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Within the European project LIQUEFACT some activities have been devoted to the experimental verification of the effectiveness of two techniques in the mitigation of soil liquefaction susceptibility: induced partial saturation (IPS) and horizontal drains. After a preliminary check of their efficiency via centrifuge tests, the two techniques have been studied by means of some large scale shaking tests carried out in a field trial located in the Emilia-Romagna Region (Italy). A preliminary extensive in situ and laboratory investigation was necessary to identify the shallow liquefiable soil layer in which the mitigation techniques and the monitoring instrumentations (pore pressure transducers and geophones) had to be installed. Both techniques required the installation of horizontal well screens via a directional controlled drilling technique: the pipes were used as drainage systems (linear HDL and rhomboidal configurations HDR) or for the air injection in the area treated with IPS technique. The in situ experimental evidences showed that both techniques are able to avoid liquefaction triggering, that on the contrary was attained during the tests in the untreated testing area. The processing of in situ data highlighted that the efficiency of the two techniques is strictly related to chosen arrangement of the horizontal drains and the induced degree of saturation.

The paper presents the results of 5 case studies on complex site effects selected within the project for the level 3 seismic microzonation of several municipalities of Central Italy damaged by the 2016 seismic sequence. The case studies are characterized by different geological and morphological configurations: Monte San Martino is located along a hill slope, Montedinove and Arquata del Tronto villages are located at ridge top whereas Capitignano and Norcia lie in correspondence of sediment-filled valleys. Peculiarities of the sites are constituted by the presence of weathered/jointed rock mass, fault zone, shear wave velocity inversion, complex surface and buried morphologies. These factors make the definition of the subsoil model and the evaluation of the local response particularly complex and difficult to ascertain. For each site, after the discussion of the subsoil model, the results of site response numerical analyses are presented in terms of amplification factors and acceleration response spectra in selected points. The physical phenomena governing the site response have also been investigated at each site by comparing 1D and 2D numerical analyses. Implications are deduced for seismic microzonation studies in similar geological and morphological conditions.

The pathogenesis of acute myeloid leukemia is associated with the appearance of oncogenic fusion proteins generated as a consequence of specific chromosome translocations. Of the two components of each fusion protein, one is generally a transcription factor, whereas the other partner is more variable in function, but often involved in the control of cell survival and apoptosis. As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators that interfere with the process of myeloid differentiation, determine a stage-specific arrest of maturation and enhance cell survival in a cell-type specific manner. The abnormal regulation of transcriptional networks occurs through common mechanisms that include recruitment of aberrant co-repressor complexes, alterations in chromatin remodeling, and disruption of specific subnuclear compartments. The identification and analysis of common and specific target genes regulated by AML fusion proteins will be of fundamental importance for the full understanding of acute myeloid leukemogenesis and for the implementation of disease-specific drug design.

The prediction of earthquake-induced excess pore water pressure is becoming a crucial step for liquefaction-related problems, such as the prediction of settlements, assessment of bearing capacity of shallow foundations, and efficiency of liquefaction mitigation measurements. The goal of this review is to provide a state of the art of the available methods for estimating excess pore water pressure from the most simplified approaches, based on simple hand-made calculations, to the most simplified models for pore pressure prediction, and finally to the most advanced models implemented in computer codes for seismic site response analysis. The hierarchy of the methods is enriched with exemplificative applications from real cases to help understand the classification provided and the usability of each method according to the needs of the professional practice.

The first step for learning any calculation code for seismic response analysis is an adequate understanding of how to properly set the boundary conditions and the properties of the soil model at the initial stage, i.e., before the shaking event. To pursue this aim, nine different computer codes suitable for seismic response analyses of soil profiles have been reviewed. An ideal twenty-meter soil column with visco-elastic linear behavior, subjected to a pulse-like input motion, has been reproduced with the different codes with the scope to practically show the differences and peculiarities of each of them. In the definition of the soil properties in the small-strain range, special attention has been devoted to the definition of the damping ratio, usually defined in non-linear codes as viscous damping according to the Rayleigh formulation. This simple one-dimensional exercise has been considered as a useful benchmark for verifying the rightness of the application of the boundary conditions and setting the initial soil properties. The same analysis can be easily reproduced by beginner users and, therefore, constitutes a starting point in the learning phase of new and/or more sophisticated 2D and 3D calculation codes for seismic site response analysis.

Alterations in glucose and glutamine utilizing pathways and in fatty acid metabolism are currently considered the most significant and prevalent metabolic changes observed in almost all types of tumors. Glucose, glutamine and fatty acids are the substrates for the hexosamine biosynthetic pathway (HBP). This metabolic pathway generates the “sensing molecule” UDP-N-Acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is the substrate for the enzymes involved in protein N- and O-glycosylation, two important post-translational modifications (PTMs) identified in several proteins localized in the extracellular space, on the cell membrane and in the cytoplasm, nucleus and mitochondria. Since protein glycosylation controls several key aspects of cell physiology, aberrant protein glycosylation has been associated with different human diseases, including cancer. Here we review recent evidence indicating the tight association between the HBP flux and cell metabolism, with particular emphasis on the post-transcriptional and transcriptional mechanisms regulated by the HBP that may cause the metabolic rewiring observed in cancer. We describe the implications of both protein O- and N-glycosylation in cancer cell metabolism and bioenergetics; focusing our attention on the effect of these PTMs on nutrient transport and on the transcriptional regulation and function of cancer-specific metabolic pathways.

