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The effectiveness of a Marine Protected Area (MPA) is strongly related to its zoning design, management, and surveillance, and fish communities are considered indicators of conservation effects. Posidonia oceanica beds and fish assemblages were studied here to evaluate the fishing impacts and the effectiveness of the Marine Protected Areas (MPAs) of Santa Maria di Castellabate (SMC) and Costa degli Infreschi e della Masseta (CIM) in the South Tyrrhenian Sea, Italy. P. oceanica characteristics were estimated counting and collecting shoots, while fish communities were investigated by visual census. Multivariate analyses were performed to detect differences in fish assemblages among the MPA protection levels and seagrass characteristics. Significant differences in fish communities were observed between the depth and protection levels. The latter are probably due to the zoning design at SMC, which does not allow a spillover effect, and to fishing activities, as showed by the ABC curve results. Trophic analyses suggested the use of longlines at SMC, due to the dominance of planktivorous fish species, and of trammel nets at CIM, due to the great heterogeneity of the fish trophic groups. Shoot density and leaf length were significantly correlated with fish communities. CCA analyses showed omnivorous species, mostly belonging to the Sparidae family, correlated with the highest shoot densities, with their feeding habits mostly directed to crustaceans, while macro- and microinvertivores, mainly belonging to the Serranidae and Labridae families, correlated with the highest leaf lengths, where they sough shelter and feed. In conclusion, the data suggest that a zoning redesign at SMC and an increase in the surveillance of fishing activities at CIM might enhance the effectiveness of these MPAs, highlighting the role of fish community studies in identifying MPA efficiency issues and providing trustful guidelines for their management.

[Image: see text] The NRF2-ARE pathway is an intrinsic mechanism of defense against oxidative stress. Inhibition of the interaction between NRF2 and its main negative regulator KEAP1 is an attractive strategy toward neuroprotective agents. We report here the identification of nonacidic tetrahydroisoquinolines (THIQs) that inhibit the KEAP1/NRF2 protein–protein interaction. Peptide SAR at one residue is utilized as a tool to probe structural changes within a specific pocket of the KEAP1 binding site. We used structural information from peptide screening at the P2 pocket, noncovalent small-molecules inhibitors, and the outcome from an explorative SAR at position 5 of THIQs to identify a series of neutral THIQ analogs that bind to KEAP1 in the low micromolar range. These analogs establish new H-bond interactions at the P3 and P2 pockets allowing the replacement of the carboxylic acid functionality by a neutral primary carboxamide. X-ray crystallographic studies reveal the novel binding mode of these molecules to KEAP1.

Red coral is one of the most important species belonging to the coralligenous habitats, being a structuring organism and highly sensitive to human pressure. The presence of red coral populations is historically well documented along the Campania coast (Tyrrhenian Sea), and, due to its high economic value, it has been commercially overharvested since ancient times. Red coral populations along several cliffs on the “Regno di Nettuno” MPA of the Gulf of Naples were investigated using ROV-imaging techniques. Coralligenous habitats were characterized in terms of percent cover and number of morphological groups. Pizzaco site showed the richest and most diverse community. Density of red coral colonies was calculated and compared with morphometric parameters. Results show an inversely correlated trend between colonies density and their size. Finally, fishing pressure was estimated through frequency of lost fishing gears, and S. Angelo site resulted the most stressed one. Anthropic stress plays a key role in the degradation of coralligenous habitats and the dramatic reduction of red coral populations recorded in recent years allows to suspect a more extensive degradation of the entire community. An assessment of the distribution and state of the populations can provide useful information to take measures for a better MPAs management.

Benthic organisms are considered among the best bioindicators being closely associated to sediments in which many pollutants are stored. In this study, macrophytes and meiofauna have been investigated in a transitional area (Venice lagoon, Italy) characterized by numerous anthropogenic pressures. Macrophyte Quality Index and meiofaunal richness were used to assess Ecological Quality (EcoQ) status in line with Water Framework and Marine Strategy Framework Directives. Comparing the EcoQ classes, the results appeared consistent in 24 sites, whereas, in the remaining 5 ones, the values significantly diverged. These results could be related i) to the presence of the seagrass Cymodocea nodosa that could affect meiofaunal taxa with the production of tannins; ii) to the different time response of these communities to human impacts. This synergistic investigation has allowed an accurate description of the spatial and temporal changes of meiofauna through data on abiotic and biotic parameters characterizing the ecosystem trophic level.

