Developing a risk-informed decision-support system for earthquake early warning at a critical seaport

Earthquake early warning (EEW) systems are used to provide timely alerts on ongoing earthquakes, which can facilitate important risk-mitigation actions before potentially damaging seismic waves reach target sites. A major shortcoming of existing EEW approaches is that the earthquake-related conditions for activating alerts are not generally defined according to a formal decision-support system (DSS) that accounts for possible risk-based consequences of triggering/not triggering the alarm. This paper exploits a next-generation risk-informed EEW DSS, which incorporates Multi-Criteria Decision-Making for evaluating the optimal decision. The proposed DSS integrates engineering-driven loss predictions associated with issuing/not issuing an EEW alert during an event, also considering possible system malfunctions. The DSS is demonstrated for the strategic Gioia Tauro seaport, located in the region of Italy with the highest seismic hazard. Real-time seismic risk analyses are conducted for various earthquake scenarios, accounting for event-parameter uncertainties that are integral to any EEW process and considering the multicomponent nature of the port as a system of interconnected elements. The results of these analyses are used as input to the proposed EEW DSS along with end-user risk preferences, to evaluate the optimal decision in each case and to define a series of risk-informed EEW warning thresholds for the port

The lack of the Celf2a splicing factor converts a Duchenne genotype into a Becker phenotype

Substitutions, deletions and duplications in the dystrophin gene lead to either the severe Duchenne muscular dystrophy (DMD) or mild Becker muscular dystrophy depending on whether out-of-frame or in-frame transcripts are produced. We identified a DMD case (GSΔ44) where the correlation between genotype and phenotype is not respected, even if carrying a typical Duchenne mutation (exon 44 deletion) a Becker-like phenotype was observed. Here we report that in this patient, partial restoration of an in-frame transcript occurs by natural skipping of exon 45 and that this is due to the lack of Celf2a, a splicing factor that interacts with exon 45 in the dystrophin pre-mRNA. Several experiments are presented that demonstrate the central role of Celf2a in controlling exon 45 splicing; our data point to this factor as a potential target for the improvement of those DMD therapeutic treatments, which requires exon 45 skipping

RAPPRESENTAZIONE IN CARTA DELLE CARATTERISTICHE DEI SENTIERI AI FINI DELLA MITIGAZIONE DEL RISCHIO GEOMORFOLOGICO

L’ambiente naturale di alcuni particolari ambiti geografici è in rapida evoluzione non solo per quanto riguarda le sue variabili, legate alle tendenze climatiche in atto, ma anche in relazione all’aumentata frequentazione turistica. La maggiore diffusione dei mezzi di risalita in montagna e di navigazione lungo le coste, rende possibile l’accesso anche a siti altrimenti difficilmente raggiungibili: ciò porta ad un contatto rapido e diretto con ambienti talvolta mutevoli in tempi brevi. La crescente richiesta di una maggiore conoscenza dell’ambiente naturale, che si esplica per lo più attraverso la frequentazione della rete sentieristica, implica la necessità di abbinare alle proposte di percorsi ed itinerari, note illustrative e carte tematiche di immediata lettura, che evidenzino sia i siti di interesse naturalistico - culturale sia le possibili situazioni di rischio e di difficoltà di percorrenza degli itinerari stessi. Esistono infatti alcuni elementi morfologici del territorio che di per sé non costituiscono una pericolosità in senso stretto ma che, a seconda delle capacità del fruitore, possono essere fonte indiretta di danno, in quanto rendono difficile l’attraversamento di alcuni punti specifici o la percorrenza di particolari tratti di sentiero. Contemporaneamente la stagionalità in alcune regioni climatiche e la variabilità meteorologica possono incrementare sia la pericolosità sia la vulnerabilità e di conseguenza il rischio per il frequentatore. Obiettivo del presente lavoro è quello di proporre una simbologia adeguata da inserire sulle carte dei sentieri, e più specificatamente su quelle geoturistiche, per una rapida e facile identificazione di specifiche situazioni riscontrabili lungo itinerari: questi simboli, che dovranno riferirsi solo alla percorribilità dell’itinerario e non alla valorizzazione naturalistica dello stesso, andranno rappresentati su base topografica separata, al fine di non appesantire la lettura dell’elaborato cartografico principale e dovranno fornire solo informazioni oggettive che saranno poi interpretate dal fruitore dell’itinerario. La simbologia e le note terranno conto sia delle caratteristiche costanti dei sentieri che degli elementi variabili, in funzione anche delle condizioni climatiche o stagionali, a seconda dei diversi ambienti interessati

miRNAs as serum biomarkers for Duchenne muscular dystrophy

Dystrophin absence in Duchenne muscular dystrophy (DMD) causes severe muscle degeneration. We describe that, as consequence of fibre damage, specific muscle-miRNAs are released in to the bloodstream of DMD patients and their levels correlate with the severity of the disease. The same miRNAs are abundant also in the blood of mdx mice and recover to wild-type levels in animals ‘cured’ through exon skipping. Even though creatine kinase (CK) blood levels have been utilized as diagnostic markers of several neuromuscular diseases, including DMD, we demonstrate that they correlate less well with the disease severity. Although the analysis of a larger number of patients should allow to obtain more refined correlations with the different stages of disease progression, we propose that miR-1, miR-133, and miR-206 are new and valuable biomarkers for the diagnosis of DMD and possibly also for monitoring the outcomes of therapeutic interventions in humans. Despite many different DMD therapeutic approaches are now entering clinical trials, a unifying method for assessing the benefit of different treatments is still lacking

