Immunodeficiency, auto-inflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic auto-inflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1, a component the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin-1β (IL-1β) was compromised in the patients’ fibroblasts. By contrast, the patients’ mononuclear leukocytes, particularly monocytes, were hyperresponsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of auto-inflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1β responses differently in different cell types

L'adolescent face aux vandalismes scolaires

Coslin Pierre G., Agou Marie Claire, Majoux Carole. L'adolescent face aux vandalismes scolaires. In: Bulletin de psychologie, tome 42 n°392, 1989. pp. 738-740

A limited number of species is sufficient to assign a vegetation plot to a forest vegetation unit

International audienceAims: Inventorying the habitats composing Natura 2000 sites is mandatory in the European Union and is necessary to implement relevant conservation measures. Vegetation plots, recording the presence or abundance of all plant species co-occurring within a plot, are currently used to identify terrestrial Natura 2000 habitat types, whose descriptions are mainly based on phytosociological units. However, vegetation plots are time-consuming and frequently restricted to the growing season. Moreover, no vegetation plots can be regarded as exhaustive, and significant inter-observer variation has been highlighted. We studied whether reducing the number of recorded species and the time spent carrying out a vegetation plot had an impact on vegetation unit assignment using species presence. We also studied if vegetation plots recorded in winter could be used for vegetation unit assignment.Location: Mainland France.Methods: We used 273 vegetation plots covering French temperate and mountainous forests. The time at which species were sighted was recorded. We also estimated whether a species was recognisable in winter. We used a classification program to compare assignments based on complete and incomplete vegetation plots.Results: Ten species and five minutes were sufficient to assign a plot to an association, and to an alliance, seven species and four minutes. Vegetation unit assignment proved feasible in winter, especially at the alliance level.Conclusions: We confirmed that a limited number of species is sufficient to assign vegetation plots to vegetation units. However, mapping habitats requires habitat identification and delimitation. This study confirms current field habits, particularly when creating a habitat map, usually based on a limited number of recorded species. Lastly, it confirms that the use of vegetation plots coming from a great variety of sources is relevant to create habitat time series, crucial tools for monitoring habitats at a national scale

Structural and catalytic properties and homology modeling of the human nucleoside diphosphate kinase C, product of the DRnm23 gene

The human DRnm23 gene was identified by differential screening of a cDNA library obtained from chronic myeloid leukaemia-blast crisis primary cells. The over-expression of this gene inhibits differentiation and induces the apoptosis of myeloid precursor cell lines. We overproduced in bacteria a truncated form of the encoded protein lacking the first 17 N-terminal amino acids. This truncated protein was called nucleoside diphosphate (NDP) kinase C . NDP kinase C had similar kinetic properties to the major human NDP kinases A and B, but was significantly more stable to denaturation by urea and heat. Analysis of denaturation by urea, using size exclusion chromatography, indicated unfolding without the dissociation of subunits, whereas renaturation occurred via a folded monomer. The stability of the protein depended primarily on subunit interactions. Homology modelling of the structure of NDP kinase C , based on the crystal structure of NDP kinase B, indicated that NDP kinase C had several additional stabilizing interactions. The overall structure of the two enzymes appears to be identical because NDP kinase C readily formed mixed hexamers with NDP kinase A. It is possible that mixed hexamers can be observed in vivo

Site selection and system sizing of desalination plants powered with renewable energy sources based on a web-GIS platform

International audiencePurpose The combination of desalination technology with renewable energy sources (RES) provides a sustainable approach for increasing potable water availability without imposing negative environmental effects. This paper aims to present the development of a platform, which is an internet-based tool integrating the design optimization of desalination systems with spatial modeling based on a geographic information system (GIS). Design/methodology/approach The proposed platform assists decision-makers to select the optimal location and configuration of both the energy- and water-related subsystems of desalination plants that are power-supplied by RES, such that the lifetime cost of the overall desalination plant is minimized. It enables to optimize the desalination plant site selection and sizing with various hybrid power supply (solar, wind, wave and electrical grid power systems) and desalination technologies combinations, while simultaneously exploiting spatial technologies in an internet-based GIS platform. Findings A pilot study for the optimal design of stand-alone and grid-connected desalination plants powered by RES is presented, which demonstrates the functionality and features of the proposed platform. It is also shown that a grid-connected desalination plant designed by the proposed software design tool exhibits significantly lower lifetime installation and maintenance costs compared to its stand-alone counterpart. Originality/value The proposed platform combines technological, scientific and industrial knowledge with information about societal/political conditions and geo-spatial technologies in a user-friendly graphical interface. Therefore, it provides a design tool enabling its users to secure water supply in a sustainable and economically viable manner

Lack of interaction between NEMO and SHARPIN impairs linear ubiquitination and NF-κB activation and leads to incontinentia pigmenti.

International audienceBackgroundIncontinentia pigmenti (IP; MIM308300) is a severe, male-lethal, X-linked, dominant genodermatosis resulting from loss-of-function mutations in the IKBKG gene encoding nuclear factor κB (NF-κB) essential modulator (NEMO; the regulatory subunit of the IκB kinase [IKK] complex). In 80% of cases of IP, the deletion of exons 4 to 10 leads to the absence of NEMO and total inhibition of NF-κB signaling. Here we describe a new IKBKG mutation responsible for IP resulting in an inactive truncated form of NEMO.ObjectivesWe sought to identify the mechanism or mechanisms by which the truncated NEMO protein inhibits the NF-κB signaling pathway.MethodsWe sequenced the IKBKG gene in patients with IP and performed complementation and transactivation assays in NEMO-deficient cells. We also used immunoprecipitation assays, immunoblotting, and an in situ proximity ligation assay to characterize the truncated NEMO protein interactions with IKK-α, IKK-β, TNF receptor-associated factor 6, TNF receptor-associated factor 2, receptor-interacting protein 1, Hemo-oxidized iron regulatory protein 2 ligase 1 (HOIL-1), HOIL-1-interacting protein, and SHANK-associated RH domain-interacting protein. Lastly, we assessed NEMO linear ubiquitination using immunoblotting and investigated the formation of NEMO-containing structures (using immunostaining and confocal microscopy) after cell stimulation with IL-1β.ResultsWe identified a novel splice mutation in IKBKG (c.518+2T>G, resulting in an in-frame deletion: p.DelQ134_R256). The mutant NEMO lacked part of the CC1 coiled-coil and HLX2 helical domain. The p.DelQ134_R256 mutation caused inhibition of NF-κB signaling, although the truncated NEMO protein interacted with proteins involved in activation of NF-κB signaling. The IL-1β-induced formation of NEMO-containing structures was impaired in fibroblasts from patients with IP carrying the truncated NEMO form (as also observed in HOIL-1(-/-) cells). The truncated NEMO interaction with SHANK-associated RH domain-interacting protein was impaired in a male fetus with IP, leading to defective linear ubiquitination.ConclusionWe identified a hitherto unreported disease mechanism (defective linear ubiquitination) in patients with IP