Quadrature formulas based on rational interpolation

We consider quadrature formulas based on interpolation using the basis functions $1/(1+t_kx)$ $(k=1,2,3,\ldots)$ on $[-1,1]$, where $t_k$ are parameters on the interval $(-1,1)$. We investigate two types of quadratures: quadrature formulas of maximum accuracy which correctly integrate as many basis functions as possible (Gaussian quadrature), and quadrature formulas whose nodes are the zeros of the orthogonal functions obtained by orthogonalizing the system of basis functions (orthogonal quadrature). We show that both approaches involve orthogonal polynomials with modified (or varying) weights which depend on the number of quadrature nodes. The asymptotic distribution of the nodes is obtained as well as various interlacing properties and monotonicity results for the nodes

1,25-Dihydroxyvitamin D-3 and its analog TX527 promote a stable regulatory T cell phenotype in T cells from type 1 diabetes patients

The emergence of regulatory T cells (Tregs) as central mediators of peripheral tolerance in the immune system has led to an important area of clinical investigation to target these cells for the treatment of autoimmune diseases such as type 1 diabetes. We have demonstrated earlier that in vitro treatment of T cells from healthy individuals with TX527, a low-calcemic analog of bioactive vitamin D, can promote a CD4(+)CD25(high)CD127(low) regulatory profile and imprint a migratory signature specific for homing to sites of inflammation. Towards clinical application of vitamin D-induced Tregs in autologous adoptive immunotherapy for type 1 diabetes, we show here that 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] and TX527 similarly imprint T cells from type 1 diabetes patients with a CD4(+)CD25(high)CD127(low) regulatory profile, modulate surface expression of skin- and inflammation-homing receptors, and increase expression of CTLA-4 and OX-40. Also, 1,25(OH)(2)D-3 and TX527 treatment inhibit the production of effector cytokines IFN-gamma, IL-9, and IL-17. Importantly, 1,25(OH)(2)D-3 and TX527 promote the induction of IL-10-producing CD4(+)CD25(high)CD127(low) T cells with a stable phenotype and the functional capacity to suppress proliferation of autologous responder T cells in vitro. These findings warrant additional validation of vitamin D-induced Tregs in view of future autologous adoptive immunotherapy in type 1 diabetes

Vitamin D (1,25(OH

Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH) D3) in human CD4 T cells revealed that 1,25(OH) D3 potently induced expression of the gene SERPINA1, encoding the anti-protease α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH) D3-treated CD4 T cells, but not in CD8 T cells or monocytes. α-1-Antitrypsin promotes anti-inflammatory IL-10 synthesis in other immune cell populations. We therefore investigated its immune-regulatory effects in CD4 T cells. Plasma-derived α-1-antitrypsin drove IL-10 synthesis by CD4 T cells, which was not dependent on anti-protease activity, but appeared to require a serum-binding factor, since this could not be achieved with recombinant protein. α-1-Antitrypsin is reported to bind complement components, which regulate T cell function. A role for this interaction was therefore probed. Plasma-derived, but not recombinant α-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated α-1-antitrypsin binding to C3a. Addition of C3a to CD4 T cells cultured with recombinant α-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived α-1-antitrypsin. To interrogate an endogenous role for the α-1-antitrypsin-C3a axis in 1,25(OH) D3-driven CD4 T cell IL-10 synthesis, we treated cells from healthy or α-1-antitrypsin-deficient individuals (which transcribe SERPINA1 but do not secrete protein) with 1,25(OH) D3. A significant correlation was identified between SERPINA1 and IL10 gene expression in healthy donor CD4 T cells, which was absent in cells from α-1-antitrypsin-deficient individuals. Therefore, α-1-antitrypsin is required for 1,25(OH) D3-induced IL-10 expression in CD4 T cells, interacting with C3a to drive IL-10 expression. [Abstract copyright: Copyright © 2019. Published by Elsevier Ltd.

