Functional analyses of the conserved Cysteine-rich with EGF-like domains (Creld) protein family in <em>Mus musculus</em>

The Cysteine-rich with EGF-like domains (Creld) protein family is highly conserved between species. However, its physiological function remained elusive. Using Creld1 knock-out (Creld1KO) mice, Creld1 was identified as an important regulator of the calcineurin/nuclear factor of activated - cells c1 (NFATc1) signaling pathway during heart valve formation. Creld1KO embryos die at embryonic day E11.5 due to cardiac dysfunction. At E10.5, Creld1KO embryos display defects in the formation of the atrioventricular cushion, the precursor of the heart valve. Heart-valve formation crucially relies on the calcineurin/NFATc1 cascade. The results showed that in the Creld1KO endocardium, from where the heart valves originate, nuclear translocation of NFATc1 is impaired. This results in a decrease of NFATc1 target-gene expression thereby, proliferation within the atrioventricular cushions is impaired. We could demonstrate that Creld1 directly interacts with calcineurin B, the regulatory subunit of calcineurin, thus controlling NFATc1 translocation to the nucleus. In a heterologous system, expression of Creld1 is sufficient to endorse NFATc1 translocation to the nucleus. Sequential deletion of the different functional domains or the introduction of various point mutations indicate that the conserved WE domain of Creld1 is important for regulating the calcineurin phosphatase activity

Thyroid-like function in the urochordate Ciona intestinalis

In the studies reported in the manuscript I investigated the involvement of Iodine and thyroxine (Thyroid Hormone, T4) in Ciona intestinalis metamorphosis. To date, the mechanisms regulating the metamorphosis of ascidians remain largely unknown. In vivo treatment of swimming larvae with exogenous L-thyroxine and goitrogens (methimazole, thiourea and Potassium Perchlorate), demonstrated the role that the intact thyroid hormone biosynthetic molecular machinery plays in the control of metamorphosis. I further supported the idea of a vertebrate-like thyroid function in tunicates, by reinforcing the phylogenetic link between thyroid gland and the endostyle organ through the identification, amongst the proteins extracted from Ciona endostyle, of a protein, CRELD, apparently not related to vertebrate thyroglobulin, that hypothetically could represent the scaffold for TH synthesis in Ciona intestinalis. My present studies have also demonstrated that the Ciona CiNR1, previously reported as inactive, is a functional thyroid receptor, further strengthening the idea that a thyroid function, comparable to that of vertebrates, is present also in tunicates

Neomarxisme — Kultuurkritiek tussen die Mislukking van die revolusie in die ooste en die versuim van die revolusie in die Weste

This introduction to "Neomarxism” begins by a formal analysis of the concept itself. It is suggested here that this term refers to the philosophical revival and revision of Marxist theory in the West. The philosophic-historical context of Neomarxism is consequently outlined so as to elucidate the basic elements of this revision. It appears that this context is determined by the dual experience of the betrayed revolution in the East and the abandoned revolution in the West. Against this background an explanation is then given as to why Neomarxist criticism of Marx concentrates especially on the so-called reductivist and deterministic elements in historical materialism. Finally the leitmotif of the Neomarxist critique of culture is defined. Their rejection of the technocratic ideal of progress not only demonstrates their departure from Marx and the Marxist belief in the emancipatory effect of the rational control of nature. In addition it justifies the view that a radical critique of Marx simultaneously implies a critique of the very roots of modern Western society

Die toekoms van die geesteswetenskappe

The humanities are today being threatened by the overwhelming demand for manpower for the industries, the demands of  professionalising and of national interest in South Africa. 'The danger in this lies in the fact that the balance in society may be upset, at the cost of the cultural development of the people. The ideal of universal man is being relinquished more and more at the cost of specialization in the sciences. 'I here is thus a very real need today that the humanities should not be neglected, but should rather be studied more intensively

Noves idees sobre la formació del humus

Abstract not availabl

Congenital Heart Disease in Down Syndrome

Down syndrome remains the most common chromosomal abnormality in live-born infants in the world today. The association between Down syndrome and congenital heart disease (CHD) is well known, and it is widely recognized that CHD contributes significantly to the morbidity of children with Down syndrome. The reported incidence of CHD in Down syndrome patients is between 40 and 60%. The most commonly described defect is complete atrioventricular septal defect (AVSD), which comprises 30–40% of all cardiac defects. Complex genetic factors are involved. Routine cardiac screening of all newborn babies with Down syndrome is recommended. Expert groups suggest that the cardiac status of all children with Down syndrome should be established by 6 weeks of age to permit appropriate and timely treatment avoiding the establishment of irreversible pulmonary vascular disease that would make corrective surgery impossible

