Measuring societal attitudes and behaviours towards radon indoors: A case study of Slovenia.

Public opinion surveys play a crucial role in assessing public awareness, knowledge, and radon risk perception in the context of national Radon Action Plans. However, many of these surveys are constructed without a solid foundation in behavioural theories, health protection theory, or social science methodology. This lack of foundation can lead to misguided priorities in radon mitigation interventions and ineffective communication strategies, ultimately resulting in low compliance with testing and mitigation in private homes. By developing and testing scales that measure a wide range of theory-based socio-psychological concepts influencing protective behaviour of individuals facing radon risk, this study provides researchers, authorities, and practitioners with a useful and versatile survey tool to explore the complexity of human behaviour in the context of radon. The results of this survey, conducted in Slovenia with a representative sample of respondents from low, middle, and high radon risk areas (N = 2012), offer a foundation for assessing gaps and strategies to increase testing and remediation of homes. The findings suggest that communication interventions need to be more precisely tailored to specific population groups and should go beyond enhancing awareness, knowledge and radon risk perception. Effective strategies should evoke emotions, share personal stories, highlight successful mitigation cases, and use personal testimonies from individuals affected by lung cancer. Moreover, incorporating positive social norms can inspire more individuals to engage in testing and mitigation measures. Assessing theory-driven socio-psychological concepts through a survey allows researchers and policymakers to craft more effective strategies aimed at promoting radon testing and mitigation, thereby enhancing overall public health.

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome.

The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome.

Max Weber's antinomies of the Fall: Paradisiacal ethics and the populist Zeitgeist.

This article points out that the way the biblical myth of the Fall has been interpreted in the Judeo-Christian tradition is a crucial heuristic in the works of Max Weber, an assessment that hitherto largely remained unnoticed. Nevertheless, Weber's understanding of everyday action is closely related to the various religious interpretations of what deprivations were suffered by humanity as a consequence of Adam's original sin and the paradisiacal yearning for salvation it engenders. Moreover, Weber's interpretation of the Fall is characteristic for his tragic sociology in the sense that it guarantees the freedom to subjectively create self-conscious meaning that is, however, no longer embedded in a context of common knowledge. His solution to this epistemological problem involves a Nietzschean heroic existentialism whereby individuals give personality to one's character by freely choosing their own values. Yet, he also realizes that many will not be able to choose by themselves and, therefore, will be attracted by charismatic leaders that can invoke a paradisiacal community of choice. Weber's modern antinomical interpretation of the Fall is still relevant today because it provides insight in the epistemological underpinnings of the contemporary populist Zeitgeist.

How to Communicate Food Safety after Radiological Contamination: The Effectiveness of Numerical and Narrative News Messages.

Food risk and the safety of foodstuffs in the aftermath of contamination are highly sensitive issues to communicate. Food risks receive extensive attention from the news media, which requires messages to be carefully drafted to minimize harm and avoid unnecessary boycotts. Once a food risk is deemed eliminated, communication efforts must rebuild trust among consumers. The latter is a particularly difficult task after radiological contamination. This study tests whether numerical messages, narrative messages, or messages combining both elements are more effective in persuading the public to consume foodstuffs from Fukushima, a region that continues to battle stigma since the nuclear accident in 2011. We employ a survey-embedded experiment on a sample of the general Belgian population (N = 1085), during which respondents are presented with a mock news article presenting either a (1) numerical, (2) narrative, or (3) a combined message and test their subsequent evaluation of the article. We find that the numerical message leads to significantly higher perceived credibility and message acceptance than both the combined and the narrative message. Furthermore, we find that attitudes towards nuclear energy have a strong independent effect on message acceptance and evaluation, with those respondents who report a more positive stance towards nuclear energy more readily accepting the message. Food risk and safety communication may thus benefit from adopting a more detached, numerical approach for sensitive issues.

Radiation risks and uncertainties: a scoping review to support communication and informed decision-making.