Zika virus (ZIKV) is a member of the Flaviviridae family that can cause neurological disorders and congenital malformations. The NS2B-NS3 viral serine protease is an attractive target for the development of new antiviral agents against ZIKV. We report here a SAR study on a series of substrate-like linear tripeptides that inhibit in a non-covalent manner the NS2B-NS3 protease. Optimization of the residues at positions P1, P2, P3 and of the N-terminal and C-terminal portions of the tripeptide allowed the identification of inhibitors with sub-micromolar potency with phenylglycine as arginine-mimicking group and benzylamide as C-terminal fragment. Further SAR exploration and application of these structural changes to a series of peptides having a 4-substituted phenylglycine residue at the P1 position led to potent compounds showing double digit nanomolar inhibition of the Zika protease (IC

EO4GEO is an Erasmus+ Project aiming at defining a long-term and sustainable strategy to fill the gap between supply of and demand for space/geospatial education and training in the Copernicus domain. To test and validate the approach a series of training actions are ongoing for selected scenarios in three sub-sectors: 1) Integrated Applications, 2) Smart Cities, 3) Climate Change. ISPRA, which includes the Geological Survey of Italy, is contributing to the development of Integrated Applications, coordinating different scenarios fostering the uptake of EO data, services and standardized methodologies of analysis. Available EO data were tested to evaluate their effectiveness and efficiency in different fields (e.g. ground motion monitoring on Cultural Heritage, agro monitoring to support regional decision-making; land change detection, geohazard zoning, risk assessment, etc.). Here we present the preliminary results concerning the InSAR analysis and the development of different training actions on ground motion monitoring on potential slope instabilities affecting Cultural Heritage sites. The selected site is the Roman Thermae at Baia (Naples), being part of the “Parco Archeologico dei Campi Flegrei”, located close to active calderas. The area is characterized by a sequence (from the bottom to the top) of volcanic breccia, pyroclastic deposits and surge deposits; Phlegrean Fields represent an exceptional example of volcanic-related subsidence with unrest cycles characterized by intense ground uplift and lowering. The instability phenomena depend mainly on the acclivity of the top sector of the slope, with the activation of small collapse events, and on the lack of ordinary management and maintenance of the area (e.g. invasive vegetation, absence of drainage system). A preliminary InSAR analysis was performed exploiting ERS datasets (1993–2003), showing regional ground lowering, with deformation rates (5-10 mm/yr) that are consistent with the general down lift cycle affecting the whole area in that that period. Ongoing InSAR data processing are focused on SENTINEL-1 data (April 2016 - August 2020) allowing us to explore most recent evolution of instability phenomena. Data processing has been performed using the SeNtinel’s Application Platform (SNAP-ESA) and the Stanford Method of Persistent Scatterers (StaMPS). The dataset is composed by 79 descending and 81 ascending scenes, and the single master stack contains 76 interferograms from the descending and 80 from the ascending geometry. Additionally, SRTM DEM was used in the interferometric processing. Obtained results clearly show a ground uplifting in the investigated period, with displacement rates ranging between 5 and 10 mm/yr (5.2 mm/yr average value of the study area). Any differential displacement has been observed on the exposed elements of the site. A training module focused on this use case is under development, thus contributing to fill the gap between supply and demand in the Copernicus domain, main goal of the EO4GEO project. The definition of step-by-step methodology from EO data to final processing will be defined and connected to learning outcomes, sectorial and transversal skills contributing to finalize the main goal of the EO4GEO project.

