The Immunogenicity of the Tumor-Associated Antigen α-Fetoprotein Is Enhanced by a Fusion with a Transmembrane Domain

Aim. To investigate the ability of recombinant modified vaccinia virus Ankara (rMVA) vector to induce an immune response against a well-tolerated self-antigen. Methods. rMVA vectors expressing different form of α-fetoprotein (AFP) were produced and characterized. Naïve mice were vaccinated with MVA vectors expressing the AFP antigen in either a secreted, or a membrane-bound, or an intracellular form. The immune response was monitored by an IFNΓ ELISpot assay and antibody detection. Results. Vaccination with the membrane-associated form of AFP induced a stronger CD8+ T-cell response compared to the ones obtained with the MVA encoding the secreted or the intracellular forms of AFP. Moreover, the vaccination with the membrane-bound AFP elicited the production of AFP-specific antibodies. Conclusions. The AFP transmembrane form is more immunogenic. Expressing a membrane-bound form in the context of an MVA vaccination could enhance the immunogenicity of a self-antigen

Abordagem por Competências no Currículo Escolar em Cabo Verde: Desfazendo Equívocos para uma Mudança Significativa nas Políticas e Práxis Educacionais

A abordagem curricular por competências, enquanto fenómeno recente no discurso educativo em Cabo Verde, corre o risco de não passar de mero modismo, sem se traduzir numa inovação efectiva ao nível das práxis educacionais, se não for correctamente compreendida pelos diversos actores envolvidos na obra educativa e, em particular, nos processos de deliberação, gestão e realização dos currículos escolares. O presente artigo procura esclarecer alguns equívocos que em Cabo Verde, como em outras latitudes, acompanham a defesa da pedagogia por competências. Assim, importa elucidar que a abordagem curricular por competências vem aprofundar, entre outras, as abordagens por conteúdos e por objectivos e não, pura e simplesmente, substituí-las, por serem, alegadamente, tradicionais. Outrossim, no contexto da educação escolar, as competências não devem ser encaradas numa perspectiva redutora, focalizada na transferibilidade de conhecimentos para o mercado de trabalho, mas, fundamentalmente, no sentido da mobilização do conhecimento escolar para a resolução dos problemas nos diversos contextos ou situações da vida, que não se esgota no mercado

KRILLPODYM: a mechanistic, spatially resolved model of Antarctic krill distribution and abundance

Robust prediction of population responses to changing environments requires the integration of factors controlling population dynamics with processes affecting distribution. This is true everywhere but especially in polar pelagic environments. Biological cycles for many polar species are synchronised to extreme seasonality, while their distributions may be influenced by both the prevailing oceanic circulation and sea-ice distribution. Antarctic krill (krill, Euphausia superba) is one such species exhibiting a complex life history that is finely tuned to the extreme seasonality of the Southern Ocean. Dependencies on the timing of optimal seasonal conditions have led to concerns over the effects of future climate on krill’s population status, particularly given the species’ important role within Southern Ocean ecosystems. Under a changing climate, established correlations between environment and species may breakdown. Developing the capacity for predicting krill responses to climate change therefore requires methods that can explicitly consider the interplay between life history, biological conditions, and transport. The Spatial Ecosystem And Population Dynamics Model (SEAPODYM) is one such framework that integrates population and general circulation modelling to simulate the spatial dynamics of key organisms. Here, we describe a modification to SEAPODYM, creating a novel model – KRILLPODYM – that generates spatially resolved estimates of krill biomass and demographics. This new model consists of three major components: (1) an age-structured population consisting of five key life stages, each with multiple age classes, which undergo age-dependent growth and mortality, (2) six key habitats that mediate the production of larvae and life stage survival, and (3) spatial dynamics driven by both the underlying circulation of ocean currents and advection of sea-ice. We present the first results of KRILLPODYM, using published deterministic functions of population processes and habitat suitability rules. Initialising from a non-informative uniform density across the Southern Ocean our model independently develops a circumpolar population distribution of krill that approximates observations. The model framework lends itself to applied experiments aimed at resolving key population parameters, life-stage specific habitat requirements, and dominant transport regimes, ultimately informing sustainable fishery management

Generation of cattle knockout for galactose‐α1,3‐galactose and N‐glycolylneuraminic acid antigens

Two well-characterized carbohydrate epitopes are absent in humans but present in other mammals. These are galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc) which are introduced by the activities of two enzymes including α(1,3) galactosyltransferase (encoded by the GGTA1 gene) and CMP-Neu5Gc hydroxylase (encoded by the CMAH gene) that are inactive in humans but present in cattle. Hence, bovine-derived products are antigenic in humans who receive bioprosthetic heart valves (BHVs) or those that suffer from red meat syndrome. Using programmable nucleases, we disrupted (knockout, KO) GGTA1 and CMAH genes encoding for the enzymes that catalyse the synthesis of αGal and Neu5Gc, respectively, in both male and female bovine fibroblasts. The KO in clonally selected fibroblasts was detected by polymerase chain reaction (PCR) and confirmed by Sanger sequencing. Selected fibroblasts colonies were used for somatic cell nuclear transfer (SCNT) to produce cloned embryos that were implanted in surrogate recipient heifers. Fifty-three embryos were implanted in 33 recipients heifers; 3 pregnancies were carried to term and delivered 3 live calves. Primary cell cultures were established from the 3 calves and following molecular analyses confirmed the genetic deletions. FACS analysis showed the double-KO phenotype for both antigens confirming the mutated genotypes. Availability of such cattle double-KO model lacking both αGal and Neu5Gc offers a unique opportunity to study the functionality of BHV manufactured with tissues of potentially lower immunogenicity, as well as a possible new clinical approaches to help patients with red meat allergy syndrome due to the presence of these xenoantigens in the diet

