Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease due to mutations in the ABCD1 (ALD) gene, encoding a peroxisomal ATP-binding cassette transporter (ALDP). Overexpression of adrenoleukodystrophy-related protein, an ALDP homologue encoded by the ABCD2 (adrenoleukodystrophy-related) gene, can compensate for ALDP deficiency. 4-Phenylbutyrate (PBA) has been shown to induce both ABCD2 expression and peroxisome proliferation in human fibroblasts. We show that peroxisome proliferation with unusual shapes and clusters occurred in liver of PBA-treated rodents in a PPARα-independent way. PBA activated Abcd2 in cultured glial cells, making PBA a candidate drug for therapy of X-ALD. The Abcd2 induction observed was partially PPARα independent in hepatocytes and totally independent in fibroblasts. We demonstrate that a GC box and a CCAAT box of the Abcd2 promoter are the key elements of the PBA-dependent Abcd2 induction, histone deacetylase (HDAC)1 being recruited by the GC box. Thus, PBA is a nonclassical peroxisome proliferator inducing pleiotropic effects, including effects at the peroxisomal level mainly through HDAC inhibition

Catalytically inactive human cathepsin D triggers fibroblast invasive growth

The aspartyl-protease cathepsin D (cath-D) is overexpressed and hypersecreted by epithelial breast cancer cells and stimulates their proliferation. As tumor epithelial–fibroblast cell interactions are important events in cancer progression, we investigated whether cath-D overexpression affects also fibroblast behavior. We demonstrate a requirement of cath-D for fibroblast invasive growth using a three-dimensional (3D) coculture assay with cancer cells secreting or not pro-cath-D. Ectopic expression of cath-D in cath-D–deficient fibroblasts stimulates 3D outgrowth that is associated with a significant increase in fibroblast proliferation, survival, motility, and invasive capacity, accompanied by activation of the ras–MAPK pathway. Interestingly, all these stimulatory effects on fibroblasts are independent of cath-D proteolytic activity. Finally, we show that pro-cath-D secreted by cancer cells is captured by fibroblasts and partially mimics effects of transfected cath-D. We conclude that cath-D is crucial for fibroblast invasive outgrowth and could act as a key paracrine communicator between cancer and stromal cells, independently of its catalytic activity

A procedure for localisation and electrophysiological characterisation of ion channels heterologously expressed in a plant context

BACKGROUND: In silico analyses based on sequence similarities with animal channels have identified a large number of plant genes likely to encode ion channels. The attempts made to characterise such putative plant channels at the functional level have most often relied on electrophysiological analyses in classical expression systems, such as Xenopus oocytes or mammalian cells. In a number of cases, these expression systems have failed so far to provide functional data and one can speculate that using a plant expression system instead of an animal one might provide a more efficient way towards functional characterisation of plant channels, and a more realistic context to investigate regulation of plant channels. RESULTS: With the aim of developing a plant expression system readily amenable to electrophysiological analyses, we optimised experimental conditions for preparation and transformation of tobacco mesophyll protoplasts and engineered expression plasmids, that were designed to allow subcellular localisation and functional characterisation of ion channels eventually in presence of their putative (possibly over-expressed) regulatory partners. Two inward K(+ )channels from the Shaker family were functionally expressed in this system: not only the compliant KAT1 but also the recalcitrant AKT1 channel, which remains electrically silent when expressed in Xenopus oocytes or in mammalian cells. CONCLUSION: The level of endogenous currents in control protoplasts seems compatible with the use of the described experimental procedures for the characterisation of plant ion channels, by studying for instance their subcellular localisation, functional properties, structure-function relationships, interacting partners and regulation, very likely in a more realistic context than the classically used animal systems

Gender, Sex and the crime of Witchcraft in English and French speaking demonologists (c. 1580-1648)

La caza de brujas y sus bases teóricas, especialmente los tratados demonológicos, frecuentemente han sido consideradas las expresiones más claras de misoginia durante la temprana modernidad europea. La desproporcionada cantidad de mujeres sobre el total de enjuiciados y condenados en la mayor parte del continente llamó la atención de la academia a lo largo del último siglo. Entre otras interpretaciones, destacan aquellas que señalan a aquel proceso como un holocausto femenino (ginocidio) dirigido por las autoridades religiosas y laicas, así como las que advierten que los intelectuales del periodo eran incapaces de imaginar la posibilidad de brujos varones. El presente artículo propone comparar los textos de los demonólogos ingleses y los francoparlantes con la intención de demostrar que, tanto para los protestantes como para los católicos, la brujería era un crimen cuya definición teórica dependía de complejas construcciones conceptuales y representaciones del género masculino y femenino.Witch-hunts and their intellectual foundations, especially demonological treatises, have been considered as one of the most flagrant expressions of misogyny in Early Modern Europe. The disproportionate representation of women amongst the accused and convicted in most parts of European territories draw the attention of academics during the last century. Amid other interpretations, this historical event was considered as a women holocaust (gynocide) perpetrated by secular and religious authorities and defended by jurists, doctors and theologians, who were considered incapable of imagining male witches. This article aims to compare English and French speaking demonologists’ texts to demonstrate that on a theoretical level for both Protestants and Catholics witchcraft was a crime defined by complex conceptual constructions and gendered representations of masculinity and femininity