Rhodolith beds (RBs) are bioconstructions characterized by coralline algae, which provide habitat for several associated species. Mediterranean RBs are usually located in the mesophotic zone (below 40 m), and thus are frequently remote and unexplored. Recently, the importance and vulnerability of these habitats have been recognized by the European Community and more attention has been drawn to their investigation and conservation. This study reports the results of an extensive monitoring program, carried out within the Marine Strategy Framework Directive (2008/56/EC), in six sites off the Campania coast (Italy, Mediterranean Sea). New insights were given into the distribution, cover, vitality (i.e., live/dead rhodolith ratio), structural complexity, and coralline algae composition of RBs. Remotely operated vehicles (ROV) investigations allowed the description of several RBs, and the discovery of a RB with rhodolith cover &gt, 65% offshore the Capri Island. Only two sites (Secchitiello and Punta Campanella) showed a very low mean cover of live rhodoliths (&lt, 10%), hence, not being classifiable as RBs. The collected rhodoliths were mostly small pralines (~2 cm), spheroidal to ellipsoidal, with growth-forms ranging from encrusting/warty to fruticose/lumpy. Coralline algae identification revealed a high diversity within each bed, with a total of 13 identified taxa. The genus Lithothamnion dominated all sites, and Phymatolithon calcareum and Lithothamnion corallioides, protected by the Habitats Directive (92/43/EEC), were detected in all RBs.

EO4GEO is an Erasmus+ Project aiming at applying innovative solutions for education and training actions. EO4GEO will define a long-term and sustainable strategy to fill the gap between supply of and demand for space/geospatial education and training. The general project strategy will be implemented by: creating and maintaining an ontology-based Body of Knowledge for the space/geospatial sector; developing and integrating a dynamic collaborative platform; designing and developing a series of curricula and a rich portfolio of training modules directly usable in the context of Copernicus and other relevant EO programs; conducting a series of training actions, to test and validate the approach, for selected scenarios in three sub-sectors: 1) Integrated Applications, 2) Smart Cities, 3) Climate Change. ISPRA will contribute to the sub-sector Integrated Applications through the implementation of four case studies selected considering geo-hazard risk scenarios affecting different categories of exposed elements: i) landslide on linear infrastructure and transportation network (Petacciato village, CB); ii) instability events affecting Cultural Heritage, (Baia Archaeological Park, NA); iii) subsidence in urban area (Como city), iv) co-seismic ground deformation (Mt. Etna). The geo-hazard risk scenarios have been selected considering data availability and stakeholders interest; geo-hazard experts and final users (both public and private) will be involved during the scenario’s implementation. Here we present the preliminary results concerning one of the listed case studies, slope instability affecting Cultural Heritage site: the Baia Archaeological Park (Naples). This area is located close by the Phlegrean Fields caldera, representing a unique example of volcanic-related subsidence with unrest cycles characterized by intense ground uplift and down lift; it extends exactly along the inner side of the western sector of the volcanic building of Baia. The particular location of the site, along the steep internal slopes of the volcano, required a strong control over the area development with massive terracing works. The instability phenomena seem to be related to the very high acclivity values of top sector of the slope favoring the activation of modest collapse phenomena as well as by ordinary management and maintenance of the area (e.g. invasive vegetation, absence of drainage systems). Preliminary InSAR analysis were performed exploiting ERS and COSMO Sky-Med datasets; the fist dataset show ground lowering phenomena, highlighting that subsidence affected areas close Phlegrean Fields during that period (1993 – 2003). The deformation rates (5-10 mm/yr) recorded in the investigated time interval are consistent with the general down lift cycle, while time series show some small uplift events. Forthcoming InSAR data processing will take into consideration the most recent SENTINEL-1 data, allowing us to assess the instability phenomena evolution of the area in a recent time interval. In the general scope of the EO4GEO project ISPRA will develop all the case studies fostering the uptake of EO data, services and standardized methodologies of analysis. Available EO data provided from different satellite missions, both European and international (e.g. Sentinel from Copernicus program, COSMO-Sky-Med from ASI), will be tested to evaluate their effectiveness and efficiency in the field of geo-hazard monitoring and risk assessment.

[Image: see text] The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. These compounds are again based on an alternative ZBG with respect to the ortho-anilide that is featured in HDAC3 selective compounds reported to date.

Deep coralligenous banks are remote and not yet sufficiently explored habitats, harboring several benthic species living in generally stable conditions. These high biodiversity spots, represent also refugia for numerous demersal organisms from adverse environmental conditions and provide several ecosystem functions. Recently, the wide employ of Remotely Operated Vehicles (ROVs) as standard tools for monitoring programs has shed light on the effects of the increasing human activities and global changes on these sensitive habitats. As a consequence, the impacts of different stress conditions on the slow-growing species of coralligenous communities have become more and more evident. In order to evaluate the status of deep coralligenous banks of Mediterranean Sea, a monitoring project was implemented to improve their knowledge, and to investigate on the principal issues characterizing these communities. In particular, ROV-video analysis revealed, among the main stressors, the increase of sediment resuspension and deposition probably due to trawl fishing, causing a decrease of coralligenous cover. The impact of this pressure leads to an overall loss of diversity and abundance, with changes in community structure and dynamics. Monitoring activities on large spatio-temporal scales are therefore very useful and needed to assess change patterns and to suggest appropriate management and conservation tools.