Creld1 controls T cell homeostasis in mouse and human

Cysteine-rich with EGF-like domains 1 (Creld1) was recently found to be fundamental for the VEGF-mediated activation of NFATc1 during heart development. Creld1 complete KO in mice is lethal due to developmental problems during heart formation. Due to the broad expression of Creld1 across almost all cell types and tissues, I wanted to identify additional roles this protein might have in other cellular contexts. In this thesis, I could show how Creld1 functions as a modulator in both the canonical and non-canonical Wnt signalling pathway using an overexpression cell culture system and a conditional KO mouse model for Creld1 in T lymphocytes (CD4Cre; Creld1flox/flox). Furthermore, I could show how Creld1 acts as a plasma membrane protein through its cytosol-facing C-terminus, physically interacting with Wnt signalling components, upstream of β-Catenin and NFAT activation but downstream of Wnt binding to the Frizzled receptor. These data were confirmed in Creld1 KO CD4+ T cells where a general downregulation of both canonical and non-canonical Wnt signalling was observed in homeostasis. Both, ex vivo and in vivo, Creld1 promote viability in CD4+ T cells showing, in a conditional KO model, a dramatic increase of apoptotic cell death ex vivo and a marked reduction of total cell number in one-year-old animals in vivo. Furthermore, Creld1 depletion in CD4+ T cells also affects main T cell effector functions showing an imbalanced activation kinetic and a differential proliferative capacity in accordance with current models of Wnt signalling as modulators of CD4+ T cell homeostasis. Transcriptomic analysis of Creld1-deficient CD4+ T cells further confirmed the cell-intrinsic defect in cell homeostasis and Wnt signalling activation and allowed the definition of a transcriptional footprint of Creld1 in T cells. This transcriptional signature was then shown to be conserved in human CD4+ T cells when individual with low CRELD1 expression were compared to high expressing ones showing a conserved role of CRELD1 in human CD4+ T cells. CRELD1low transcriptional analysis also recapitulated the main phenotype found in the murine mouse model with a general down-regulation of Wnt signalling hallmark genes and an obvious apoptotic signature. The CRELD1-dependent transcriptional regulation was then shown to be conserved also in other immune cells and even visible in total PBMCs. Interestingly, I correlated changes in CRELD1 expression to the process of immunosenescence in accordance with the phenotype of one-year-old mice. Taken together, this work suggests Creld1 as an important regulator of the Wnt signalling pathway in both mouse and human preventing the process of senescence of immune cells and highlighting this protein as a possible target in the treatment of age-related diseases

Annual reports of the selectmen and other town officers and board of education of the town of Merrimack, N.H. for the fiscal year ending February 15, 1908.

This is an annual report containing vital statistics for a town/city in the state of New Hampshire

El programa AQUAD como generador de teorías sobre la reflexión : el caso de una profesora de ciencias en Secundaria

El artículo describe la forma en que un programa de análisis de datos cualitativos, AQUAD, se aplica en un contexto determinado de investigación. El objetivo es la búsqueda de los núcleos duros de lo que hemos denominado Teorías Explícitas de la Reflexión. Se indaga en un conjunto de unidades información ya codificadas de reflexiones de una profesora, la cual pertenece a un grupo de profesoras inmersas en un proceso de innovación curricular en enseñanza secundaria. A partir de un sistema de categorías, que se han ido re-construyendo durante todo el proceso de investigación, indagamos en aquellas categorías que representan verdaderos obstáculos para su práctica docente, en base a su presencia en las reflexiones de la profesora y en su capacidad de vincularse a otras categorías para conformar los núcleos duros. Tales núcleos, como se demuestra, son muy estables y resistenttes en el tiempo._________________________________This paper describes the form in which a program of analysis of qualitative data, AQUAD, is applied in a determined context of research. Our goals is the search for the hard cores of what we have called Reflection Explicit Theories. We focus on in a set of codified units information of reflections of a teacher who belongs to a group of teachers involved in a curricular innovation process in secondary education. From a system of categories, which have been re-constructed throughout the investigation process, we dealt with those categories that represent true obstacles for their educational practice, on the basis of their presence in the teacher's reflections and their capacity to match other categories, to conform the hard cores. Such cores, as it is highlighted in this paper, are very stable and time resistant