Design And Synthesis of a Novel Potent Myelin Basic Protein Epitope 87−99 Cyclic Analogue: Enhanced Stability and Biological Properties of Mimics Render Them a Potentially New Class of Immunomodulators †

A cyclic analogue, [cyclo(87−99)MBP87-99], of the human immunodominant MBP87-99 epitope, was designed based on ROESY/NMR distance information and modeling data for linear epitope 87−99, taking into account T-cell (Phe89, Lys91, Pro96) and HLA (His88, Phe90, Ile93) contact side-chain information. The cyclic analogue was found to induce experimental allergic encephalomyelitis (EAE), to bind HLA-DR4, and to increase CD4 T-cell line proliferation, like that of the conformationally related linear MBP87-99 epitope peptide. The mutant cyclic peptides, the cyclo(91−99)[Ala96]MBP87-99 and the cyclo(87−99)[Arg91Ala96]MBP87-99, reported previously for suppressing, to a varying degree, autoimmune encephalomyelitis in a rat animal model, were found in this study to possess the following immunomodulatory properties:  (i) they suppressed the proliferation of a CD4 T-cell line raised from a multiple sclerosis patient, (ii) they scored the best in vitro TH2/TH1 cytokine ratio in peripheral blood mononuclear cell cultures derived from 13 multiple sclerosis patients, inducing IL-10 selectively, and (iii) they bound to HLA-DR4, first to be reported for cyclic MBP peptides. In addition, cyclic peptides were found to be more stable to lysosomal enzymes and Cathepsin B, D, and H, compared to their linear counterparts. Taken together, these data render cyclic mimics as putative drugs for treating multiple sclerosis and potentially other Th1-mediated autoimmune diseases

Matrix Metalloproteinase Proteolysis of the Myelin Basic Protein Isoforms Is a Source of Immunogenic Peptides in Autoimmune Multiple Sclerosis

Matrix metalloproteinases (MMPs) play a significant role in the fragmentation of myelin basic protein (MBP) and demyelination leading to autoimmune multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). The classic MBP isoforms are predominantly expressed in the oligodendrocytes of the CNS. The splice variants of the single MBP gene (Golli-MBP BG21 and J37) are widely expressed in the neurons and also in the immune cells. The relative contribution of the individual MMPs to the MBP cleavage is not known.To elucidate which MMP plays the primary role in cleaving MBP, we determined the efficiency of MMP-2, MMP-8, MMP-9, MMP-10, MMP-12, MT1-MMP, MT2-MMP, MT3-MMP, MT4-MMP, MT5-MMP and MT6-MMP in the cleavage of the MBP, BG21 and J37 isoforms in the in vitro cleavage reactions followed by mass-spectroscopy analysis of the cleavage fragments. As a result, we identified the MMP cleavage sites and the sequence of the resulting fragments. We determined that MBP, BG21 and J37 are highly sensitive to redundant MMP proteolysis. MT6-MMP (initially called leukolysin), however, was superior over all of the other MMPs in cleaving the MBP isoforms. Using the mixed lymphocyte culture assay, we demonstrated that MT6-MMP proteolysis of the MBP isoforms readily generated, with a near quantitative yield, the immunogenic N-terminal 1-15 MBP peptide. This peptide selectively stimulated the proliferation of the PGPR7.5 T cell clone isolated from mice with EAE and specific for the 1-15 MBP fragment presented in the MHC H-2(U) context.In sum, our biochemical observations led us to hypothesize that MT6-MMP, which is activated by furin and associated with the lipid rafts, plays an important role in MS pathology and that MT6-MMP is a novel and promising drug target in MS especially when compared with other individual MMPs

An empirical analysis of the determinants of mobile instant messaging appropriation in university learning

Published ArticleResearch on technology adoption often profiles device usability (such as perceived usefulness) and user dispositions (such as perceived ease of use) as the prime determinants of effective technology adoption. Since any process of technology adoption cannot be conceived out of its situated contexts, this paper argues that any pre-occupation with technology acceptance from the perspective of device usability and user dispositions potentially negates enabling contexts that make successful adoption a reality. Contributing to contemporary debates on technology adoption, this study presents flexible mobile learning contexts comprising cost (device cost and communication cost), device capabilities (portability, collaborative capabilities), and learner traits (learner control) as antecedents that enable the sustainable uptake of emerging technologies. To explore the acceptance and capacity of mobile instant messaging systems to improve student performance, the study draws on these antecedents, develops a factor model and empirically tests it on tertiary students at a South African University of Technology. The study involved 223 national diploma and bachelor’s degree students and employed partial least squares for statistical analysis. Overall, the proposed model displayed a good fit with the data and rendered satisfactory explanatory power for students’ acceptance of mobile learning. Findings suggest that device portability, communication cost, collaborative capabilities of device and learner control are the main drivers of flexible learning in mobile environments. Flexible learning context facilitated by learner control was found to have a positive influence on attitude towards mobile learning and exhibited the highest path coefficient of the overall model. The study implication is that educators need to create varied learning opportunities that leverage learner control of learning in mobile learning systems to enhance flexible mobile learning. The study also confirmed the statistical significance of the original Technology Acceptance Model constructs