The global interest in the assessment of quality condition of some benthic habitats on hard bottoms, such as the coralligenous bioconstruction particularly important for the biodiversity maintenance in the Mediterranean Sea, is recently increasing. Using a synthesis of recent knowledge and ROV (Remotely Operated Vehicles) imaging data acquired in the Bay of Naples (Tyrrhenian Sea, Italy), the Coralligenous Bioconstruction Quality Index (CBQI) was developed. This new index can compare different types of coralligenous habitat (rocky cliffs, submerged shoals, and platform banks) located at both shallow and deep bottoms, and calculate their quality status taking into account coralligenous communities structuring, bottom abiotic factors and anthropic stress evaluation. The data analysis was relatively fast and easy to perform due to the use of morphological groups for coralligenous characterization and anthropic impact categories mainly related to fishing activities. The CBQI may provide a useful tool for the establishment of monitoring protocols and management programs to assess the quality of coralligenous bioconstructions, in different areas of Mediterranean Sea, since it takes into account and discerns the change in communities due to environmental characteristics and/or to anthropic pressure.

A previous publication from our laboratory reported the identification of a new class of 2-(1H-imidazo-2-yl)piperazines as potent T. brucei growth inhibitors as potential treatment for Human African Trypanosomiasis (HAT). This work describes the structure–activity relationship (SAR) around the hit compound 1, which led to the identification of the optimized compound 18, a single digit nanomolar inhibitor (EC50 7 nM), not cytotoxic and with optimal in vivo profile that made it a suitable candidate for efficacy studies in a mouse model mimicking the second stage of disease.

On January 13th 2012, the cruise ship Costa Concordia was stranded in front of Punta Gabbianara, in the North-Western coast of Giglio Island (Tuscany, Italy). To support the Search and Rescue (SaR) and removal operations, a sophisticated monitoring system was implemented. The Terrestrial Laser Scanner device was integrated in a ground-based monitoring system network, to detect the vessel displacements. The location of this instrument permitted to perform a semiautomatic geomechanical survey of the observed portion of Punta Gabbianara rock mass. Furthermore, a traditional geomechanical field survey was performed to integrate the results of the semiautomatic processing.

Impact of fishing gears and marine litter is a recognized global socio-ecological issue. Little is known about the extent of the problem in the Mediterranean seabed; even less information is available regarding litter distribution and its effects on deep rhodolith beds. Indeed, Mediterranean rhodolith beds are often remote and not yet sufficiently explored habitats, despite being internationally protected and recognized among the most important benthic communities for biodiversity maintenance. In this study, a quantitative assessment of marine litter and lost fishing gears, observed using a remotely operated vehicle, was carried out in 6 sites off the Campania Coast (Tyrrhenian Sea) characterized by different rhodolith covers. A negative correlation between abundance and richness of both marine litter and abandoned fishing gears with respect to the rhodolith cover was detected, suggesting that indirect human pressure along the coasts and direct effect of fishing activities might negatively damage these habitats. In fact, a lot of abandoned fishing gears and litter were recorded in all the 4 sites of the Gulf of Naples, confirming the high impact of maritime activities in this overcrowded area. Particularly, the Secchitiello site showed a very low mean cover of rhodoliths (