Étude du phénotype et de l'expression des miARNs chez les patients présentant une greffe combinée rein-foie

Introduction : Les études animales et cliniques suggèrent que, lors d'une greffe combinée rein-foie, l'allogreffe hépatique protégerait la greffe rénale des phénomènes de rejets. Nous avons comparé le phénotype sanguin et les profils d'expression des miARNs de patients présentant une greffe combinée rein-foie (CLK) avec des patients simples transplantés foie (L-STA) ou rein (K-STA). Pour évaluer l'effet positif de la greffe combinée, les profils d'expression des miARNs des CLK ont été comparés avec ceux de patients tolérants transplantés foie (L-TOL) ou rein (K-TOL). Méthode : Nous avons effectué un phénotypage exhaustif des CMSP en cytométrie en flux et un profilage de l'expression des miRNAs grâce à la technologie TLDA. Toutes les différences d'expression des miARNs ont été confirmées par PCR TaqMan individuelles sur une cohorte indépendante. Résultats : Les CLK présentent plus de B mémoires CD19+CD24+CD38Low que les L-STA et plus de Treg CD3+CD4+CD25HighCD127LowFOXP3+Helios+ que les K-STA. Par ailleurs, le phénotype sanguin des CLK diffère de celui des patients tolérants L-TOL et K-TOL. Au niveau moléculaire les CLK expriment un profil miARN mixte influencé par les deux greffons et n'ayant rien de commun avec les profils miARN observés chez les patients L-TOL et K-TOL. Ceci se traduit par la mise en place de réseaux de gènes différents entre les patients CLK, L-TOL et K-TOL. Conclusion : L'influence de la greffe combinée engendre un phénotype sanguin et un profil miRNA à mi-chemin entre L-STA et K-STA, non partagé par les patients tolérants.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Deciphering the role of TRIB1 in regulatory T-cells

International audienceThe role of regulatory T-cells (Tregs) is crucial to maintain immune homoeostasis by controlling peripheral tolerance. A better understanding in the molecular mechanisms involved in the biology of these Tregs could improve their expansion and selection to treat immune-related diseases, achieve immunosuppression-free organ transplantation and to specifically target them in cancer. We reported on the overexpression of tribbles-1 (TRIB1) in Tregs compared with their counterpart naive T-cells and that TRIB1 interacts with the master molecule of Tregs, forkhead box P3 (FOXP3), a transcription factor essential for Treg suppressive activity. We demonstrated that these two molecules interact together in the nucleus of Tregs and TRIB1 overexpression is associated with a decrease in their proliferative capacities. Since TRIB1 was reported to be overexpressed in the blood of renal transplanted patients with chronic antibody-mediated rejection (CAMR), altogether, these results suggest TRIB1 could be linked to the decrease proportion of Tregs in patients exhibiting CAMR and a key player in Tregs through its FOXP3 interaction. In addition, yeast two-hybrid screening experiments highlighted that TRIB1 potentially interacts with molecules playing roles in intracellular events following T-cell activation and particularly cluster of differentiation (CD)4+ T-cells. This suggests still non explored potential links between TRIB1 in Tregs. Our goal is thus to decipher the role of TRIB1 in the Treg biology, notably in pathways known to involved its partner and main transcriptional factor of Tregs, FOXP3 and to determine the role of TRIB1 in immune pathologies

Des lymphocytes « très spéciaux » ciblent des antigènes du soi dans l’hépatite auto-immune

International audienc

Internalization of the rat AT1a and AT1b receptors: pharmacological and functional requirements

AbstractThe capacity of the angiotensin II (AngII) agonist [Sar1]AngII, the antagonist [Sar1-I1e8]AngII and the non-peptidic antagonist DuP753 to undergo receptor internalization were studied in Chinese hamster ovary cells expressing rat AngII type 1a or 1b receptors (AT1a or AT1b) or a mutant of AT1a (Asn74) unable to couple G-protein. In this expression system, the ligand-induced internalization of rat AT1a and AT1b are similar. Moreover, peptidic ligands, either the agonist or antagonist, induce a significant internalization of AT1 receptors, but the non-peptidic antagonist DuP753 is far less potent. Finally, the normal internalization of the mutant Asn74 demonstrates that receptor activation and G-protein coupling are not required for AT1ainternalization