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Vårdnadshavarnas perspektiv på förskolans uppdrag och kommunikation

Syftet med studien är att undersöka vårdnadshavares perspektiv på förskolans uppdrag och hur förskolan lyckas kommunicera detta uppdrag utåt. Vi fokuserar på följande målområden: literacy, matematik och naturvetenskap. Vi använder kvantitativ metod för att samla in empiriska data med hjälp av enkäter som besvaras av vårdnadshavare vars barn går i förskolan i en tätort i en svensk kommun. Insamlade data redovisas genom beskrivande statistik och tolkas sedan utifrån begreppen intention, livsvärld och typifiering inom det fenomenologiska perspektivet för att fånga vårdnadshavarnas upplevelser.Resultatet kring vårdnadshavarnas perspektiv på förskolans uppdrag visar att vårdnadshavarna upplever att det finns specifika mål inom förskolans verksamhet. De lägger fokus på omsorg och social utveckling. Matematik och naturvetenskap önskas inte i lika hög grad. Literacy önskas i högre grad då det uppfattas av vårdnadshavare som språkutvecklande. Materialet visar att kommunikationen med förskolan generellt upplevs som bra. Av vårdnadshavarna upplever 88,2% att kommunikationen med personalen är bra eller bättre. Trots detta upplever en femtedel av de deltagande vårdnadshavarna att deras synpunkter i låg grad blir uppmärksammade av förskolan. Resultatet visar även att vårdnadshavarnas och förskolans typifieringar kan skilja sig åt. Förskolan har möjlighet att omförhandla dessa typifieringar genom hur den kommunicerar och delger information till vårdnadshavarna

Vårdnadshavarnas perspektiv på förskolans uppdrag och kommunikation

Syftet med studien är att undersöka vårdnadshavares perspektiv på förskolans uppdrag och hur förskolan lyckas kommunicera detta uppdrag utåt. Vi fokuserar på följande målområden: literacy, matematik och naturvetenskap. Vi använder kvantitativ metod för att samla in empiriska data med hjälp av enkäter som besvaras av vårdnadshavare vars barn går i förskolan i en tätort i en svensk kommun. Insamlade data redovisas genom beskrivande statistik och tolkas sedan utifrån begreppen intention, livsvärld och typifiering inom det fenomenologiska perspektivet för att fånga vårdnadshavarnas upplevelser. Resultatet kring vårdnadshavarnas perspektiv på förskolans uppdrag visar att vårdnadshavarna upplever att det finns specifika mål inom förskolans verksamhet. De lägger fokus på omsorg och social utveckling. Matematik och naturvetenskap önskas inte i lika hög grad. Literacy önskas i högre grad då det uppfattas av vårdnadshavare som språkutvecklande. Materialet visar att kommunikationen med förskolan generellt upplevs som bra. Av vårdnadshavarna upplever 88,2% att kommunikationen med personalen är bra eller bättre. Trots detta upplever en femtedel av de deltagande vårdnadshavarna att deras synpunkter i låg grad blir uppmärksammade av förskolan. Resultatet visar även att vårdnadshavarnas och förskolans typifieringar kan skilja sig åt. Förskolan har möjlighet att omförhandla dessa typifieringar genom hur den kommunicerar och delger information till vårdnadshavarna

Geography and the determinants of firm exports in Indonesia

This paper uses data from the Indonesian manufacturing census in order to uncover the determinants of firm exports over the period 1990-2005. We examine to what extent differences in firm export propensity and intensity are a consequence of firm-level (microeconomic), of place-based (macroeconomic) first- and second-nature geography characteristics, or of a combination of the two. The results indicate that both internal and external factors matter. Second-nature, rather than first-nature, geography makes an important difference. The conditions of a firm’s province and those of neighboring provinces shape firm exports. Agglomeration effects, education and transport infrastructure endowment play a particularly relevant role in Indonesian firms’ export propensity, while export spillovers increase export intensity