Molluscan assemblage of coastal area facing the very polluted Sarno River estuary to offshore (Gulf of Naples, Italy) was studied, focusing on temporal and depth-related distribution of species diversity, quali-quantitative composition and trophic guilds structure. A total of 9 stations, at depths ranging between 7 and 95m, were sampled in triplicate by means of a 0.17 m 2 Van Veen grab in four sampling occasions (2 seasons, winter and summer, during 2 years, 2015 and 2016). A total of 1,744 individuals, belonging to 78 species and 3 classes (Bivalvia, Gastropoda and Scaphopoda), was recorded. Bivalves, followed by gastropods, qualitatively and quantitatively dominated the mollusc assemblages and both these taxonomic groups showed the highest values in the shallower stations down to about 25 m depth. In the deeper stations, only the bivalve taxon was dominant, even though exhibiting a much lower species richness and abundance. On the overall, the molluscan species were ascribed to 6 feeding guilds: Suspension and deposit feeders were the dominant trophic groups, occurring at all stations along the bathymetrical gradient, while predators, detritus feeders, ecto-parasites and scavengers were poorly represented and mainly occurred in the shallowest stations. The mollusc composition and distribution pattern along the bathymetrical gradient over time show signs of structural stability that might be mainly due to the continuous supply of organic matter from the river mouth expanding to all area. These results are of primary importance for filling the knowledge gaps on benthic biodiversity over a still poorly known and very fragile coastal area under continuous anthropogenic pressures mainly through the runoff of a very polluted river.

On 10 March 2010, because of the heavy rainfall in the preceding days, the Montaguto landslide (Southern Italy) reactivated, affecting both state road 90 Delle Puglie and the Rome–Bari railway. A similar event occurred on May 2005 and on September 2009. As a result, the National Civil Protection Department (DPC) started an accurate monitoring and analysis program. A monitoring project using the GB-InSAR (ground-based interferometric synthetic aperture radar) system was emplaced to investigate the landslide kinematics, plan urgent safety measures for risk mitigation and design long-term stabilization work.Here, we present the GB-InSAR monitoring system results and its applications in the observational method (OM) approach. GB-InSAR is an established instrument for long-term campaigns aimed at early warning and monitoring during construction works. Our paper further develops these aspects in that it highlights how the OM based on the GB-InSAR technique can produce savings in terms of cost and time in engineering projects without compromising safety. This study focuses on the key role played by the monitoring activities during the design and planning activities, with special reference to the emergency phase.

The identification of a new series of growth inhibitors of Trypanosoma brucei rhodesiense, causative agent of Human African Trypanosomiasis (HAT), is described. A selection of compounds from our in-house compound collection was screened in vitro against the parasite leading to the identification of compounds with nanomolar inhibition of T. brucei growth. Preliminary SAR on the hit compound led to the identification of compound 34 that shows low nanomolar parasite growth inhibition (T. brucei EC50 5 nM), is not cytotoxic (HeLa CC50 > 25,000 nM) and is selective over other parasites, such as Trypanosoma cruzi and Plasmodium falciparum (T. cruzi EC50 8120 nM, P. falciparum EC50 3624 nM).

In this manuscript, an integrated strategy that exploits both phase and amplitude features of satellite SAR (synthetic aperture radar) images and ground data is proposed for deriving the deformation field induced by a complex landslide that affected part of the village of Ponzano (Abruzzi Region, Central Italy). The February 12, 2017, landslide was triggered by the combined effects of intense rainfalls and snowmelt that saturated the slope. The SqueeSAR algorithm was applied to two C-band SAR datasets, composed by Radarsat-2 and Sentinel-1 images, spanning a nine-year time interval before the landslide occurrence. Moreover, the amplitude information carried by two TerraSAR-X images, acquired immediately before and after the event, was exploited to derive the total displacement generated by the landslide movement by means of the RMT (rapid motion tracking) algorithm. The obtained results allow describing the landslide behavior before and after its failure. In particular, the back-monitoring analysis shows that the landslide was already slowly moving, with deformation rates increasing from the Radarsat-2 to the Sentinel-1 monitored periods, 10 years before its complete mobilization. The landslide failure of February 2017 produced maximum displacements of about 10 m in some sectors of the affected area. The registered deformation rates and the localization of the maximum displacements areas were confirmed by field data, collected during a field campaign and a helicopter recognizance of the damaged areas, both performed after the event.

