A framework for evaluating the effectiveness of flood emergency management systems in Europe

Calls for enhancing societal resilience to flooding are echoed across Europe alongside mounting evidence that flood risk will increase in response to climate change amongst other risk-enhancing factors. At a time where it is now widely accepted that flooding cannot be fully prevented, resilience discourse in public policy stresses the importance of improving societal capacities to absorb and recover from flood events. Flood emergency management has thus emerged as a crucial strategy in flood risk management. However, the extent to which emergency management supports societal resilience is dependent on the effectiveness of governance and performance in practice. Drawing from the extensive body of literature documenting the success conditions of so-called effective emergency management more broadly, this study formulates an evaluation framework specifically tailored to the study of Flood Emergency Management Systems (FEMS) in Europe. Applying this framework, this research performs a cross-country comparison of FEMS in the Netherlands, England, Poland, France, and Sweden. Important differences are observed in how FEMS have evolved in relation to differing contextual backgrounds (political, cultural, administrative and socio-economic) and exposures to flood hazard. Whereas the organization and coordination of actors are functioning effectively, other aspects of effective FEMS are relatively under-developed in several countries, such as provisions for institutional learning, recovery-based activities and community preparedness. Drawing from examples of good practice, this paper provides a critical reflection on the opportunities and constraints to enhancing the effectiveness of FEMS in Europe

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

Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma

Abstract Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain

Mechanism of Cobalamin-Mediated Reductive Dehalogenation of Chloroethylenes

Reductive dehalogenation involving cobalamin has been proved to be a promising strategy for decontamination of the polluted environment. However, cob­(I)­alamin can act both as a strong reductant and a powerful nucleophile, and thus, several competing dehalogenation pathways may be involved. This work uses experimentally calibrated density functional theory on a realistic cobalamin model to resolve controversies of cobalamin-mediated reduction of chloroethylenes by exploring mechanisms of electron transfer, nucleophilic substitution, and nucleophilic addition. The computational results provide molecular-level insight into the competing pathways for chloroethylenes reacting with cob­(I)­alamin: the computed ratios of inner-sphere to outer-sphere pathways for perchloroethylene and trichloroethylene are 17:1 and 3.5:1, respectively, in accord with the corresponding experimental ratios of >10:1 and >2.3:1, while the computed outer-sphere pathway for other less-chlorinated ethylenes is hampered by high barriers (>25 kcal/mol). Thus, a new mechanistic picture has been obtained in which the highly chlorinated ethylenes primarily react via an inner-sphere nucleophilic-substitution pathway, whereas the less-chlorinated ethylenes mainly react through an inner-sphere nucleophilic-addition pathway. Especially, the quantitative comparison of standard reduction potentials between the formed chlorinated-cobalamin and cob­(II)­alamin/cob­(I)­alamin couple can be used to distinguish whether the inner-sphere pathway can proceed or not, and linear free-energy relationships have been developed to predict the reductive dehalogenation reactivity within a given mechanism. Finally, we propose new dual-isotope analyses for distinguishing the various environmental dehalogenation mechanisms

Ergo, SMIRK is Safe: A Safety Case for a Machine Learning Component in a Pedestrian Automatic Emergency Brake System

Integration of Machine Learning (ML) components in critical applications introduces novel challenges for software certification and verification. New safety standards and technical guidelines are under development to support the safety of ML-based systems, e.g., ISO 21448 SOTIF for the automotive domain and the Assurance of Machine Learning for use in Autonomous Systems (AMLAS) framework. SOTIF and AMLAS provide high-level guidance but the details must be chiseled out for each specific case. We report results from an industry-academia collaboration on safety assurance of SMIRK, an ML-based pedestrian automatic emergency braking demonstrator running in an industry-grade simulator. We present the outcome of applying AMLAS on SMIRK for a minimalistic operational design domain, i.e., a complete safety case for its integrated ML-based component. Finally, we report lessons learned and provide both SMIRK and the safety case under an open-source licence for the research community to reuse.Comment: Under revie

