IAL SPACE: A test laboratory for the ISO cryogenic payload

The ESA Infrared Space Observatory (ISO) satellite is a 3 axes pointed platform designed to make accurate pointed observations of astronomical objects and sources in the wavelength range between 2.5 and 200 microns. ISO is composed of a service module and a payload module which is a large cylindrical vacuum vessel. The vessel is in fact a cryostat (capacity of 2250 l of liquid He II) which contains the telescope and the four focal scientific instruments. The latter being cooled up to a temperature less than 4 K. The qualification of the payload requires the measurement respectively of: the image quality of the telescope through wave front error (WFE) measurements; and the optical alignment of the scientific instruments with respect to the telescope axis and the telescope focus, and this under cryogenic conditions. Consequently, since 1988, the FOCAL 5 IAL Space facility has been upgraded in order to perform the cryogenic optical tests of the ISO optical subsystems

Defining the clonal dynamics leading to mouse skin tumour initiation.

The changes in cell dynamics after oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the effect of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, initiated tumour formation upon oncogenic hedgehog signalling. This difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase in symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours. Our work reveals that the capacity of oncogene-targeted cells to induce tumour formation is dependent not only on their long-term survival and expansion, but also on the specific clonal dynamics of the cancer cell of origin.C.B. is an investigator of WELBIO. A.S-D. and JC.L. are supported by a fellowship of the FNRS and FRIA respectively. B.D.S. and E.H. are supported by the Wellcome Trust (grant number 098357/Z/12/Z and 110326/Z/15/Z). EH is supported by a fellowship from Trinity College, Cambridge. This work was supported by the FNRS, the IUAP program, the Fondation contre le Cancer, the ULB fondation, the foundation Bettencourt Schueller, the foundation Baillet Latour, a consolidator grant of the European Research Council.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nature1906

Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration

In the age of stem cell engineering it is critical to understand how stem cell activity is regulated during regeneration. Hairs are mini-organs that undergo cyclic regeneration throughout adult life1, and are an important model for organ regeneration. Hair stem cells located in the follicle bulge2 are regulated by the surrounding microenvironment, or niche3. The activation of such stem cells is cyclic, involving periodic -catenin activity4, 5, 6, 7. In the adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extrafollicular environment. Here we show that unexpected periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 in the dermis regulates this process. This BMP cycle is out of phase with the WNT/-catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signalling, respectively. Overexpression of noggin, a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wild-type host showed that follicles in donor and host can affect their cycling behaviours mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. These results show that BMPs may be the long-sought 'chalone' inhibitors of hair growth postulated by classical experiments. Taken together, results presented in this study provide an example of hierarchical regulation of local organ stem cell homeostasis by the inter-organ macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiological integration between these two thermo-regulatory organs. Our findings have practical importance for studies using mouse skin as a model for carcinogenesis, intra-cutaneous drug delivery and stem cell engineering studies, because they highlight the acute need to differentiate supportive versus inhibitory regions in the host skin

The role of CC chemokine receptor 5 (CCR5) and RANTES/CCL5 during chronic fungal asthma in mice1

In the present study, we explored the role of CC chemokine receptor 5 (CCR5) in a murine model of chronic fungal asthma induced by an intrapulmonary challenge with Aspergillus fumigatus conidia (or spores). Airway hyperresponsiveness was significantly lower in A. fumigatus‐sensitized mice lacking CCR5 (CCR5‐/‐) compared with similarly sensitized wild‐type (CCR5+/+) control mice at days 2, 21, 30, and 40 after the conidia challenge. CCR5‐/‐ mice exhibited significantly less peribronchial T‐cell and eosinophil accumulation and airway‐remodeling features, such as goblet cell hyperplasia and peribronchial fibrosis, compared with CCR5+/+ mice at these times after conidia. However, both groups of mice exhibited similar allergic airway disease at day 12 after the conidia challenge. In CCR5‐/‐ mice at day 12, the allergic airway disease was associated with airway hyperresponsiveness, peribronchial allergic inflammation, and goblet cell hyperplasia. Immunoneutralization of RANTES/CCL5 in sensitized CCR5+/+ and CCR5‐/‐ mice for 12 days after the conidia challenge significantly reduced the peribronchial inflammation and airway hyperresponsiveness in comparison with control wild‐type and knockout mice at this time. These data demonstrate that functional CCR5 and RANTES/CCL5 are required for the persistence of chronic fungal asthma in mice.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154329/1/fsb2fj010528fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154329/2/fsb2fj010528fje-sup-0001.pd