Coralligenous bioconstructions are among the most important Mediterranean habitats for biodiversity maintenance. However some characteristic and sensitive organisms, such as the fan corals, are considered endangered in the international community; indeed, they may be severely damaged by fishing activities causing mechanical damage and increasing sedimentation rate. ROV (Remotely Operated Vehicle) investigations were carried out in order to characterize different morphological types of coralligenous habitat (rim, bank and shoal) located in the southern Bay of Naples (Italy), and to assess the presence of lost fishing gears and their impact on these benthic communities. A rapid classification of different fishing pressures and impacts was obtained through the development of new, representative and synthetic categories. Image analysis revealed the presence of rich and diversified communities, characterized by several fan coral colonies. However, fishing activity dramatically affects these coralligenous habitats, entangling and covering benthic assemblages and leading to necrosis and to parasitic epibionts growth especially on branched organisms. Monitoring programmes may provide a detailed assessment of coralligenous habitats characterization, distribution and health status. An accurate evaluation of fishing pressure and impact may be considered a useful tool to improve sustainable management of these valuable habitats.

Sciaphilous organisms compose the Mediterranean coralligenous assemblages which have solar irradiance reduction in the water column as a main structuring environmental factor. These communities and associated habitats are taken into consideration for protection at European level, and monitoring activities of their status are mandatory (Marine Strategy Framework Directive, 2008/56/EC) representing hot spots of biodiversity. However, sampling activities of these habitats are often very expensive, thus, in recent years, remote surveys performed by underwater robots (ROVs) are more and more applied. In the present investigation Morphological Groups (MGs), which are parataxonomic proxies allowing to describe coralligenous assemblages using ROV images, are used to assess community structure and diversity of six randomly chosen sites in the Gulf of Naples, as representative of three substrate types (boulders/debris, rocky cliff and sand/mud) at two depths (De Results show that the most abundant MGs in all substrates and depths are represented by crustose coralline algae and encrusting sponges, which account for significant quantitative differences only among sites (p Such findings suggest that, i) similar coralligenous assemblages structures are strictly related to edaphic factors; ii) the apparent contradiction between high CBQI values and low heterogeneities might be explained by the long successional process of bioconstruction formation, converging in similar assemblages coherently with substrate and depth-related factors. Thus, to this respect, a low small-scale heterogeneity of assemblages (as a proxy of β-diversity measure) may be considered as a reliable indicator of high quality status.

Landslides are common phenomena that occur worldwide and are a main cause of loss of life and damage to property. The hazards associated with landslides are a challenging concern in many countries, including Italy. Over the last 15 years, an increasing number of applications have aimed to demonstrate the applicability of images captured by space-borne Synthetic Aperture Radar (SAR) sensors in slope instability investigations. InSAR (SAR interferometry) is currently one of the most exploited techniques for the assessment of ground displacements, and it is becoming a consolidated tool for Civil Protection institutions in addressing landslide risk. This paper presents a subset of the results obtained in Italy within the framework of SAR-based programmes and applications intended to test the potential application of C- and X-band satellite interferometry during different Civil Protection activities (namely prevention, prevision, emergency response and post-emergency phases) performed to manage landslide risk. Analysis of satellite SAR data is demonstrated to play a major role in the investigation of landslide-related events at different stages, including detection, mapping, monitoring, characterization and prediction. In addition, this paper also discusses the limitations that still exist and must be overcome in the coming years to manage the transition of satellite SAR systems towards complete operational use in landslide risk management practices.

The shipwreck of the Costa Concordia cruise ship, which ran aground on 13 January 2012 on the northwestern coast of Giglio Island (Italy), required continuous monitoring of the position and movement of the vessel to guarantee the security of workers and rescuers operating around and within the wreck and to support shipwreck removal operations. Furthermore, understanding the geomechanical properties and stability behaviour of the coastal rock mass and rocky seabed underlying the ship was of similar importance. To assess the stability conditions of the ship, a ground-based monitoring system was installed in front of the wreck. The network included a terrestrial laser scanner (TLS) device, which was used to perform remote semiautomatic geomechanical characterization of the observed rock mass. Using TLS survey techniques, three main discontinuity sets were identified in the granitic rock mass of Giglio Island. Furthermore, a multibeam bathymetric survey was used to qualitatively characterize the seabed. To integrate the processed TLS data and quantitatively describe the rock mass quality, a subsequent field survey was carried out to provide a rock mass geomechanical evaluation (from very good to moderate quality). Based on the acquired information, kinematic and stability analyses were performed to create a spatial prediction of rock failure mechanisms in the study area. The obtained kinematic hazard index values were generally low; only the plane failure index reached slightly higher values. The general stability of the rock mass was confirmed by the stability analysis, which yielded a high safety factor value (approximately 12).