Although radiation protection is challenged by many uncertainties, there is no systematic study investigating the definitions and types of these uncertainties. To address this gap, in this paper we offer a scoping review to comprehensively analyse, for the first time, peer-reviewed scientific articles (n = 33) related to uncertainties in the following radiation exposure situations: nuclear emergencies, decommissioning of nuclear/radiological installations and long-term radiological exposure situations (e.g. naturally occurring radioactive materials). The results suggest that firstly, there is no agreement regarding definitions of uncertainty, which is mainly defined based on its sources, types or categories rather than by its meaning. Secondly, different actors are faced with different types of uncertainties. Uncertainties of the scientific community are mostly data and methodology-driven (e.g. dose-response relationships), those of the decision-makers are related to the likely consequences of decision options and public reactions, while laypeople's uncertainties are mainly related to the trustworthiness of experts or the emotional potential of specific risk exposures. Furthermore, the majority of articles focus on the uncertainties of the scientific community, while those of the information receivers (i.e. decision-makers and laypeople) receive much less consideration. Finally, there was no difference in types of uncertainties across the different risk-related study areas analysed (radiation versus other risks). Based on these findings, we provide some preliminary recommendations regarding research on uncertainty related to radiation protection, as well as communication practices.

Vesicourethral reflux-induced renal failure in a patient with ICF syndrome due to a novel DNMT3B mutation.

ICF syndrome is a primary immunodeficiency disease characterized by hypo- or agammaglobulinemia, centromeric instability mainly on chromosomes 1, 9, and 16 and facial anomalies. ICF syndrome presents with frequent respiratory tract infections in infancy. A 20-month-old female patient was referred to our clinic due to frequent lower respiratory tract infections. ICF syndrome was considered because of comorbidity of hypogammaglobulinemia, facial anomalies, and neuromotor growth retardation. Metaphase chromosome analysis revealed centromeric instability on chromosomes 1, 9, and 16 and through Sanger a previously unreported homozygous missense mutation (c.1805T>C; [p.V602A]) was identified in the DNMT3B, confirming ICF1. The patient was found to have a breakdown in renal function 1 year later; the urinary system was examined and bilateral vesicoureteral reflux was found, warranting the need for dialysis in time. This report expands the mutation spectrum of ICF1 and is the first to describe bilateral vesicoureteral reflux accompanying ICF syndrome. © 2016 Wiley Periodicals, Inc.

Intergenerational solidarity: the paradox of reciprocity imbalance in ageing welfare states.

In this article a new theoretical framework is applied to a research field that is somewhat fragmented, namely that of intergenerational solidarity in ageing welfare states. Inspired by utilitarian considerations many scholars tend to problematize the lack of reciprocity characterizing intergenerational exchanges. As some generations are longer old and more numerous they may receive excessive state-administered support of the younger generations, especially in a democratic setting. However, in reality there is limited empirical evidence of intergenerational conflict and theoretical explanations of this paradox are rare. An integrated and dynamical approach that incorporates Durkheim's solidarity theory, Honneth's intersubjective recognition theory, and the current work on reciprocal exchange is necessary in order to understand the survival of intergenerational solidarity in ageing welfare states. According to this model reciprocal recognition leading to the empathization of exchanges is the driving force of intergenerational solidarity in a prefigurative and democratized culture where the status of the young has risen dramatically. Hence, we come to the paradoxical conclusion that attempts to preserve intergenerational solidarity by openly denouncing excessive transfers and trying to bypass them institutionally sometimes might be counterproductive because they may erode their empathic underpinnings.

Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals.

For genetically heterogeneous diseases a better understanding of how the underlying gene defects are functionally interconnected will be important for dissecting disease etiology. The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is a chromatin disorder characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS Here, we generated a Zbtb24 BTB domain deletion mouse and found that loss of functional Zbtb24 leads to early embryonic lethality. Transcriptome analysis identified Cdca7 as the top down-regulated gene in Zbtb24 homozygous mutant mESCs, which can be restored by ectopic ZBTB24 expression. We further demonstrate enrichment of ZBTB24 at the CDCA7 promoter suggesting that ZBTB24 can function as a transcription factor directly controlling Cdca7 expression. Finally, we show that this regulation is conserved between species and that CDCA7 levels are reduced in patients carrying ZBTB24 nonsense mutations. Together, our findings demonstrate convergence of the two ICF genes ZBTB24 and CDCA7 at the level of transcription.

Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4.

Facioscapulohumeral muscular dystrophy is caused by incomplete epigenetic repression of the transcription factor DUX4 in skeletal muscle. A copy of DUX4 is located within each unit of the D4Z4 macrosatellite repeat array and its derepression in somatic cells is caused by either repeat array contraction (FSHD1) or by mutations in the chromatin repressor SMCHD1 (FSHD2). While DUX4 expression has thus far only been detected in FSHD muscle and muscle cell cultures, and increases with in vitro myogenic differentiation, the D4Z4 chromatin structure has only been studied in proliferating myoblasts or non-myogenic cells. We here show that SMCHD1 protein levels at D4Z4 decline during muscle cell differentiation and correlate with DUX4 derepression. In FSHD2, but not FSHD1, the loss of SMCHD1 repressor activity is partially compensated by increased Polycomb Repressive Complex 2 (PRC2)-mediated H3K27 trimethylation at D4Z4, a situation that can be mimicked by SMCHD1 knockdown in control myotubes. In contrast, moderate overexpression of SMCHD1 results in DUX4 silencing in FSHD1 and FSHD2 myotubes demonstrating that DUX4 derepression in FSHD is reversible. Together, we show that in FSHD1 and FSHD2 the decline in SMCHD1 protein levels during muscle cell differentiation renders skeletal muscle sensitive to DUX4.

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome.

The life-threatening Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome is a genetically heterogeneous autosomal recessive disorder. Twenty percent of patients cannot be explained by mutations in the known ICF genes DNA methyltransferase 3B or zinc-finger and BTB domain containing 24. Here we report mutations in the cell division cycle associated 7 and the helicase, lymphoid-specific genes in 10 unexplained ICF cases. Our data highlight the genetic heterogeneity of ICF syndrome; however, they provide evidence that all genes act in common or converging pathways leading to the ICF phenotype.

The de-ubiquitylating enzymes USP26 and USP37 regulate homologous recombination by counteracting RAP80.

The faithful repair of DNA double-strand breaks (DSBs) is essential to safeguard genome stability. DSBs elicit a signaling cascade involving the E3 ubiquitin ligases RNF8/RNF168 and the ubiquitin-dependent assembly of the BRCA1-Abraxas-RAP80-MERIT40 complex. The association of BRCA1 with ubiquitin conjugates through RAP80 is known to be inhibitory to DSB repair by homologous recombination (HR). However, the precise regulation of this mechanism remains poorly understood. Through genetic screens we identified USP26 and USP37 as key de-ubiquitylating enzymes (DUBs) that limit the repressive impact of RNF8/RNF168 on HR. Both DUBs are recruited to DSBs where they actively remove RNF168-induced ubiquitin conjugates. Depletion of USP26 or USP37 disrupts the execution of HR and this effect is alleviated by the simultaneous depletion of RAP80. We demonstrate that USP26 and USP37 prevent excessive spreading of RAP80-BRCA1 from DSBs. On the other hand, we also found that USP26 and USP37 promote the efficient association of BRCA1 with PALB2. This suggests that these DUBs limit the ubiquitin-dependent sequestration of BRCA1 via the BRCA1-Abraxas-RAP80-MERIT40 complex, while promoting complex formation and cooperation of BRCA1 with PALB2-BRCA2-RAD51 during HR. These findings reveal a novel ubiquitin-dependent mechanism that regulates distinct BRCA1-containing complexes for efficient repair of DSBs by HR.

DNA methylation signatures link prenatal famine exposure to growth and metabolism.

Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. However, a comprehensive assessment of the characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs) is lacking in humans. Here we report on a genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter. We show that P-DMRs preferentially occur at regulatory regions, are characterized by intermediate levels of DNA methylation and map to genes enriched for differential expression during early development. Validation and further exploratory analysis of six P-DMRs highlight the critical role of gestational timing. Interestingly, differential methylation of the P-DMRs extends along pathways related to growth and metabolism. P-DMRs located in INSR and CPT1A have enhancer activity in vitro and differential methylation is associated with birth weight and serum LDL cholesterol. Epigenetic modulation of pathways by prenatal malnutrition may promote an adverse metabolic phenotype in later life.

Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers.

BACKGROUND: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans. METHODS: We measured LTL in 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses thereof (mean age 59 years) from the Leiden Longevity Study (LLS). RESULTS: We found that shorter LTL is associated with increased prospective mortality in middle (30-80 years; hazard ratio (HR)=0.75, P=0.001) and highly advanced age (≥90 years; HR=0.92, P=0.028), and show that this association cannot be explained by the association of LTL with the immune-related markers insulin-like growth factor 1 to insulin-like growth factor binding protein 3 molar ratio, C-reactive protein, interleukin 6, cytomegalovirus serostatus or white blood cell counts. We found no difference in LTL between the middle-aged LLS offspring and their spouses (ß=0.006, P=0.932). Neither did we observe an association of LTL-associated genetic variants with mortality in a prospective meta-analysis of multiple cohorts (n=8165). CONCLUSIONS: We confirm LTL to be a marker of prospective mortality in middle and highly advanced age and additionally show that this association could not be explained by the association of LTL with various immune-related markers. Furthermore, the approaches performed here do not further support the hypothesis that LTL variation contributes to the genetic propensity for longevity.

DUX4 promotes transcription of FRG2 by directly activating its promoter in facioscapulohumeral muscular dystrophy.

BACKGROUND: The most common form of facioscapulohumeral muscular dystrophy (FSHD) is caused by a genetic contraction of the polymorphic D4Z4 macrosatellite repeat array in the subtelomeric region of chromosome 4q. In some studies, genes centromeric to the D4Z4 repeat array have been reported to be over-expressed in FSHD, including FRG1 and FRG2, presumably due to decreased long-distance repression by the shorter array through a mechanism similar to position-effect variegation. Differential regulation of FRG1 in FSHD has never been unequivocally proven, however, FRG2 has been reproducibly shown to be induced in primary FSHD-derived muscle cells when differentiated in vitro. The molecular function of FRG2 and a possible contribution to FSHD pathology remain unclear. Recent evidence has identified the mis-expression of DUX4, located within the D4Z4 repeat unit, in skeletal muscle as the cause of FSHD. DUX4 is a double homeobox transcription factor that has been shown to be toxic when expressed in muscle cells. METHODS: We used a combination of expression analysis by qRT/PCR and RNA sequencing to determine the transcriptional activation of FRG2 and DUX4. We examined this in both differentiating control and FSHD derived muscle cell cultures or DUX4 transduced control cell lines. Next, we used ChIP-seq analysis and luciferase reporter assays to determine the potential DUX4 transactivation effect on the FRG2 promoter. RESULTS: We show that DUX4 directly activates the expression of FRG2. Increased expression of FRG2 was observed following expression of DUX4 in myoblasts and fibroblasts derived from control individuals. Moreover, we identified DUX4 binding sites at the FRG2 promoter by chromatin immunoprecipitation followed by deep sequencing and confirmed the direct regulation of DUX4 on the FRG2 promoter by luciferase reporter assays. Activation of luciferase was dependent on both DUX4 expression and the presence of the DUX4 DNA binding motifs in the FRG2 promoter. CONCLUSION: We show that the FSHD-specific upregulation of FRG2 is a direct consequence of the activity of DUX4 protein rather than representing a regional de-repression secondary to fewer D4Z4 repeats.

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.

Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii) low-density lipoprotein receptor-related protein 4 (Lrp4), which responds to neural Agrin by binding and stimulating MuSK. Passive transfer studies in mice have shown that IgG4 antibodies from MuSK MG patients cause disease without requiring complement or other immune components, suggesting that these MuSK antibodies cause disease by directly interfering with MuSK function. Here we show that pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation. In contrast, these IgG4 antibodies have no direct effect on MuSK dimerization or MuSK internalization. These results provide insight into the unique pathogenesis of MuSK MG and provide clues toward development of specific treatment options.