The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells.

Vascular calcification is a hallmark of advanced atherosclerosis. Here we show that deletion of the nuclear receptor PPARγ in vascular smooth muscle cells of low density lipoprotein receptor (LDLr)-deficient mice fed an atherogenic diet high in cholesterol, accelerates vascular calcification with chondrogenic metaplasia within the lesions. Vascular calcification in the absence of PPARγ requires expression of the transmembrane receptor LDLr-related protein-1 in vascular smooth muscle cells. LDLr-related protein-1 promotes a previously unknown Wnt5a-dependent prochondrogenic pathway. We show that PPARγ protects against vascular calcification by inducing the expression of secreted frizzled-related protein-2, which functions as a Wnt5a antagonist. Targeting this signalling pathway may have clinical implications in the context of common complications of atherosclerosis, including coronary artery calcification and valvular sclerosis.

Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors.

BACKGROUND: It has been proposed that the innate immune system plays a central role in driving the autoimmune T-cell cascade leading to psoriasis; however, there is no direct evidence for this. OBSERVATIONS: We observed aggravation and spreading of a psoriatic plaque when treated topically with the toll-like receptor (TLR) 7 agonist imiquimod. The exacerbation of psoriasis was accompanied by a massive induction of lesional type I interferon activity, detected by MxA expression after imiquimod therapy. Since imiquimod induces large amounts of type I interferon production from TLR7-expressing plasmacytoid dendritic cell precursors (PDCs), the natural interferon-producing cells of the peripheral blood, we asked whether PDCs are present in psoriatic skin. We identified high numbers of PDCs in psoriatic skin lesions (up to 16% of the total dermal infiltrate) based on their coexpression of BDCA2 and CD123. By contrast, PDCs were present at very low levels in atopic dermatitis and not detected in normal human skin. CONCLUSIONS: This study shows that psoriasis can be driven by the innate immune system through TLR ligation. Furthermore, our finding that large numbers of PDCs infiltrate psoriatic skin suggests a role of lesional PDCs as type I interferon-producing targets for the TLR7 agonist imiquimod.

The histone-interacting domain of nuclear factor I activates simian virus 40 DNA replication in vivo.

Efficient initiation of SV40 DNA replication requires transcription factors that bind auxiliary sequences flanking the minimally required origin. To evaluate the possibility that transcription factors may activate SV40 replication by acting on the chromatin structure of the origin, we used an in vivo replication system in which we targeted GAL4 fusion proteins to the minimally required origin. We found that the proline-rich transcriptional activation domain of nuclear factor I (NF-I), which has been previously shown to interact with histone H3, specifically activates replication. Evaluation of a series of deletion and point mutants of NF-I indicates that the H3-binding domain and the replication activity coincide perfectly. Assays with other transcription factors, such as Sp1, confirmed the correlation between the interaction with H3 and the activation of replication. These findings imply that transcription factors such as NF-I can activate SV40 replication via direct interaction with chromatin components, thereby contributing to the relief of nucleosomal repression at the SV40 origin.

Joc, humanisme i pedagogia : la virtut de l'eutrapèlia

Aquest treball té per objectiu mostrar que el joc constitueix un dels trets inherents de la cultura universal i, per extensió, de la tradició occidental. Naturalment, el joc ha estat objecte de diverses consideracions morals, lligades en més d’una ocasió a la religió. En alguns moments –i també des del cristianisme– s’han condemnat amb rigor i severitat les pràctiques lúdiques i, molt especialment, els jocs d’atzar i el món dels espectacles. De fet, la realitat històrica aquí analitzada –a través del cas concret del jeu de paume– confirma l’existència d’una activitat lúdica ben significativa que, malgrat totes les prevencions, va ser tolerada –i fins i tot aprovada– pels humanistes del Renaixement en acceptar la seva vàlua educativa. Sortosament, aquells savis humanistes comptaven amb l’eutrapèlia, una virtut d’arrel aristotèlica que va ser cristianitzada per sant Tomàs d’Aquino i que, com es veurà a continuació, també va arribar a casa nostra a la Baixa Edat Mitjana a través de Francesc Eiximenis. Si algú pensa que la gent d’abans no es divertia, comet un gran error, perquè el nostre passat històric és curull de jocs i activitats lúdiques. Nogensmenys, l’eutrapèlia també es perfila com una virtut social, tal com apareix en diferents autors de l’Edat Moderna, com ara Cervantes, Gracián i Feijoo.

