Local scale multiple quantitative risk assessment and uncertainty evaluation in a densely urbanised area (Brescia, Italy)

Abstract. The study of the interactions between natural and anthropogenic risks is necessary for quantitative risk assessment in areas affected by active natural processes, high population density and strong economic activities. We present a multiple quantitative risk assessment on a 420 km2 high risk area (Brescia and surroundings, Lombardy, Northern Italy), for flood, seismic and industrial accident scenarios. Expected economic annual losses are quantified for each scenario and annual exceedance probability-loss curves are calculated. Uncertainty on the input variables is propagated by means of three different methodologies: Monte-Carlo-Simulation, First Order Second Moment, and point estimate. Expected losses calculated by means of the three approaches show similar values for the whole study area, about 64 000 000 € for earthquakes, about 10 000 000 € for floods, and about 3000 € for industrial accidents. Locally, expected losses assume quite different values if calculated with the three different approaches, with differences up to 19%. The uncertainties on the expected losses and their propagation, performed with the three methods, are compared and discussed in the paper. In some cases, uncertainty reaches significant values (up to almost 50% of the expected loss). This underlines the necessity of including uncertainty in quantitative risk assessment, especially when it is used as a support for territorial planning and decision making. The method is developed thinking at a possible application at a regional-national scale, on the basis of data available in Italy over the national territory

Integration of natural and technological risks in Lombardy, Italy

Abstract. Multi-risk assessment is becoming a valuable tool for land planning, emergency management and the deployment of mitigation strategies. Multi-risk maps combine all available information about hazard, vulnerability, and exposed values related to different dangerous phenomena, and provide a quantitative support to complex decision making. We analyse and integrate through an indicator-based approach nine major threats affecting the Lombardy Region (Northern Italy, 25 000 km2), namely landslide, avalanche, flood, wildfire, seismic, meteorological, industrial (technological) risks; road accidents, and work injuries. For each threat, we develop a set of indicators that express the physical risk and the coping capacity or system resilience. By combining these indicators through different weighting strategies (i.e. budgetary allocation, and fuzzy logic), we calculate a total risk for each threat. Then, we integrate these risks by applying AHP (Analytic Hierarchy Process) weighting, and we derive a set of multi-risk maps. Eventually, we identify the dominant risks for each zone, and a number of risk hot-spot areas. The proposed approach can be applied with different degree of detail depending on the quality of the available data. This allows the application of the method even in case of non homogeneous data, which is often the case for regional scale analyses. Moreover, it allows the integration of different risk types or metrics. Relative risk scores are provided from this methodology, not directly accounting for the temporal occurrence probability of the phenomena

Soil slips and debris flows on terraced slopes

International audienceTerraces cover large areas along the flanks of many alpine and prealpine valleys. Soil slips and soil slips-debris flows are recurrent phenomena along terraced slopes. These landslides cause damages to people, settlements and cultivations. This study investigates the processes related to the triggering of soil slip-debris flows in these settings, analysing those occurred in Valtellina (Central Alps, Italy) on November 2000 after heavy prolonged rainfalls. 260 landslides have been recognised, mostly along the northern valley flank. About 200 soil slips and slumps occurred in terraced areas and a third of them evolved into debris flows. Field work allowed to recognise the settings at soil slip-debris flow source areas. Landslides affected up to 2.5 m of glacial, fluvioglacial and anthropically reworked deposits overlying metamorphic basement. Laboratory and in situ tests allowed to characterise the geotechnical and hydraulic properties of the terrains involved in the initial failure. Several stratigraphic and hydrogeologic factors have been individuated as significant in determining instabilities on terraced slopes. They are the vertical changes of physical soil properties, the presence of buried hollows where groundwater convergence occurs, the rising up of perched groundwater tables, the overflow and lateral infiltration from superficial drainage network, the runoff concentration by means of pathways and the insufficient drainage of retaining walls

Modelling and simulation of biased agonism dynamics at a G protein-coupled receptor.