LKB1 as the ghostwriter of crypt history

Familial cancer syndromes present rare insights into malignant tumor development. The molecular background of polyp formation and the cancer prone state in Peutz-Jeghers syndrome remain enigmatic to this day. Previously, we proposed that Peutz-Jeghers polyps are not pre-malignant lesions, but an epiphenomenon to the malignant condition. However, Peutz-Jeghers polyp formation and the cancer-prone state must both be accounted for by the same molecular mechanism. Our contribution focuses on the histopathology of the characteristic Peutz-Jeghers polyp and recent research on stem cell dynamics and how these concepts relate to Peutz-Jeghers polyposis. We discuss a protracted clonal evolution scenario in Peutz-Jeghers syndrome due to a germline LKB1 mutation. Peutz-Jeghers polyp formation and malignant transformation are separately mediated through the same molecular mechanism played out on different timescales. Thus, a single mechanism accounts for the development of benign Peutz-Jeghers polyps and for malignant transformation in Peutz-Jeghers syndrome

Keystone symposium: The role of microenvironment in tumor induction and progression, Banff, Canada, 5–10 February 2005

The first Keystone symposium on the role of microenvironment in tumor induction and progression attracted 274 delegates from 13 countries to Banff in the heart of the Canadian Rockies. The meeting was organized by Mina Bissell, Ronald DePinho and Luis Parada, and was held concurrently with the Keystone symposium on cancer and development, chaired by Matthew Scott and Roeland Nusse. The 30 oral presentations and over 130 posters provided an excellent forum for discussing emerging data in this rapidly advancing field

Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium

During development, multipotent progenitor cells establish lineage-specific programmers of gene activation and silencing underlying their differentiation into specialized cell types. We show that the Polycomb component Cbx4 serves as a critical determinant that maintains the epithelial identity in the developing epidermis by repressing nonepidermal gene expression programs. Cbx4 ablation in mice results in a marked decrease of the epidermal thickness and keratinocyte (KC) proliferation associated with activation of numerous neuronal genes and genes encoding cyclin-dependent kinase inhibitors (p16/p19 and p57). Furthermore, the chromodomain- and SUMO E3 ligase–dependent Cbx4 activities differentially regulate proliferation, differentiation, and expression of nonepidermal genes in KCs. Finally, Cbx4 expression in KCs is directly regulated by p63 transcription factor, whereas Cbx4 overexpression is capable of partially rescuing the effects of p63 ablation on epidermal development. These data demonstrate that Cbx4 plays a crucial role in the p63-regulated program of epidermal differentiation, maintaining the epithelial identity and proliferative activity in KCs via repression of the selected nonepidermal lineage and cell cycle inhibitor genes

Systematic analysis of the ability of Nitric Oxide donors to dislodge biofilms formed by Salmonella enterica and Escherichia coli O157:H7

Biofilms in the industrial environment could be problematic. Encased in extracellular polymeric substances, pathogens within biofilms are significantly more resistant to chlorine and other disinfectants. Recent studies suggest that compounds capable of manipulating nitric oxide-mediated signaling in bacteria could induce dispersal of sessile bacteria and provide a foundation for novel approaches to controlling biofilms formed by some microorganisms. In this work, we compared the ability of five nitric oxide donors (molsidomine, MAHMA NONOate, diethylamine NONOate, diethylamine NONOate diethylammonium salt, spermine NONOate) to dislodge biofilms formed by non-typhoidal Salmonella enterica and pathogenic E. coli on plastic and stainless steel surfaces at different temperatures. All five nitric oxide donors induced significant (35-80%) dispersal of biofilms, however, the degree of dispersal and the optimal dispersal conditions varied. MAHMA NONOate and molsidomine were strong dispersants of the Salmonella biofilms formed on polystyrene. Importantly, molsidomine induced dispersal of up to 50% of the pre-formed Salmonella biofilm at 4 degrees C, suggesting that it could be effective even under refrigerated conditions. Biofilms formed by E. coli O157:H7 were also significantly dispersed. Nitric oxide donor molecules were highly active within 6 hours of application. To better understand mode of action of these compounds, we identified Salmonella genomic region recA-hydN, deletion of which led to an insensitivity to the nitric oxide donors