Allorestricted T lymphocytes with a high avidity T-cell receptor towards NY-ESO-1 have potent anti-tumor activity.

The cancer-testis antigen NY-ESO-1 has been targeted as a tumor-associated antigen by immunotherapeutical strategies, such as cancer vaccines. The prerequisite for a T-cell-based therapy is the induction of T cells capable of recognizing the NY-ESO-1-expressing tumor cells. In this study, we generated human T lymphocytes directed against the immunodominant NY-ESO-1(157-165) epitope known to be naturally presented with HLA-A*0201. We succeeded to isolate autorestricted and allorestricted T lymphocytes with low, intermediate or high avidity TCRs against the NY-ESO-1 peptide. The avidity of the established CTL populations correlated with their capacity of lysing HLA-A2-positive, NY-ESO-1-expressing tumor cell lines derived from different origins, e.g. melanoma and myeloma. The allorestricted NY-ESO-1-specific T lymphocytes displayed TCRs with the highest avidity and best anti-tumor recognition activity. TCRs derived from allorestricted, NY-ESO-1-specific T cells may be useful reagents for redirecting primary T cells by TCR gene transfer and, therefore, may facilitate the development of adoptive transfer regimens based on TCR-transduced T cells for the treatment of NY-ESO-1-expressing hematological malignancies and solid tumors.

A fluorescent hormone biosensor reveals the dynamics of jasmonate signalling in plants.

Activated forms of jasmonic acid (JA) are central signals coordinating plant responses to stresses, yet tools to analyse their spatial and temporal distribution are lacking. Here we describe a JA perception biosensor termed Jas9-VENUS that allows the quantification of dynamic changes in JA distribution in response to stress with high spatiotemporal sensitivity. We show that Jas9-VENUS abundance is dependent on bioactive JA isoforms, the COI1 co-receptor, a functional Jas motif and proteasome activity. We demonstrate the utility of Jas9-VENUS to analyse responses to JA in planta at a cellular scale, both quantitatively and dynamically. This included using Jas9-VENUS to determine the cotyledon-to-root JA signal velocities on wounding, revealing two distinct phases of JA activity in the root. Our results demonstrate the value of developing quantitative sensors such as Jas9-VENUS to provide high-resolution spatiotemporal data about hormone distribution in response to plant abiotic and biotic stresses.

De la puissance qu'ont les roys sur les peuples, & du pouvoir des peuples sur les roys

[Mazarinade. 1650]

De la puissance qu'ont les roys sur les peuples, & du pouvoir des peuples sur les roys

[Mazarinade. 1650]

Estabelecimento de normas DRIS para o algodoeiro com diferentes critérios de seleção da população de referência

O objetivo deste trabalho foi avaliar o efeito de critérios de seleção de populações de referência no estabelecimento de normas DRIS na cultura do algodoeiro. Criou-se um banco de dados com a produtividade e os teores foliares de macro e micronutrientes, obtidos de talhões médios de 100 ha. Os critérios para o estabelecimento das subpopulações de alta produtividade foram talhões com: produtividade acima da média (4.380 kg ha-1); produtividade acima da média + 2/3 desvio-padrão (acima de 4.650 kg ha-1); produtividade acima da média + 1 desvio-padrão (acima de 4.785 kg ha-1); e produtividade acima da média + 4/3 desvio-padrão (acima de 4.920 kg ha-1). Os critérios de seleção da população de referência proporcionam baixa frequência de relações nutricionais concordantes, para cada norma DRIS avaliada. Independentemente do critério de seleção utilizado, os dados de produtividade média e o índice de balanço nutricional relacionam-se significativamente; e essa relação intensifica-se com o aumento no rigor do critério de inclusão de lavouras na população de referência.