Bridges over troubled waters: an interdisciplinary framework for evaluating the interconnectedness within fragmented domestic flood risk management systems

Diversification of strategies in Flood Risk Management (FRM) is widely regarded as a necessary step forward in terms of lessening the likelihood and magnitude of flooding, as well as minimizing the exposure of people and property, and in turn the disruption, economic damage, health impacts and other adverse consequences that ensue when floods occur. Thus, diversification is often heralded as an essential condition for enhancing societal resilience to flooding. However, an inevitable consequence of diversifying strategies and practices in FRM is that it can lead to fragmentation within FRM systems, in terms of the distribution of responsibilities between actors and governing rules enacted within different policy domains. This can prove detrimental to the effectiveness of FRM. Building upon the notion of fragmentation developed in legal and governance literature, this paper introduces the concept of ‘bridging mechanisms’, i.e. instruments that remedy fragmentation by enhancing interconnectedness between relevant actors through information transfer, coordination and cooperation. This paper develops a typology of both fragmentation and bridging mechanisms and analyzes their relations, partly drawing upon empirical research conducted within the EU ‘STAR-FLOOD’ project. In turn, this paper outlines a novel interdisciplinary methodological framework for evaluating the degree and quality of the interconnectedness within fragmented domestic FRM systems. A pragmatic, flexible and broadly applicable tool, this framework is both suited for academic purposes, as well as for practically oriented analysis and (re)development of fragmented FRM systems, and potentially other fragmented systems, within the EU and abroad

Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells

Contains fulltext : 88395.pdf (publisher's version ) (Open Access)BACKGROUND: ATP-binding cassette (ABC) transporters protect cells against unrelated (toxic) substances by pumping them across cell membranes. Earlier we showed that many ABC transporters are highly expressed in hematopoietic stem cells (HSCs) compared to more committed progenitor cells. The ABC transporter expression signature may guarantee lifelong protection of HSCs but may also preserve stem cell integrity by extrusion of agents that trigger their differentiation. Here we have studied whether non-hematopoietic stem cells (non-HSCs) exhibit a similar ABC transporter expression signature as HSCs. RESULTS: ABC transporter expression profiles were determined in non-hematopoietic stem cells (non-HSCs) from embryonic, neonatal and adult origin as well as in various mature blood cell types. Over 11,000 individual ABC transporter expression values were generated by Taqman Low Density Arrays (TLDA) to obtain a sensitivity comparable with quantitative real-time polymerase chain reactions. We found that the vast majority of transporters are significantly higher expressed in HSCs compared to non-HSCs. Furthermore, regardless their origin, non-HSCs exhibited strikingly similar ABC transporter expression profiles that were distinct from those in HSCs. Yet, sets of transporters characteristic for different stem cell types could be identified, suggesting restricted functions in stem cell physiology. Remarkably, in HSCs we could not pinpoint any single transporter expressed at an evidently elevated level when compared to all the mature blood cell types studied. CONCLUSIONS: These findings challenge the concept that individual ABC transporters are implicated in maintaining stem cell integrity. Instead, a distinct ABC transporter expression signature may be essential for stem cell function. The high expression of specific transporters in non-HSCs and mature blood cells suggests a specialized, cell type dependent function and warrants further functional experiments to determine their exact roles in cellular (patho)physiology

De novo variants disturbing the transactivation capacity of POU3F3 cause a characteristic neurodevelopmental disorder

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations

Exome sequencing of an isolated Chilean population affected by Specific Language Impairment (SLI)