MicroRNAs and Hematopoietic Differentiation

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SMaRT lncRNA controls translation of a G-quadruplex-containing mRNA antagonizing the DHX36 helicase

Guanine-quadruplexes (G4) included in RNA molecules exert several functions in controlling gene expression at post-transcriptional level; however, the molecular mechanisms of G4-mediated regulation are still poorly understood. Here, we describe a regulatory circuitry operating in the early phases of murine muscle differentiation in which a long non-coding RNA (SMaRT) base pairs with a G4-containing mRNA (Mlx-γ) and represses its translation by counteracting the activity of the DHX36 RNA helicase. The time-restricted, specific effect of lnc-SMaRT on the translation of Mlx-γ isoform modulates the general subcellular localization of total MLX proteins, impacting on their transcriptional output and promoting proper myogenesis and mature myotube formation. Therefore, the circuitry made of lnc-SMaRT, Mlx-γ, and DHX36 not only plays an important role in the control of myogenesis but also unravels a molecular mechanism where G4 structures and G4 unwinding activities are regulated in living cells

Pur-alpha functionally interacts with FUS carrying ALS-associated mutations

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to motor neuron loss. Fused in sarcoma (FUS) protein carrying ALS-associated mutations localizes to stress granules and causes their coalescence into larger aggregates. Here we show that Pur-alpha physically interacts with mutated FUS in an RNA-dependent manner. Pur-alpha colocalizes with FUS carrying mutations in stress granules of motoneuronal cells differentiated from induced pluripotent stem cells and that are derived from ALS patients. We observe that both Pur-alpha and mutated FUS upregulate phosphorylation of the translation initiation factor eukaryotic translation initiation factor 2 alpha and consistently inhibit global protein synthesis. In vivo expression of Pur-alpha in different Drosophila tissues significatively exacerbates the neurodegeneration caused by mutated FUS. Conversely, the downregulation of Pur-alpha in neurons expressing mutated FUS significatively improves fly climbing activity. All these findings suggest that Pur-alpha, through the control of mRNA translation, might be involved in the pathogenesis of ALS associated with the mutation of FUS, and that an alteration of protein synthesis may be directly implicated in the disease. Finally, in vivo RNAi-mediated ablation of Pur-alpha produced locomotion defects in Drosophila, indicating a pivotal role for this protein in the motoneuronal function

3D Engineering Geological Modeling to Investigate a Liquefaction Site: An Example in Alluvial Holocene Sediments in the Po Plain, Italy

Liquefaction-induced surface manifestations are the result of a complex geological–geotechnical phenomenon, driven by several controlling factors. We propose a multidisciplinary methodological approach, involving engineering geologists, geomorphologists, sedimentologists, and geotechnical engineers, to build a 3D engineering geological model for liquefaction assessment studies. The study area is Cavezzo (Po Plain, Italy), which is a municipality hit by superficial liquefaction manifestations during the Emilia seismic crisis of May–June 2012. The site is characterized by a Holocene alluvial sequence of the floodplain, fluvial channel, and crevasse splay deposits prone to liquefaction. The integration of different geotechnical investigations, such as boreholes, CPTm, CPTu, and laboratory tests, allowed us to recognize potentially liquefiable lithological units, crucial for hazard assessment studies. The resulting 3D engineering geological model reveals a strict correlation of co-seismic surface manifestations with buried silty sands and sandy silts within the shallow 10 m in fluvial channel setting, which is capped and laterally confined by clayey and silty deposits

Intronic determinants coordinate charme lncRNA nuclear activity through the interaction with MATR3 and PTBP1

Chromatin architect of muscle expression (Charme) is a muscle-restricted long noncoding RNA (lncRNA) that plays an important role in myogenesis. Earlier evidence indicates that the nuclear Charme isoform, named pCharme, acts on the chromatin by assisting the formation of chromatin domains where myogenic transcription occurs. By combining RNA antisense purification (RAP) with mass spectrometry and loss-of-function analyses, we have now identified the proteins that assist these chromatin activities. These proteins—which include a sub-set of splicing regulators, principally PTBP1 and the multifunctional RNA/DNA binding protein MATR3—bind to sequences located within the alternatively spliced intron-1 to form nuclear aggregates. Consistent with the functional importance of pCharme interactome in vivo, a targeted deletion of the intron-1 by a CRISPR-Cas9 approach in mouse causes the release of pCharme from the chromatin and results in cardiac defects similar to what was observed upon knockout of the full-length transcript

Trans-generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy

Exon skipping is an effective strategy for the treatment of many Duchenne Muscular Dystrophy (DMD) mutations. Natural exon skipping observed in several DMD cases can help in identifying novel therapeutic tools. Here, we show a DMD study case where the lack of a splicing factor (Celf2a), which results in exon skipping and dystrophin rescue, is due to a maternally inherited trans-generational epigenetic silencing. We found that the study case and his mother express a repressive long non-coding RNA, DUXAP8, whose presence correlates with silencing of the Celf2a coding region. We also demonstrate that DUXAP8 expression is lost upon cell reprogramming and that, upon induction of iPSCs into myoblasts, Celf2a expression is recovered leading to the loss of exon skipping and loss of dystrophin synthesis. Finally, CRISPR/Cas9 inactivation of the splicing factor Celf2a was proven to ameliorate the pathological state in other DMD backgrounds establishing Celf2a ablation or inactivation as a novel therapeutic approach for the treatment of Duchenne Muscular Dystrophy