Functional measurement in the field of ethics in politics

We present, in a synthetic way, some of the main findings from ten studies that were conducted in the field of ethics in politics, using the Functional Measurement framework. These studies were about (a) Angolan and Mozambican people’s views about the legitimacy of military-humanitarian interventions, (b) French people’s perspectives regarding the government’s responsibility for the health of consumers of illicit substances, (c) Togolese people’s views about the acceptability of political amnesties in a time of political transition, (d) the perspective of victims of the genocide of the Tutsis in Rwanda regarding the attribution of guilt by association to offspring of perpetrators, (e) slave descendants’ views about the acceptability of national policies on reparations for slavery, (f) Colombian people’s willingness to forgive perpetrators of violence who harmed family members during the civil war, (g) the attitudes of French and Colombian people about national drug control policies, (h) Indian students’ views about the appropriateness of the death penalty for murder or rape, (i) Colombian people’s perspectives regarding corruption, and finally (j) Venezuelan people’s conceptualization of human rights. The main findings are discussed in reference to six of the foundations of Moral Foundations Theory.Este texto presenta, de forma resumida, algunos de los principales resultados de diez estudios que se realizaron en el campo de la ética y la política, en el marco de la Medición Funcional. Estos estudios trataron de: (a) los puntos de vista de la gente de Angola y Mozambique sobre la legitimidad de las intervenciones militares-humanitaria; (b) las perspectivas de los franceses con respecto a la responsabilidad del gobierno con la salud de los consumidores de sustancias ilícitas; (c) las perspectivas de las personas de Togo acerca de la aceptabilidad de amnistías políticas en un momento de transición política; (d) las perspectivas de las víctimas del genocidio de los Tutsis en Ruanda en cuanto a la atribución de culpabilidad a los descendientes de los perpetradores de violencia; (e) los puntos de vista de los descendientes de esclavos acerca de la aceptabilidad de las políticas nacionales de reparaciones por la esclavitud; (f) la disposición de los colombianos a perdonar autores de la violencia que causaron daño a miembros de la familia durante el conflicto armado interno; (g) las actitudes de los franceses y colombianos acerca de las políticas nacionales de control de drogas; (h) los puntos de vista de los estudiantes indios acerca de la idoneidad de la pena de muerte por asesinato o violación; (i) las perspectivas de los colombianos con respecto a la corrupción, y, finalmente, (j) la conceptualización de los derechos humanos en la población venezolana. Los principales resultados se discuten en relación con seis de los fundamentos de la Teoría de los Fundamentos Morales

Trypanosoma cruzi infection induces up-regulation of cardiac muscarinic acetylcholine receptors in vivo and in vitro

The pathogenesis of chagasic cardiomyopathy is not completely understood, but it has been correlated with parasympathetic denervation (neurogenic theory) and inflammatory activity (immunogenic theory) that could affect heart muscarinic acetylcholine receptor (mAChR) expression. In order to further understand whether neurogenic and/or immunogenic alterations are related to changes in mAChR expression, we studied two models of Trypanosoma cruzi infection: 1) in 3-week-old male Sprague Dawley rats chronically infected with T. cruzi and 2) isolated primary cardiomyocytes co-cultured with T. cruzi and peripheral blood mononuclear cells (PBMC). Using [³H]-quinuclidinylbenzilate ([³H]-QNB) binding assays, we evaluated mAChR expression in homogenates from selected cardiac regions, PBMC, and cultured cardiomyocytes. We also determined in vitro protein expression and pro-inflammatory cytokine expression in serum and cell culture medium by ELISA. Our results showed that: 1) mAChR were significantly (P < 0.05) up-regulated in right ventricular myocardium (means ± SEM; control: 58.69 ± 5.54, N = 29; Chagas: 72.29 ± 5.79 fmol/mg, N = 34) and PBMC (control: 12.88 ± 2.45, N = 18; Chagas: 20.22 ± 1.82 fmol/mg, N = 19), as well as in cardiomyocyte transmembranes cultured with either PBMC/T. cruzi co-cultures (control: 24.33 ± 3.83; Chagas: 43.62 ± 5.08 fmol/mg, N = 7 for both) or their conditioned medium (control: 37.84 ± 3.84, N = 4; Chagas: 54.38 ± 6.28 fmol/mg, N = 20); 2) [³H]-leucine uptake was increased in cardiomyocytes co-cultured with PBMC/T. cruzi-conditioned medium (Chagas: 21,030 ± 2321; control 10,940 ± 2385 dpm, N = 7 for both; P < 0.05); 3) plasma IL-6 was increased in chagasic rats, IL-1&#946;, was increased in both plasma of chagasic rats and in the culture medium, and TNF-&#945; level was decreased in the culture medium. In conclusion, our results suggest that cytokines are involved in the up-regulation of mAChR in chronic Chagas disease

Lysine relay mechanism coordinates intermediate transfer in vitamin B6 biosynthesis.

International audienceSubstrate channeling has emerged as a common mechanism for enzymatic intermediate transfer. A conspicuous gap in knowledge concerns the use of covalent lysine imines in the transfer of carbonyl-group-containing intermediates, despite their wideuse in enzymatic catalysis. Here we show how imine chemistry operates in the transfer of covalent intermediates in pyridoxal 5'-phosphate biosynthesis by the $Arabidopsis\ thaliana$ enzyme Pdx1. An initial ribose 5-phosphate lysine imine is converted to the chromophoric I$_{320}$ intermediate, simultaneously bound to two lysine residues and partially vacating the active site, which creates space for glyceraldehyde 3-phosphate to bind. Crystal structures show how substrate binding, catalysis and shuttling are coupled to conformational changes around strand $\beta$6 of the Pdx1 ($\beta \alpha$)$_8$-barrel. The dual-specificity active site and imine relay mechanism for migration of carbonyl intermediates provide elegant solutions to the challenge of coordinating a complex sequence of reactions that follow a path of over 20 ${\AA}$ between substrate- and product-binding sites

T-Cell Reactivity against Streptococcal Antigens in the Periphery Mirrors Reactivity of Heart-Infiltrating T Lymphocytes in Rheumatic Heart Disease Patients

T-cell molecular mimicry between streptococcal and heart proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic heart disease (RHD). We searched for immunodominant T-cell M5 epitopes among RHD patients with defined clinical outcomes and compared the T-cell reactivities of peripheral blood and intralesional T cells from patients with severe RHD. The role of HLA class II molecules in the presentation of M5 peptides was also evaluated. We studied the T-cell reactivity against M5 peptides and heart proteins on peripheral blood mononuclear cells (PBMC) from 74 RHD patients grouped according to the severity of disease, along with intralesional and peripheral T-cell clones from RHD patients. Peptides encompassing residues 1 to 25, 81 to 103, 125 to 139, and 163 to 177 were more frequently recognized by PBMC from RHD patients than by those from controls. The M5 peptide encompassing residues 81 to 96 [M5(81–96) peptide] was most frequently recognized by PBMC from HLA-DR7(+) DR53(+) patients with severe RHD, and 46.9% (15 of 32) and 43% (3 of 7) of heart-infiltrating and PBMC-derived peptide-reactive T-cell clones, respectively, recognized the M5(81–103) region. Heart proteins were recognized more frequently by PBMC from patients with severe RHD than by those from patients with mild RHD. The similar pattern of T-cell reactivity found with both peripheral blood and heart-infiltrating T cells is consistent with the migration of M-protein-sensitized T cells to the heart tissue. Conversely, the presence of heart-reactive T cells in the PBMC of patients with severe RHD also suggests a spillover of sensitized T cells from the heart lesion