Theoretical models of G protein-coupled receptor (GPCR) concentration-response relationships often assume an agonist producing a single functional response via a single active state of the receptor. These models have largely been analysed assuming steady-state conditions. There is now much experimental evidence to suggest that many GPCRs can exist in multiple receptor conformations and elicit numerous functional responses, with ligands having the potential to activate different signalling pathways to varying extents-a concept referred to as biased agonism, functional selectivity or pluri-dimensional efficacy. Moreover, recent experimental results indicate a clear possibility for time-dependent bias, whereby an agonist's bias with respect to different pathways may vary dynamically. Efforts towards understanding the implications of temporal bias by characterising and quantifying ligand effects on multiple pathways will clearly be aided by extending current equilibrium binding and biased activation models to include G protein activation dynamics. Here, we present a new model of time-dependent biased agonism, based on ordinary differential equations for multiple cubic ternary complex activation models with G protein cycle dynamics. This model allows simulation and analysis of multi-pathway activation bias dynamics at a single receptor for the first time, at the level of active G protein (αGTP), towards the analysis of dynamic functional responses. The model is generally applicable to systems with NG G proteins and N* active receptor states. Numerical simulations for NG=N*=2 reveal new insights into the effects of system parameters (including cooperativities, and ligand and receptor concentrations) on bias dynamics, highlighting new phenomena including the dynamic inter-conversion of bias direction. Further, we fit this model to 'wet' experimental data for two competing G proteins (Gi and Gs) that become activated upon stimulation of the adenosine A1 receptor with adenosine derivative compounds. Finally, we show that our model can qualitatively describe the temporal dynamics of this competing G protein activation

Hereditary neuropathy with liability to pressure palsy (HNPP): Report of a family with a new point mutation in PMP22 gene

Background: Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disorder most commonly presenting with acute-onset, non-painful focal sensory and motor mononeuropathy. Approximately 80% of patients carry a 1.5 Mb deletion of chromosome 17p11.2 involving the peripheral myelin protein 22 gene (PMP22), the same duplicated in Charcot-Marie-Tooth 1A patients. In a small proportion of patients the disease is caused by PMP22 point mutations. Case presentation: We report on a familial case harbouring a new point mutation in the PMP22 gene. The proband is a 4-years-old girl with acute onset of focal numbness and weakness in her right hand. Electroneurography demonstrated transient sensory and motor radial nerves involvement. In her father, reporting chronic symptoms (cramps and exercise-induced myalgia), we uncovered mild atrophy and areflexia on clinical examination and a mixed (predominantly demyelinating) polyneuropathy with sensory-motor involvement on electrophysiological study. Both carried a nucleotidic substitution c.178 + 2 T > C on intron 3 of the PMP22 gene, involving the splicing donor site, not reported on databases but predicted to be likely pathogenic. Conclusions: We described a previously unreported point mutation in PMP22 gene, which led to the development of a HNPP phenotype in a child and her father. In children evaluated for a sensory and motor transient episode, HNPP disorder due to PMP22 mutations should be suspected. Clinical and electrophysiological studies should be extended to all family members even in the absence of previous episodes suggestive for HNPP

An exo-cell assay for examining real-time γ-secretase activity and inhibition

γ-Secretase is an aspartyl protease that cleaves multiple substrates that are involved in broad biological processes ranging from stem cell development to neurodegeneration. The investigation of γ-secretase has been limited by currently available assays that require genetic or biochemical manipulation in the form of substrate transfection or membrane preparation. Here we report an exo-cell assay that is capable of characterizing γ-secretase activity in any cellular system without limitation. Using a highly active, recombinant substrate this assay can quickly and easily ascertain the status of γ-secretase activity in cell systems and patient samples. We have applied this method to determine the activity of γ-secretase in primary cell samples where transfection and/or membrane isolation are not viable options. Importantly, it allows for the detection of real time γ-secretase activity after inhibitor or drug treatment. The application of this assay to determine the role of γ-secretase in physiological and pathological conditions will greatly facilitate our characterization of this complex protease and help in the development and evaluation of γ-secretase-targeted therapies in Alzheimer's disease or a variety of neoplasms