Open image in new window On October 24th 2015, following a period of heavy rainfall, a landslide triggered in the Calatabiano Municipality (Sicily Island, Southern Italy) causing the rupture of a water pipeline transect of the aqueduct supplying water to the city of Messina. This event, caused critical water shortages for several days to a large part of the city inhabitants. In order to restore the city water supplies, a provisional by-pass, consisting of three 350 m long pipes passing through the landslide area, was carried out. On November 11th 2015, a landslide monitoring system was installed, based on the combined use of advanced remote sensing techniques such as Ground-Based Interferometric Synthetic Aperture Radar (GB-InSAR), Terrestrial Laser Scanning (TLS) and Infrared Thermography (IRT). The installed monitoring system allowed to: (i) analyze the landslide geomorphological and kinematic features in order to assess the landslide residual risk; (ii) support the early warning procedures needed to ensure the safety of the personnel involved in the by-pass realization and the landslide stabilization works. In this work, the preliminary results of the monitoring activities and a 3-D mapping of the landslide area are presented.

5-(Trifluoroacetyl)thiophene-2-carboxamides were found to be potent and selective class II HDAC inhibitors. This paper describes their further development and the investigation on the cause for the lack of cell-based activity. A rapid screening assay was set up which enabled the identification of more metabolic stable compounds as potent and selective class II HDAC inhibitors.

Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR·HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions.

The identification of class II HDAC inhibitors has been hampered by lack of efficient enzyme assays, in the preceding paper two assays have been developed to improve the efficiency of these enzymes: mutating an active site histidine to tyrosine, or by the use of a trifluoroacetamide lysine substrate, allowing screening to identify class II HDAC inhibitors. Herein, 2-trifluoroacetylthiophenes have been demonstrated to inhibit class II HDACs, resulting in the development of a series of 5-(trifluoroacetyl)thiophene-2-carboxamides as novel, potent and selective class II HDAC inhibitors. X-ray crystal structures of the HDAC 4 catalytic domain with a bound inhibitor demonstrate these compounds are active site inhibitors and bind in their hydrated form.

Coral reefs are amongst the most diverse ecosystems in the biosphere. However, they also represent one of the most threatened marine systems. Apart from global change, especially fishing and tourism affect coral reefs either with mechanical damage or with increase of pollution and sedimentation. Recently, the increase of disturbances has induced extensive changes in community structure and composition of coral reefs. Well-balanced and rich communities can better resist disturbances and show a more rapid recovery, compared to less biodiverse systems. This study assesses the status of coral reefs subjected to several anthropogenic pressures, using a modified version of Coral Condition Index (CCI) that takes into account all Acropora and Pocillopora growth forms and considers a further category of coral damage: the presence of disease. The investigations were carried out at Bangka Island (North Sulawesi, Indonesia), where some of the most flourishing reefs in the country are present. The CCI takes into account the extent of different damages on coral colonies, particularly of the genera Acropora and Pocillopora, being among the most widespread bioconstructors of local coral reefs and very sensitive to anthropogenic disturbances. The aim of the present work is to test whether the CCI is a reliable index in different coral reefs, and to evaluate if highly biodiverse reefs show a better resistance to several human stressors. Data showed high values of CCI (0.9 on average) at all the investigated sites and at the two depths (3 and 9 m) for each site, with the most abundant category represented by “healthy coral colonies”. These data indicate a reasonably good health status of the reef in the study area (CCI > 0.8). The presence of different types of human pressure in the study area was evaluated through the use of metric proxies. Results do not seem to show any significant influence of such human activities on reef coral status, as shown by the low values of correlation between CCI values and the distances of the study sites from the three main sources of stress (Villages, Resorts and Other). Moreover, the present data seem to confirm that highly biodiverse and well-structured assemblages can resist disturbances more efficiently and that human pressure in the study area is sustainable. Compared to fishing activities, the impact of Scuba diving on coral reef is lower, resulting more sustainable and ecologically non-destructive. CCI summarizes many kinds of information and can be applicable in various areas with different pressures. It is a useful tool that might help to assist and guide management decisions towards alternative development models.

