Selenocarbamates As a Prodrug-Based Approach to Carbonic Anhydrase Inhibition

A study on the activity of selenocarbamates as a novel chemotype acting as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors is reported. Undergoing CA-mediated hydrolysis, selenocarbamates release selenolates behaving as zinc binding groups and effectively inhibiting CAs. A series of selenocarbamates characterised by high molecular diversity and complexity have been studied against different human CA isoforms such as hCA I, II, IX and XII. Selenocarbamates behave as masked selenols with potential biological applications as prodrugs for CAs inhibition-based strategies. X-ray studies provided insights into the binding mode of this novel class of CA inhibitors.     

Detection of Germline Variants in 450 Breast/Ovarian Cancer Families with a Multi-Gene Panel Including Coding and Regulatory Regions

With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5′UTR and 3′UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband’s group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3′UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice.     

Evidence for a Negative Correlation between Human Reactive Enamine-Imine Intermediate Deaminase A (RIDA) Activity and Cell Proliferation Rate: Role of Lysine Succinylation of RIDA

Reactive intermediate deaminase (Rid) proteins are enzymes conserved in all domains of life. UK114, a mammalian member of RidA subfamily, has been firstly identified as a component of liver perchloric acid-soluble proteins (L-PSP). Although still poorly defined, several functions have been attributed to the mammalian protein UK114/RIDA, including the reactive intermediate deamination activity. The expression of UK114/RIDA has been observed in some tumors, arousing interest in this protein as an evaluable tumor marker. However, other studies reported a negative correlation between UK114/RIDA expression, tumor differentiation degree and cell proliferation. This work addressed the question of UK114/RIDA expression in human non-tumor HEK293 cell lines and in some human tumor cell lines. Here we reported that human RIDA (hRIDA) was expressed in all the analyzed cell line and subjected to lysine (K-)succinylation. In HEK293, hRIDA K-succinylation was negatively correlated to the cell proliferation rate and was under the control of SIRT5. Moreover, K-succinylation clearly altered hRIDA quantification by immunoblotting, explaining, at least in part, some discrepancies about RIDA expression reported in previous studies. We found that hRIDA was able to deaminate reactive enamine-imine intermediates and that K-succinylation drastically reduced deaminase activity. As predicted by in silico analysis, the observed reduction of deaminase activity has been related to the drastic alterations of hRIDA structure inferred by K-succinylation. The role of hRIDA and the importance of its K-succinylation in cell metabolism, especially in cancer biology, have been discussed.     

A log mining approach for process monitoring in SCADA

SCADA (supervisory control and data acquisition) systems are used for controlling and monitoring industrial processes. We propose a methodology to systematically identify potential process-related threats in SCADA. Process-related threats take place when an attacker gains user access rights and performs actions, which look legitimate, but which are intended to disrupt the SCADA process. To detect such threats, we propose a semi-automated approach of log processing. We conduct experiments on a real-life water treatment facility. A preliminary case study suggests that our approach is effective in detecting anomalous events that might alter the regular process workflow.     

Postfailure Mechanics of Landslides: Laboratory Investigation of Flowslides in Pyroclastic Soils

Of all landslides, subaerial flowslides are the most dangerous. According to the literature, flowslides in saturated granular deposits are caused by static liquefaction induced by loss of stability. However, the catastrophic flowslides that occurred on steep slopes in Campania (southern Italy) in 1998, 1999, and 2005 were triggered by rainwater infiltration into shallow deposits of pyroclastic soils, which were initially unsaturated. Starting from the experience collected during the investigations of some of these landslides, the writers consider flowslide evolution as a result of a mechanical chain process characterized by saturation increase due to rainwater infiltration, mechanical degradation, volumetric collapse, and static liquefaction, culminating in complete fluidization of the soil. In the paper this chain process is investigated through wetting tests both in suction controlled triaxial apparatuses and in a well-equipped small scale slope model.     

A hybrid approach to the single line scheduling problem with multiple products and sequence-dependent time

The present paper presents a hybrid approach for solving manufacturing scheduling problems, based on the integration between Constraint Logic Programming (CLP) and Genetic Algorithm (GA) approaches. The proposed methodology is applied to a single line with multiple products and sequence-dependent time. This system model derives from a real case of a company producing sheets for catalytic converters. A sensitivity analysis of the hybrid methodology is carried out to compare the performance of the CLP, GA and integrated CLP–GA approaches.     

Semantic annotation of narrative media objects

This paper addresses the annotation of the narrative features of media objects. Based on a relevant narratological and computational background, we introduce an ontology?Cbased model called Drammar, an annotation schema for the narrative features of media objects based on Drammar and a software tool, Cinematic, for annotating these objects and validating the annotation. Annotated media objects can also be automatically edited into sequences, with the twofold goal of testing the validity of the annotation??through the reconstruction of the baseline sequence??and exploring the possibility of alternative sequences. The software tool encodes both the narrative model and the annotation itself in ontological format, and relies on external ontologies for representing world knowledge and limit the arbitrariness of the annotation. The paper opens the way to the design of a general annotation schema for narrative multimedia with the long?Cterm goal of building large corpora of annotated video material and of bridging the gap between the low?Clevel signal analysis and the high?Clevel semantic representation of the narrative content of the media objects. Finally, the paper illustrates a few projects elaborated with the Drammar annotation and the Cinematic tool, with purposes of artistic research and cross?Cmedia analysis, that provide an empirical validation of the annotation process.