Abstract Plotinus' outline of his method on inquiry on eternity and time in 3.7(45).1.4 includes a reference to 'concentrated apprehensions of thought' ([...] ταῖς τῆς ἐννοίας ἀθροωτέραις ἐπιβολαῖς [...]). Scholars sometimes argue that Plotinus is here referring to the Epicurean notion of ἀθρόα ἐπιβολή (Epic., Ep. Hdt. 35.9; PHerc. 346, col. 4.24-28). I suggest instead that Gal., mm x.38 Kühn provides the closest parallel to Plotinus' passage. Further parallels between 3.7 and Galens' lost On Demonstration suggest that Galen, not Epicurus, is Plotinus' immediate source.

Different evidence has indicated metabolic rewiring as a necessity for pancreatic cancer (PC) growth, invasion, and chemotherapy resistance. A relevant role has been assigned to glucose metabolism. In particular, an enhanced flux through the Hexosamine Biosynthetic Pathway (HBP) has been tightly linked to PC development. Here, we show that enhancement of the HBP, through the upregulation of the enzyme Phosphoacetylglucosamine Mutase 3 (PGM3), is associated with the onset of gemcitabine (GEM) resistance in PC. Indeed, mRNA profiles of GEM sensitive and resistant patient-derived tumor xenografts (PDXs) indicate that PGM3 expression is specifically increased in GEM-resistant PDXs. Of note, PGM3 results also overexpressed in human PC tissues as compared to paired adjacent normal tissues and its higher expression in PC patients is associated with worse median overall survival (OS). Strikingly, genetic or pharmacological PGM3 inhibition reduces PC cell growth, migration, invasion, in vivo tumor growth and enhances GEM sensitivity. Thus, combined treatment between a specific inhibitor of PGM3, named FR054, and GEM results in a potent reduction of xenograft tumor growth without any obvious side effects in normal tissues. Mechanistically, PGM3 inhibition, reducing protein glycosylation, causes a sustained Unfolded Protein Response (UPR), a significant attenuation of the pro-tumorigenic Epidermal Growth Factor Receptor (EGFR)-Akt axis, and finally cell death. In conclusion this study identifies the HBP as a metabolic pathway involved in GEM resistance and provides a strong rationale for a PC therapy addressing the combined treatment with the PGM3 inhibitor and GEM.

Rail transport is increasingly preferred for its safety and reliability, which can be achieved through a variety of advanced design solutions and technological supports. Among them, ensuring a continuous power supply is crucial for the reliable execution of energy-dependent critical operations. Inspired by the Italian railway infrastructure, here the focus is on Integrated Power Supply (IPS) systems that support critical functionalities, such as the signaling system that regulates railway traffic movement. Fault-tolerant IPS designs are implemented to address unforeseen fault events at the IPS level, which could lead to safety or availability issues. This paper presents a refined stochastic model-based evaluation framework to aid in comparing various IPS redundant architectures with respect to dependability characteristics, mainly focusing on reliability and availability metrics. Major contributions pertain to i) the modeling of four IPS architectures; ii) the integration of models to analyze the IPS behavior under normal and critical conditions; iii) the consideration and modeling of battery failures; iv) a comprehensive analysis campaign to compare the considered IPS architectures in terms of both dependability and cost. A designer can effectively utilize the findings from this analysis to determine the most appropriate IPS organization that meets dependability criteria while also considering potential energy consumption savings. The analyses conducted under realistic parameter settings demonstrate that architectures featuring redundancy at the level of individual IPS components yield the best performance in terms of both dependability and cost. For instance, under specific parameter settings, the CR and IR architectures outperform the SR and MR architectures by roughly three orders of magnitude in terms of Mean Time Between Failures (MTBF), achieving MTBF values of up to approximately h.

To assess the evidence on SARS-CoV2 infection and Covid-19 in relation to deficiency and supplementation of vitamin D, we conducted a systematic review up to April 2021. We summarised data from 38 eligible studies, which presented risk estimates for at least one endpoint, including two RCT and 27 cohort-studies: 205565 patients with information on 25OHD status and 2022 taking vitamin D supplementation with a total of 1197 admitted to the ICU or who needed invasive mechanical ventilation or intubation and hospital stay, and more than 910 Covid-19 deaths. Primary outcomes were severity and mortality and the main aim was to evaluate the association with vitamin D supplementation. Random effects models showed that supplementation was associated with a significant lower risk of both Covid-19 severe disease (SRR 0.38, 95% CI 0.20–0.72, 6 studies) and mortality (SRR 0.35, 95% CI 0.17–0.70, 8 studies). There were no statistically significant dose differences between studies: summary estimates with regular doses remain statistically significant, suggesting that higher doses are not necessary. For patients on vitamin D supplementation, a greater reduction in mortality risk emerged in older individuals and at higher latitudes. Regarding the quality of studies, assessed using the New Castle-Ottawa quality scale, the analysis revealed in most cases no statistically significant differences between low, medium or high quality studies. We found significant associations of vitamin D supplementation with Covid-19, encompassing risks of disease worsening and mortality, especially in seasons characterized by 25OHD deficiency and with not severe patients. Dedicated randomized clinical studies are encouraged to confirm these results.