The identification of a new series of P. falciparum growth inhibitors is described. Starting from a series of known human class I HDAC inhibitors a SAR exploration based on growth inhibitory activity in parasite and human cells-based assays led to the identification of compounds with submicromolar inhibition of P. falciparum growth (EC50500 nM) and good selectivity over the activity of human HDAC in cells (up to50-fold). Inhibition of parasital HDACs as the mechanism of action of this new class of selective growth inhibitors is supported by hyperacetylation studies.

Stromboli volcano (Aeolian Archipelago, Southern Italy) experienced an increase in its volcanic activity from late December 2012 to March 2013, when it produced several lava overflows, major Strombolian explosions, crater-wall collapses pyroclastic density currents and intense spatter activity. An analysis of the displacement of the NE portion of the summit crater terrace and the unstable NW flank of the volcano (Sciara del Fuoco depression) has been performed with a ground-based interferometric synthetic aperture radar (GBInSAR) by dividing the monitored part of the volcano into five sectors, three in the summit vents region and two in the Sciara del Fuoco. Changes in the displacement rate were observed in sectors 2 and 3. Field and thermal surveys revealed the presence of an alignment of fumaroles confirming the existence of an area of structural discontinuity between sectors 2 and 3. High displacement rates in sector 2 are interpreted to indicate the increase in the magmastatic pressure within the shallow plumbing systems, related to the rise of the magma level within the conduits, while increased displacement rates in sector 3 are connected to the lateral expansion of the shallow plumbing system. The increases and decreases in the displacement rate registered by the GBInSAR system in the upper part of the volcano have been used as a proxy for changes in the pressure conditions in the shallow plumbing system of Stromboli volcano and hence to forecast the occurrence of phases of higher-intensity volcanic activity.

The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development.

5-Aryl-2-(trifluoroacetyl)thiophenes were identified as a new series of class II HDAC inhibitors (HDACi). Further development of this new series led to compounds such as 6h, a potent inhibitor of HDAC4 and HDAC6 (HDAC4 WT IC(50) = 310 nM, HDAC6 IC(50) = 70 nM) that displays 40-fold selectivity over HDAC1 and improved stability in HCT116 cancer cells (t(1/2) = 11 h). Compounds 6h and 2 show inhibition of alpha-tubulin deacetylation in HCT116 cells at 1 microM concentration and antiproliferation effects only at concentrations where inhibition of histone H3 deacetylation is observed.

We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.

We report the synthesis and biological evaluation of N-[(1-aryl-1H-indazol-5-yl)methyl]amide derivatives as Smoothened antagonists and inhibitors of the Hedgehog pathway. Identification of the lead structure 1 by HTS, followed by SAR study on the amide and aryl portions led to the discovery of antagonists with nanomolar activity.

Trifluoroacetylthiophene carboxamides have recently been reported to be class II HDAC inhibitors, with moderate selectivity. Exploration of replacements for the carboxamide with bioisosteric pentatomic heteroaromatic like 1,3,4-oxadiazoles, 1,2,4-oxadiazoles and 1,3-thiazoles, led to the discovery that 2-trifluoroacetylthiophene 1,3,4-oxadiazole derivatives are very potent low nanomolar HDAC4 inhibitors, highly selective over class I HDACs (HDAC 1 and 3), and moderately stable in HCT116 cell culture.

On 24 October 2015, following a period of heavy rainfall, a landslide occurred in the Calatabiano Municipality (Sicily Island, Southern Italy), causing the rupture of a water pipeline supplying water to the city of Messina. Following this event, approximately 250,000 inhabitants of the city suffered critical water shortages for several days. Consequently, on 6 November 2015, a state of emergency was declared (O.C.D.P. 295/2015) by the National Italian Department of Civil Protection (DPC). During the emergency management phase, a provisional by-pass, consisting of three 350-m long pipes passing through the landslide area, was constructed to restore water to the city. Furthermore, on 11 November 2015, a landslide remote-sensing monitoring system was installed with the following purposes: (i) analyse the landslide geomorphological and kinematic features in order to assess the residual landslide risk and (ii) support the early warning procedures needed to ensure the safety of the personnel involved in the by-pass construction and the landslide stabilization works. The monitoring system was based on the combined use of Ground-Based Interferometric Synthetic Aperture Radar (GB-InSAR) and terrestrial laser scanning (TLS). In this work, the preliminary results of the monitoring activities and a remote 3D map of the landslide area are presented.