Speech and language impairments that are a primary deficit and have no obvious cause (e.g. a comorbid neurological disorder like autism) are diagnosed as Specific Language Impairment (SLI). SLI affects 5–8 % of preschool children and represents a lifelong disability associated with an increased risk of behavioural disorders, social problems and literacy deficits. SLI is highly heritable and twin studies indicate a strong genetic basis. Nonetheless, the underlying genetic mechanisms are expected to be multifactorial and, to date, only three risk variants have been identified. One way to increase the power to detect contributory genetic factors is to study isolated populations derived from relatively recent shared ancestors (founder populations). In 2008, Villanueva described a founder population with a particularly high incidence of SLI (10 times that expected). They inhabit the Robinson Crusoe Island, which lies 677 km to the west of Chile and was colonised in the late 19th century by 8 European and Amerindian families. 77 % of the current island population have a colonising surname and 14 % of marriages involve consanguineous unions. More than 80 % of language impaired individuals can be traced to a pair of founder brothers. This population thus has a short (5-generations) and well documented history and represents a unique resource which could make valuable contributions to the elucidation of genetic mechanisms underpinning SLI. We applied exome sequencing technologies to five language impaired individuals from this population and identified nine nonsynonymous coding changes or splice site mutations that were present in at least three of the five affected individuals sequenced. Sequencing of the entire cohort identified a single non-synonymous coding change that was significantly more frequent in cases than controls (genotype frequencies of 46 and 11 % respectively, p = 4.48 9 10-5). We suggest that this rare coding variant may contribute to the elevated frequency of SLI in this population

Comparative compositions of metabolites and dietary fibre components in doughs and breads produced from bread wheat, emmer and spelt and using yeast and sourdough processes.

Wholemeal flours from blends of bread wheat, emmer and spelt were processed into bread using yeast-based and sourdough fermentation. The bread wheat flour contained significantly higher concentrations of total dietary fibre and fructans than the spelt and emmer flours, the latter having the lowest contents. Breadmaking using sourdough and yeast systems resulted in changes in composition from flour to dough to bread including increases in organic acids and mannitol in the sourdough system and increases in amino acids and sugars (released by hydrolysis of proteins and starch, respectively) in both processing systems. The concentrations of fructans and raffinose (the major endogenous FODMAPs) were reduced by yeast and sourdough fermentation, with yeast having the greater effect. Both systems resulted in greater increases in sugars and glycerol in emmer than in bread wheat and spelt, but the significance of these differences for human health has not been established

Assessing the legitimacy of flood risk governance arrangements in Europe: insights from intra-country evaluations

Legitimacy has received comparatively less attention than societal resilience in the context of flooding, thus methods for assessing and monitoring the legitimacy of Flood Risk Governance Arrangements (FRGA) are noticeably lacking. This study attempts to address this gap by assessing the legitimacy of FRGAs in six European countries through cross-disciplinary and comparative research methods. On the basis of this assessment, recommendation

Population overlap and habitat segregation in wintering Black-tailed Godwits Limosa limosa

Distinct breeding populations of migratory species may overlap both spatially and temporally, but differ in patterns of habitat use. This has important implications for population monitoring and conservation. To quantify the extent to which two distinct breeding populations of a migratory shorebird, the Black-tailed Godwit Limosa limosa, overlap spatially, temporally and in their use of different habitats during winter. We use mid-winter counts between 1990 and 2001 to identify the most important sites in Iberia for Black-tailed Godwits. Monthly surveys of estuarine mudflats and rice-fields at one major site, the Tejo estuary in Portugal in 2005-2007, together with detailed tracking of colour-ringed individuals, are used to explore patterns of habitat use and segregation of the Icelandic subspecies L. l. islandica and the nominate continental subspecies L. l. limosa. In the period 1990-2001, over 66 000 Black-tailed Godwits were counted on average in Iberia during mid-winter (January), of which 80% occurred at just four sites: Tejo and Sado lower basins in Portugal, and Coto Dontildeana and Ebro Delta in Spain. Icelandic Black-tailed Godwits are present throughout the winter and forage primarily in estuarine habitats. Continental Black-tailed Godwits are present from December to March and primarily use rice-fields. Iberia supports about 30% of the Icelandic population in winter and most of the continental population during spring passage. While the Icelandic population is currently increasing, the continental population is declining rapidly. Although the estuarine habitats used by Icelandic godwits are largely protected as Natura 2000 sites, the habitat segregation means that conservation actions for the decreasing numbers of continental godwits should focus on protection of rice-fields and re-establishment of freshwater wetlands