The dissection of the amateur: an empirical analysis of the determinants of active cultural participation

In contrast to the amount of research dealing with the causes and consequences of receptive highbrow participation in the arts, little research has focused on active artistic participation. Our aim is to introduce active participation into cultural participation research by analyzing the mechanisms that influence active participation in the arts. Drawing on Bourdieu’s theorem of social reproduction and DiMaggio’s claims on cultural mobility, we focus on the relative influences of parental milieu vs. personal accumulated capital on active participation in the arts. Additionally, we query the possible influence of art education. Results based on stepwise multinominal logistic regression analyses on representative population data for Flanders (N=3146) yield support for both Bourdieu’s theorem on social reproduction and DiMaggio’s model of cultural mobility. We find a clear influence of the cultural milieu in which one was raised and a net effect of individually accumulated cultural and social capital. Surprisingly, the influence of educational capital disappeared, after controlling for parental cultural milieu, personal capital accumulation and the influence of taking art classes during high school. Socio-economic status of the family in which one was raised and personal economic capital prove to have no negative impact on the odds of engaging actively in the arts. Art education during high school has a positive effect on the chances of actively engaging in the arts. Moreover, we observe a cumulative impact of both receptive and active arts instructing during high school. Interaction effects between social class indicators and art education are examined. Implications of these findings for further research are discussed

Moleculaire en intracellulaire werking van Vitamine D in het immuunsysteem: Implicaties voor translatie.

Vitamin D is a hormone that can be obtained from food (e.g. fatty fish and dairy products), but is mainly made in the skin where sunlight exposure converts it into its biologically active metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The widespread expression of the vitamin D receptor (VDR) and vitamin D3-metabolizing enzymes in almost all cells of the immune system indicates a role for 1,25(OH)2D3 as a modulator of immune responses. In dendritic cells (DCs), 1,25(OH)2D3 interferes with the differentiation and maturation process resulting in the induction of a tolerogenic state. Tolerogenic DCs (tolDCs) are characterized by downregulated antigen-presentation, reduced costimulation and low pro-inflammatory cytokine production. As a result, tolDCs are poor T cell stimulators and induce T cell hyporesponsiveness. In addition, tolDC mediate a shift in T cell polarization from Th1/17 responses to more tolerogenic responses, with the induction of regulatory T cells (Tregs). On the other hand, 1,25(OH)2D3 are also able to directly modulate activated T cells. In these cells, 1,25(OH)2D3 decreases the production of pro-inflammatory cytokines and induces Tregs. An important role for 1,25(OH)2D3 and its nuclear receptor in the development of type 1 diabetes (T1D) has been suggested by the discrepancy observed between absence of ligand and absence of receptor. Vitamin D3 deficiency in early life is associated with elevated risk for T1D, while the VDR null mouse model, lacking a functional VDR, do not present with aggravated disease. This difference indicates an important role for the unliganded VDR in the immune response. In the first part of this project, we investigated whether an unliganded VDR could affect the phenotype and function of murine bone marrow-derived DCs (BMDCs). Therefore, we studied myeloid BMDCs generated ex vivo from bone marrow precursors of VDR null, with a truncated, non-functional VDR, and VDR ∆AF-2 mice, with a mutated C‑terminal activation factor AF-2 domain thus rendering ligand-induced gene transcription impossible. To our surprise, the unliganded VDR did not affect BMDC phenotype or their T cell stimulatory capacity compared to VDR null BMDCs. These data indicate that an unliganded VDR does not elicit a more inflammatory phenotype in BMDCs. Currently, no therapies for T1D are established which tackle the underlying immune attack. In general, immunotherapies focus on the inhibition of pathogenic immune cell activation and the (re-)establishment of self-tolerance against autoantigens. Given the interesting characteristics of Tregs and tolDCs to induce antigen-specific protection, cellular immunotherapies like adoptive T cell transfer and tolDC-based vaccines provide promising strategies for autoimmune diseases. In this regard, 1,25(OH)2D3 or its low‑calcemic analog TX527 are ideal for ex vivo modulation of autologous T cells and DCs. Previously, our group showed successful ex vivo modulation of T cells isolated from healthy donors by 1,25(OH)2D3 as well as its analog TX527. However, for the clinical applicability of autologous adoptive T cell therapy, validation in samples from patients with T1D is required, especially as a defect in Treg function has been shown in T1D. Therefore, we further explored whether autologous T cells obtained from patients with T1D could be ex vivo modulated by 1,25(OH)2D3 and its analog TX527. Indeed, treatment with 1,25(OH)2D3 and TX527 increased the frequency of CD4+CD25highCD127low Tregs, with elevated CTLA-4 expression in this population. Moreover, exposure to 1,25(OH)2D3 and TX527 imprinted a unique homing signature and reduced the production of effector cytokines in the T cells isolated from T1D patients. In addition, both 1,25(OH)2D3 and TX527 promoted the formation of a stable Treg phenotype, which is essential for their possible clinical application as they will be reintroduced in an inflammatory microenvironment. For the third part of this PhD project, we build further on a previous finding in our lab that demonstrated that the induction of the tolDC profile by 1,25(OH)2D3 is accompanied by an early and transcriptionally mediated metabolic reprogramming. We previously showed that glucose availability and glycolytic metabolism are crucial to induce and maintain tolDCs. This observation strokes with the emerging concept of immunometabolism which states that intracellular metabolism determines the phenotype and function of immune cells. In this regard, we aimed to find a primary target of vitamin D3 that could act as a metabolic switch in tolDCs. We identified the glycolytic enzyme PFKFB4 as strongly and directly upregulated by 1,25(OH)2D3 in differentiating monocytes. Pharmacological inhibition of PFKFB4 activity by the small molecule inhibitor 5-MPN could interfere with the increase in glucose metabolism, and more specifically glucose oxidation, which are hallmark features of tolDC. Moreover, PFKFB4 inhibition altered tolDC phenotype and their ability to induce functional Tregs. A better understanding of the metabolic pathways influenced by 1,25(OH)2D3 in human tolDCs will aid the development and improve the efficacy of tolDC-based immunotherapies.status: publishe

