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

Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells. This analysis identified several known but also many novel binding partners of these proteins

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

Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.

ABSTRACT Objective To retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA). Methods Inclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6). Results We included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18–72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14. Conclusions Our data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear

Engineering reconnaissance following the August 24, 2016 M6.0 Central Italy earthquake

An earthquake with a moment magnitude reported as 6.0 from INGV (Istituto Nazionale di Geofisica e Vulcanologia); occurred at 03:36 AM (local time) on 24 August 2016 in the central part of Italy. The epicenter was located at the borders of the Lazio, Abruzzi, Marche and Umbria regions, about 2.5 km north-east of the village of Accumoli and about 100 km from Rome. The hypocentral depth was about 8 km (INGV). We summarize preliminary findings of the Italy-US GEER (Geotechnical Extreme Events Reconnaissance) team, on damage distribution, causative faults, earthquake-induced landslides and rockfalls, building and bridge performance, and ground motion characterization. Our reconnaissance team used multidisciplinary approaches, combining expertise in geology, seismology, geomatics, geotechnical engineering, and structural engineering. Our approach was to combine traditional reconnaissance activities of on-ground recording and mapping of field conditions, with advanced imaging and damage detection routines enabled by state-of-the-art geomatics technology. We anticipate that results from this study, will be useful for future post-earthquake reconnaissance efforts, and improved emergency respons

Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy

Cell therapy for muscular dystrophy has met with limited success, mainly due to the poor engraftment of donor cells, especially in fibrotic muscle at an advanced stage of the disease. We developed a cell-mediated exon skipping that exploits the multinucleated nature of myofibers to achieve cross-correction of resident, dystrophic nuclei by the U7 small nuclear RNA engineered to skip exon 51 of the dystrophin gene. We observed that co-culture of genetically corrected human DMD myogenic cells (but not of WT cells) with their dystrophic counterparts at a ratio of either 1:10 or 1:30 leads to dystrophin production at a level several folds higher than what predicted by simple dilution. This is due to diffusion of U7 snRNA to neighbouring dystrophic resident nuclei. When transplanted into NSG-mdx-Δ51mice carrying a mutation of exon 51, genetically corrected human myogenic cells produce dystrophin at much higher level than WT cells, well in the therapeutic range, and lead to force recovery even with an engraftment of only 3-5%. This level of dystrophin production is an important step towards clinical efficacy for cell therapy

Release of U18 snoRNA from its host intron requires interaction of Nop1p with the Rnt1p endonuclease

An external stem, essential for the release of small nucleolar RNAs (snoRNAs) from their pre-mRNAs, flanks the majority of yeast intron-encoded snoRNAs. Even if this stem is not a canonical Rnt1p substrate, several experiments have indicated that the Rnt1p endonuclease is required for snoRNA processing. To identify the factors necessary for processing of intron-encoded snoRNAs, we have raised in vitro extracts able to reproduce such activity. We found that snoRNP factors are associated with the snoRNA-coding region throughout all the processing steps, and that mutants unable to assemble snoRNPs have a processing-deficient phenotype. Specific depletion of Nop1p completely prevents U18 snoRNA synthesis but does not affect processing of a dicistronic snoRNA-coding unit that has a canonical Rnt1p site. Correct cleavage of intron-encoded U18 and snR38 snoRNAs can be reproduced in vitro by incubating together purified Nop1p and Rnt1p. Pull-down experiments showed that the two proteins interact physically. These data indicate that cleavage of U18, snR38 and possibly other intron-encoded snoRNAs is a regulated process, since the stem is cleaved by the Rnt1p endonuclease only when snoRNP assembly has occurred

Effetto ipotonizzante del 5-Fluorouracile

L’effetto della somministrazione sottocongiunti-vale di 5-Fluorouracile sulla PIO è stato studiato in pazienti glaucomatosi non recentemente operati in trattamento topico cronico. Il farmaco riduceva del 30% circa la PIO dopo singola somministrazione in circa metà dei pazienti; l’effetto era massimo ad una settimana dalla somministrazione. Nei pazienti che non rispondevano alla prima somministrazione si osservava comunque una riduzione pari al 30% della PIO in seguito a 3 ulteriori somministrazioni effettuate ad una settimana di distanza. Gli effetti collaterali erano lievi e con un’incidenza globale pari al 35%. I risultati di un effetto “tossico” e reversibile sull’epitelio ciliare vengono discussi