The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity

Nucleotide-binding and oligomerization domain (NOD)-like receptors constitute a first line of defense against invading bacteria. X-linked Inhibitor of Apoptosis (XIAP) is implicated in the control of bacterial infections, and mutations in XIAP are causally linked to immunodeficiency in X-linked lymphoproliferative syndrome type-2 (XLP-2). Here, we demonstrate that the RING domain of XIAP is essential for NOD2 signaling and that XIAP contributes to exacerbation of inflammation-induced hepatitis in experimental mice. We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2. We further show that LUBAC activity is required for efficient NF-κB activation and secretion of proinflammatory cytokines after NOD2 stimulation. Remarkably, XLP-2-derived XIAP variants have impaired ubiquitin ligase activity, fail to ubiquitylate RIPK2, and cannot facilitate NOD2 signaling. We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis.

Quantitative measurements in 3-dimensional datasets of mouse lymph nodes resolve organ-wide functional dependencies

Deep tissue imaging has become state of the art in biology, but now the problem is to quantify spatial information in a global, organ-wide context. Although access to the raw data is no longer a limitation, the computational tools to extract biologically useful information out of these large data sets is still catching up. In many cases, to understand the mechanism behind a biological process, where molecules or cells interact with each other, it is mandatory to know their mutual positions. We illustrate this principle here with the immune system. Although the general functions of lymph nodes as immune sentinels are well described, many cellular and molecular details governing the interactions of lymphocytes and dendritic cells remain unclear to date and prevent an in-depth mechanistic understanding of the immune system. We imaged ex vivo lymph nodes isolated from both wild-type and transgenic mice lacking key factors for dendritic cell positioning and used software written in MATLAB to determine the spatial distances between the dendritic cells and the internal high endothelial vascular network. This allowed us to quantify the spatial localization of the dendritic cells in the lymph node, which is a critical parameter determining the effectiveness of an adaptive immune response.

Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (n = 216) and without cataplexy (n = 33) completed a self-administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (P < 0.001) and had a higher body mass index (BMI) prior to pregnancy (P < 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (P < 0.01). More patients with narcolepsy-cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy-cataplexy group compared to the narcolepsy group (P < 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy-cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy-cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

Health-related quality of life in rural children living in four European countries: the GABRIEL study

OBJECTIVE Measuring children's health-related quality of life (HRQOL) is of growing importance given increasing chronic diseases. By integrating HRQOL questions into the European GABRIEL study, we assessed differences in HRQOL between rural farm and non-farm children from Germany, Austria, Switzerland and Poland to relate it to common childhood health problems and to compare it to a representative, mostly urban German population sample (KIGGS). METHODS The parents of 10,400 school-aged children answered comprehensive questionnaires including health-related questions and the KINDL-R questions assessing HRQOL. RESULTS Austrian children reported highest KINDL-R scores (mean: 80.9; 95 % CI [80.4, 81.4]) and Polish children the lowest (74.5; [73.9, 75.0]). Farm children reported higher KINDL-R scores than non-farm children (p = 0.002). Significantly lower scores were observed in children with allergic diseases (p < 0.001), with sleeping difficulties (p < 0.001) and in overweight children (p = 0.04). The German GABRIEL sample reported higher mean scores (age 7-10 years: 80.1, [79.9, 80.4]; age 11-13 years: 77.1, [74.9, 79.2]) compared to the urban KIGGS study (age 7-10 years: 79.0, [78.7-79.3]; age 11-13 years: 75.1 [74.6-75.6]). Socio-demographic or health-related factors could not explain differences in HRQOL between countries. CONCLUSIONS Future increases in chronic diseases may negatively impact children's HRQOL.

Side effects of gender-fair language: How feminine job titles influence the evaluation of female applicants

In many languages, feminization has been used as a strategy to make language more gender-fair, because masculine terms, even in a generic function, exhibit a male bias. Up to date, little is known about possible side effects of this language use, for example, in personnel selection. In three studies, conducted in Polish, we analyzed how a female applicant was evaluated in a recruitment process, depending on whether she was introduced with a feminine or masculine job title. To avoid influences from existing occupations and terms, we used fictitious job titles in Studies 1 and 2: diarolożka (feminine) and diarolog (masculine). In Study 3, we referred to existing occupations that varied in gender stereotypicality. In all studies, female applicants with a feminine job title were evaluated less favorably than both a male applicant (Study 1) and a female applicant with a masculine job title (Studies 1, 2, and 3). This effect was independent of the gender stereotypicality of the occupation (Study 3). Participants' political attitudes, however, moderated the effect: Conservatives devaluated female applicants with a feminine title more than liberals (Studies 2 and 3).

An overview of positive and negative effects of gender-fair language use

The basic principle of gender-fair language is symmetric linguistic treatment of women and men. Depending on the structure of the respective language, two principle strategies can be deployed to make a language gender-fair. In languages with few gender-differentiating forms, such as English, there is a tendency towards neutralization. Here, gender-unmarked forms such as police officer or chairperson are used to substitute the male-biased policeman or chairman. The second strategy, feminization, implies that feminine forms of human nouns are used more frequently and systematically to make female referents visible.Since the 1970s, gender-fair language has been suggested, if not prescribed, for both scientific and official texts and its positive effects are widely documented. The use of gender-fair language increases the cognitive availability of feminine exemplars. Also in an applied context women responding to job advertisements formulated in gender-fair language feel more motivated to apply for the position. However, "side effects" of gender-fair language have also been observed: For instance, women referred to with a gender-fair title (e.g. chairperson) were evaluated as lower in status than women referred to with a masculine generic (e.g. chairman). Similarily, social initiatives framed with the use of gender-fair language were evaluated less-favourably than initiatives using traditional language. This presentation presents the gender-fair language use in the framework of a social dilemma. In order to protect themselves (or initiatives they stand for) from being ascribed incompetence or a lower status, women may avoid feminine forms and thus contribute to the perpetuation of gender-unfair language, which may be detrimental for women in general. Raising awareness for this social concern, and framing it both in terms of group and individual interest can direct the discussion about gender-fair language into a broader perspective of gender equality.

A universal description of ultraslow glass dynamics

The dynamics of glass is of importance in materials science but its nature has not yet been fully understood. Here we report that a verification of the temperature dependencies of the primary relaxation time or viscosity in the ultraslowing/ultraviscous domain of glass-forming systems can be carried out via the analysis of the inverse of the Dyre-Olsen temperature index. The subsequent analysis of experimental data indicates the possibility of the self-consistent description of glass-forming low-molecular-weight liquids, polymers, liquid crystals, orientationally disordered crystals and Ising spin-glass-like systems, as well as the prevalence of equations associated with the 'finite temperature divergence'. All these lead to a new formula for the configurational entropy in glass-forming systems. Furthermore, a link to the dominated local symmetry for a given glass former is identified here. Results obtained show a new relationship between the glass transition and critical phenomena.