Clinical Relevance of Tumor Cells with Stem-Like Properties in Pediatric Brain Tumors

BACKGROUND: Primitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). Most high-grade glioma-derived oncospheres (10/12) sustained long-term self-renewal akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumors. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P = 0.05, chi-square test). Survival analysis of the cohort showed an association between isolation of cells with long-term self-renewal abilities and a higher patient mortality rate (P = 0.013, log-rank test). Sampling of low- and high-grade glioma cultures showed that self-renewing cells forming oncospheres shared a molecular profile comprising embryonic and neural stem cell markers. Further characterization performed on subsets of high-grade gliomas and one low-grade glioma culture showed combination of this profile with mesenchymal markers, the radio-chemoresistance of the cells and the formation of aggressive tumors after intracerebral grafting. CONCLUSIONS/SIGNIFICANCE: In brain tumors affecting adult patients, TSCs have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors

La mémoire rompue : les défis de la coexistence confessionnelle au consulat lyonnais (1563-1567)

Tableau d'honneur de la Faculté des études supérieures et postdorales, 2016-2917La paix d'Amboise (1563-1567), qui suivit le premier conflit ouvert entre catholiques et protestants en France, constitue une période particulièrement riche pour l'étude des premières manifestations de la coexistence confessionnelle au sein du royaume. À Lyon, ville tombée aux mains des huguenots en 1562, le pouvoir royal imposa notamment un partage des charges municipales entre catholiques et réformés, obligeant les tenants des deux confessions à gouverner la communauté ensemble, malgré leurs réticences à travailler avec leurs ennemis d'hier. Ce mémoire vise, grâce à une analyse des délibérations consulaires, à faire état de la manière dont les consuls instrumentalisèrent la tradition du corps de ville et les rituels civiques pour faire valoir leurs intérêts respectifs dans leurs querelles, tout en respectant le cadre législatif imposé par la couronne de France.The peace succeeding the Edict of Amboise (1563-1567), which followed the first open conflict between Catholics and Protestants in France, constitutes a particularly rich period for the study of the first appearance of denominational coexistence within the kingdom. In Lyon, the royal power notably imposed that municipal offices be shared between Catholics and Protestants, forcing the members of each denomination to govern together, despite their reluctance to work with their past enemies. By way of an analysis of the city council's registers, this essay's goal is to give an account of the way city councils exploited the traditions of the "corps de ville" and its civic rituals to assert their interests during disputes whilst still respecting the legal framework imposed by the French crown

HTLV Tax: a fascinating multifunctional co-regulator of viral and cellular pathways

Human T-cell lymphotropic virus type 1 (HTLV-1) has been identified as the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus infects between 15 and 20 million people worldwide of which approximately 2–5% develop ATL. The past 35 years of research have yielded significant insight into the pathogenesis of HTLV-1, including the molecular characterization of Tax, the viral transactivator, and oncoprotein. In spite of these efforts, the mechanisms of oncogenesis of this pleiotropic protein remain to be fully elucidated. In this review, we illustrate the multiple oncogenic roles of Tax by summarizing a recent body of literature that refines our understanding of cellular transformation. A focused range of topics are discussed in this review including Tax-mediated regulation of the viral promoter and other cellular pathways, particularly the connection of the NF-κB pathway to both post-translational modifications (PTMs) of Tax and subcellular localization. Specifically, recent research on polyubiquitination of Tax as it relates to the activation of the IkappaB kinase (IKK) complex is highlighted. Regulation of the cell cycle and DNA damage responses due to Tax are also discussed, including Tax interaction with minichromosome maintenance proteins and the role of Tax in chromatin remodeling. The recent identification of HTLV-3 has amplified the importance of the characterization of emerging viral pathogens. The challenge of the molecular determination of pathogenicity and malignant disease of this virus lies in the comparison of the viral transactivators of HTLV-1, -2, and -3 in terms of transformation and immortalization. Consequently, differences between the three proteins are currently being studied to determine what factors are required for the differences in tumorogenesis