Initiative pour la promotion de la qualité et epidémiologie chez les enfants et les adolescents atteints du diabète sucré (IPQE-EAD)- Résultats 2019

Le présent rapport décrit les résultats du septième audit auquel ont participé les centres de diabétologie pédiatrique (dénommés ci-après CDP) agréés. Cet audit a permis de collecter les données de 3 365 patients atteints de diabète de type 1 âgés de moins de 19 ans et traités dans 15 CDP. Les données se rapportaient aux soins prodigués en 2019. Ce rapport explore les tendances concernant la qualité des soins et étudie les caractéristiques de la population au cours de la période 2008-2019. L’audit n’a pas permis de collecter de données de patients atteints d’un diabète de type 2. Voici les principaux résultats&nbsp;: • Certains aspects de la qualité des soins, mesurés par une large série d’indicateurs de processus et de résultats, se sont améliorés entre 2008 et 2019&nbsp;: le nombre de déterminations de l’IMC et de la tension artérielle et la proportion de patients ayant atteint l’objectif thérapeutique de l’HbA1c de 7,0, 7,5 et 9,0 % ont augmenté, tandis que le nombre de déterminations de l’HbA1c (une ou trois) et du dépistage de la coeliaquie et de l’auto-immunité thyroïdienne se sont maintenus à un niveau élevé (&gt; 80 %) pour tous les audits. • L’amélioration de l’HbA1c a été constatée dans 11 CDP sur 15, en grande partie indépendamment des caractéristiques des patients (sexe, statut de famille nucléaire, etc.). Notez que parmi les CDP où l’amélioration n’a pas été constatée, trois comptaient parmi les centres présentant la valeur HbA1c la plus faible en 2008 et un a débuté sa participation en 2017. • Le dépistage annuel de la rétinopathie a baissé de façon significative tant dans la population générale que dans la population cible au cours de la période 2008-2019. • Les résultats ont montré que la proportion de patients en surpoids a légèrement augmenté depuis 2008. Toutefois, cette tendance a également été observée dans la population générale selon le rapport 2019 de l’OCDE. • Les taux de complications aiguës et chroniques et les niveaux de facteurs de risque cardiovasculaire (à l’exception de l’IMC) sont restés stables au cours de la période 2008-2019. En conclusion, malgré les limites inhérentes à la nature transversale de l’étude et son suivi limité, le septième audit du projet IPQE-EAD a mis en lumière la poursuite de l’évolution favorable de l’HbA1c, l’un des indicateurs essentiels de la qualité des soins. Grâce à la collecte de données supplémentaires depuis 2013 (obtenues par l’échantillonnage de tous les patients éligibles au lieu de seulement 50 %), il sera désormais possible d’analyser l’évolution de l’HbA1c de chaque patient individuellement et ses déterminants, et ainsi de repérer les facteurs auxquels nous devons apporter une attention accrue afin d’améliorer la qualité des soins de diabétologie&nbsp;pédiatrique.</p