinformatic analysis was performed using R (minfi, limma, ChAMP, and DMRcate packages).Results: DNA methylation profiles in CD8+ T cells differentiate healthy controls from psoriasis patients [397 Differentially Methylated Positions (DMPs); 9 Differentially Methylated Regions (DMRs) when ≥CpGs per DMR were considered; 2 DMRs for ≥10 CpGs]. Furthermore, patients with skin psoriasis can be discriminated from PsA patients [1,861 DMPs, 20 DMRs (≥5 CpGs per region), 4 DMRs (≥10 CpGs per region)]. Gene ontology (GO) analyses considering genes with ≥1 DMP in their promoter delivered methylation defects in skin psoriasis and PsA primarily affecting the BMP signaling pathway and endopeptidase regulator activity, respectively. GO analysis of genes associated with DMRs between skin psoriasis and PsA demonstrated an enrichment of GABAergic neuron and cortex neuron development pathways. Treatment with cytokine blockers associated with DNA methylation changes [2,372 DMPs; 1,907 DMPs within promoters, 7 DMRs (≥5 CpG per ...
    Keywords psoriasis ; psoriatic arthritis ; CD8+ T cell ; chromatin ; DNA methylation ; patient stratification ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Towards stratified treatment of JIA

    Stephanie J.W. Shoop-Worrall / Saskia Lawson-Tovey / Lucy R. Wedderburn / Kimme L. Hyrich / Nophar Geifman / Aline Kimonyo / Alyssia McNeece / Andrew Dick / Andrew Morris / Annie Yarwood / Athimalaipet Ramanan / Bethany R. Jebson / Chris Wallace / Daniela Dastros-Pitei / Damian Tarasek / Elizabeth Ralph / Emil Carlsson / Emily Robinson / Emma Sumner /
    Fatema Merali / Fatjon Dekaj / Helen Neale / Hussein Al-Mossawi / Jacqui Roberts / Jenna F. Gritzfeld / Joanna Fairlie / John Bowes / John Ioannou / Melissa Kartawinata / Melissa Tordoff / Michael Barnes / Michael W. Beresford / Michael Stadler / Paul Martin / Rami Kallala / Sandra Ng / Samantha Smith / Sarah Clarke / Soumya Raychaudhuri / Stephen Eyre / Sumanta Mukherjee / Teresa Duerr / Thierry Sornasse / Vasiliki Alexiou / Victoria J. Burton / Wei-Yu Lin / Wendy Thomson / Zoe Wanstall

    EBioMedicine, Vol 100, Iss , Pp 104946- (2024)

    machine learning identifies subtypes in response to methotrexate from four UK cohortsResearch in context

    2024  

    Abstract: Summary: Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To ... ...

    Abstract Summary: Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures. Methods: Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year.Clusters of MTX ‘response’ were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment. Findings: The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65–0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns. Interpretation: Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis ...
    Keywords Juvenile idiopathic arthritis ; Machine learning ; Treatment outcome ; Epidemiology ; Methotrexate ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 310
    Language English
    Publishing date 2024-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Bacillus anthracis TIR Domain-Containing Protein Localises to Cellular Microtubule Structures and Induces Autophagy.

    Emil Carlsson / Joanne E Thwaite / Dominic C Jenner / Abigail M Spear / Helen Flick-Smith / Helen S Atkins / Bernadette Byrne / Jeak Ling Ding

    PLoS ONE, Vol 11, Iss 7, p e

    2016  Volume 0158575

    Abstract: Toll-like receptors (TLRs) recognise invading pathogens and mediate downstream immune signalling via Toll/IL-1 receptor (TIR) domains. TIR domain proteins (Tdps) have been identified in multiple pathogenic bacteria and have recently been implicated as ... ...

    Abstract Toll-like receptors (TLRs) recognise invading pathogens and mediate downstream immune signalling via Toll/IL-1 receptor (TIR) domains. TIR domain proteins (Tdps) have been identified in multiple pathogenic bacteria and have recently been implicated as negative regulators of host innate immune activation. A Tdp has been identified in Bacillus anthracis, the causative agent of anthrax. Here we present the first study of this protein, designated BaTdp. Recombinantly expressed and purified BaTdp TIR domain interacted with several human TIR domains, including that of the key TLR adaptor MyD88, although BaTdp expression in cultured HEK293 cells had no effect on TLR4- or TLR2- mediated immune activation. During expression in mammalian cells, BaTdp localised to microtubular networks and caused an increase in lipidated cytosolic microtubule-associated protein 1A/1B-light chain 3 (LC3), indicative of autophagosome formation. In vivo intra-nasal infection experiments in mice showed that a BaTdp knockout strain colonised host tissue faster with higher bacterial load within 4 days post-infection compared to the wild type B. anthracis. Taken together, these findings indicate that BaTdp does not play an immune suppressive role, but rather, its absence increases virulence. BaTdp present in wild type B. anthracis plausibly interact with the infected host cell, which undergoes autophagy in self-defence.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2016-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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