Microbial community assembly and evolution in subseafloor sediment

Bacterial and archaeal communities inhabiting the subsurface seabed live under strong energy limitation and have growth rates that are orders of magnitude slower than laboratory-grown cultures. It is not understood how subsurface microbial communities are assembled and whether populations undergo adaptive evolution or accumulate mutations as a result of impaired DNA repair under such energy-limited conditions. Here we use amplicon sequencing to explore changes of microbial communities during burial and isolation from the surface to the > 5,000-y-old subsurface of marine sediment and identify a small core set of mostly uncultured bacteria and archaea that is present throughout the sediment column. These persisting populations constitute a small fraction of the entire community at the surface but become predominant in the subsurface. We followed patterns of genome diversity with depth in four dominant lineages of the persisting populations by mapping metagenomic sequence reads onto single-cell genomes. Nucleotide sequence diversity was uniformly low and did not change with age and depth of the sediment. Likewise, therewas no detectable change inmutation rates and efficacy of selection. Our results indicate that subsurface microbial communities predominantly assemble by selective survival of taxa able to persist under extreme energy limitation

MetaRanker 2.0: a web server for prioritization of genetic variation data

MetaRanker 2.0 is a web server for prioritization of common and rare frequency genetic variation data. Based on heterogeneous data sets including genetic association data, protein–protein interactions, large-scale text-mining data, copy number variation data and gene expression experiments, MetaRanker 2.0 prioritizes the protein-coding part of the human genome to shortlist candidate genes for targeted follow-up studies. MetaRanker 2.0 is made freely available at www.cbs.dtu.dk/services/MetaRanker-2.0

Marine Deep Biosphere Microbial Communities Assemble in Near-Surface Sediments in Aarhus Bay

Analyses of microbial diversity in marine sediments have identified a core set of taxa unique to the marine deep biosphere. Previous studies have suggested that these specialized communities are shaped by processes in the surface seabed, in particular that their assembly is associated with the transition from the bioturbated upper zone to the nonbioturbated zone below. To test this hypothesis, we performed a fine-scale analysis of the distribution and activity of microbial populations within the upper 50 cm of sediment from Aarhus Bay (Denmark). Sequencing and qPCR were combined to determine the depth distributions of bacterial and archaeal taxa (16S rRNA genes) and sulfate-reducing microorganisms (SRM) (dsrB gene). Mapping of radionuclides throughout the sediment revealed a region of intense bioturbation at 0–6 cm depth. The transition from bioturbated sediment to the subsurface below (7 cm depth) was marked by a shift from dominant surface populations to common deep biosphere taxa (e.g., Chloroflexi and Atribacteria). Changes in community composition occurred in parallel to drops in microbial activity and abundance caused by reduced energy availability below the mixed sediment surface. These results offer direct evidence for the hypothesis that deep subsurface microbial communities present in Aarhus Bay mainly assemble already centimeters below the sediment surface, below the bioturbation zone

Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ∼12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH

Towards Heat-stable Oxytocin Formulations: Analysis of Degradation Kinetics and Identification of Degradation Products

Purpose. To investigate degradation kinetics of oxytocin as a function of temperature and pH, and identify the degradation products. Materials and Methods. Accelerated degradation of oxytocin formulated at pH 2.0, 4.5, 7.0 and 9.0 was performed at 40, 55, 70 and 80°C. Degradation rate constants were determined from RP-HPLC data. Formulations were characterized by HP-SEC, UV absorption and fluorescence spectroscopy. Degradation products were identified by ESI-MS/MS. Results. The loss of intact oxytocin in RP-HPLC was pH- and temperature-dependent and followed (pseudo) first order kinetics. Degradation was fastest at pH 9.0, followed by pH 7.0, pH 2.0 and pH 4.5. The Arrhenius equation proved suitable to describe the kinetics, with the highest activation energy (116.3 kJ/mol) being found for pH 4.5 formulations. At pH 2.0 deamidation of Gln 4, Asn 5, and Gly 9-NH2, as well as combinations thereof were found. At pH 4.5, 7.0 and 9.0, the formation of tri- and tetrasulfidecontaining oxytocin as well as different types of disulfide and dityrosine-linked dimers were found to occur. Beta-elimination and larger aggregates were also observed. At pH 9.0, mono-deamidation of Gln 4, Asn 5, and Gly 9-NH2 additionally occurred. Conclusions. Multiple degradation products of oxytocin have been identified unequivocally, including various deamidated species, intramolecular oligosulfides and covalent aggregates. The strongly pH dependent degradation can be described by the Arrhenius equation. KEY WORDS: aggregation; Arrhenius kinetics; degradation; mass spectrometry; oxytocin