Detection of selection signatures for ear carriage in Maltese goat breed

Selection and breeding practices in goats have led to the fixation of several traits. This is probably due to the standardization of several peculiar morphological characteristics that have always been one of the major exclusion criteria of individuals from selection. Among these, ear carriage is one of the most ancient and considered a signature of domestication in several species, such as the dog, pig, sheep and goat (Boyko et al., 2010). The availability of improved genomic analyses tools for goats may provide useful information on genes involved in this trait. By studying, for example, the homozygosity decay of haplotypes (contiguous length of alleles) such information can be detected. In the current study, we focused on the Maltese goat, a breed showing floppy ears, in comparison with other Italian breeds using a goat medium density SNP chip (Nicoloso et al., 2015). A total 48,767 SNP markers for 369 animals belonging to 16 breeds or populations were analyzed. Genotypes were imputed within population excluding markers without known position on the current genome assembly (ARS1, Bickhart et al., 2017). Population analysis using MDS, ADMIXTURE and fastSTRUCTURE confirmed the good differentiation among the populations. Integrated Haplotype Score (iHS, Sabeti et al., 2007) was performed for each population, comparing the regions detected on the Maltese breed with the others considered to detect genes that may be involved into shaping ear morphology. These results may provide new insights into ear carriage phenotype by detecting genes that play a pivotal role in shaping the goat phenotypic diversity

An Analytical Approach for the Design of Class-E Resonant DC-DC Converters

We present a new approach to design resonant dc-dc converters, that allows us to achieve both a more accurate implementation and a simpler architecture, by reducing the number of required passive components. The approach is applied to a class-E topology, and it is based on the analytic solution of the system of differential equations regulating the converter evolution. Our technique is also capable of taking into account the most important circuit nonidealities. This represents an important breakthrough with respect to the state of the art, where class-E circuit analysis is based on strong simplifying assumptions, and the final circuit design is achieved by means of numerical simulations after many time-consuming parametric sweeps. The developed methodology is dimensionless, and the achieved design curves can be denormalized to easily get the desired circuit design. Measurements on two different prototypes confirm an extremely high adherence to the developed mathematical approach.We present a new approach to design resonant dc-dc converters, that allows us to achieve both a more accurate implementation and a simpler architecture, by reducing the number of required passive components. The approach is applied to a class-E topology, and it is based on the analytic solution of the system of differential equations regulating the converter evolution. Our technique is also capable of taking into account the most important circuit nonidealities. This represents an important breakthrough with respect to the state of the art, where class-E circuit analysis is based on strong simplifying assumptions, and the final circuit design is achieved by means of numerical simulations after many time-consuming parametric sweeps. The developed methodology is dimensionless, and the achieved design curves can be denormalized to easily get the desired circuit design. Measurements on two different prototypes confirm an extremely high adherence to the developed mathematical approach

Quantum interference of tunneling paths under a double-well barrier

The tunnel effect, a hallmark of the quantum realm, involves motion across a classically forbidden region. In a driven nonlinear system, two or more tunneling paths may coherently interfere, enhancing or cancelling the tunnel effect. Since individual quantum systems are difficult to control, this interference effect has only been studied for the lowest energy states of many-body ensembles. In our experiment, we show a coherent cancellation of the tunneling amplitude in the ground and excited state manifold of an individual squeeze-driven Kerr oscillator, a consequence of the destructive interference of tunneling paths in the classically forbidden region. The tunnel splitting vanishes periodically in the spectrum as a function of the frequency of the squeeze-drive, with the periodicity given by twice the Kerr coefficient. This resonant cancellation, combined with an overall exponential reduction of tunneling as a function of both amplitude and frequency of the squeeze-drive, reduces drastically the well-switching rate under incoherent environment-induced evolution. The control of tunneling via interference effects can be applied to quantum computation, molecular, and nuclear physics