Rapid Atlantification along the Fram Strait at the beginning of the 20th century.

The recent expansion of Atlantic waters into the Arctic Ocean represents undisputable evidence of the rapid changes occurring in this region. Understanding the past variability of this "Atlantification" is thus crucial in providing a longer perspective on the modern Arctic changes. Here, we reconstruct the history of Atlantification along the eastern Fram Strait during the past 800 years using precisely dated paleoceanographic records based on organic biomarkers and benthic foraminiferal data. Our results show rapid changes in water mass properties that commenced in the early 20th century­several decades before the documented Atlantification by instrumental records. Comparison with regional records suggests a poleward expansion of subtropical waters since the end of the Little Ice Age in response to a rapid hydrographic reorganization in the North Atlantic. Understanding of this mechanism will require further investigations using climate model simulations.

Testing the applicability of random forest modeling to examine benthic foraminiferal responses to multiple environmental parameters.

The main environmental variables controlling benthic foraminiferal distributions were identified and used to assess their influence on ecological indices developed as predictors of Ecological Quality Status (EcoQS) in marine ecosystems. Gradient forest and random forest models were applied to assess the predictive value of a selection of abiotic (environmental) and biotic (foraminifera) variables in a costal marine area in the central Adriatic Sea (Italy). This approach yields evidence that the predictor variables sand, silt, Pollution Load Index, and TN have the greatest influence on the distribution of benthic foraminifera in this area. In addition, we identify thresholds for the most important environmental variables that influence ecological indices. These findings contribute to efforts to determine how to best improve sediment quality and environmental stability for marine conservation. Further application of these approaches represents a useful tool for policymakers to survey the diversity of marine organisms and to improve the ability to protect and restore marine ecosystems by identifying predictors of diversity and identifying key thresholds in these predictors.

Fault-controlled deep hydrothermal flow in a back-arc tectonic setting, SE Tyrrhenian Sea.

Understanding magmatic systems and deep hydrothermal circulation beneath arc-volcanoes provides insights into deep processes associated with slab-subduction and mantle-wedge partial melting. Here we analyze hydrothermal flow below a structural high (Capo Vaticano Ridge, CVR) located offshore Capo Vaticano (western Calabria) and affected by magmatic intrusions generated from above the Ionian subducting-slab. In order to explain observations, we combine geophysical and numerical modelling results. Fluid-flow modelling shows that temperature distribution and geothermal gradient are controlled mainly by hydrothermal circulation, in turn affected by heat source, fault pattern, rock permeability, basement topography and sediment thickness. Two main faults, shaping the structural high and fracturing intensely the continental crust, enable deep hydrothermal circulation and shallow fluid discharge. Distribution of seismicity at depth supports the hypothesis of a slab below Capo Vaticano, deep enough to enable mantle-wedge partial melting above the subduction zone. Melt migration at shallow levels forms the magmatic intrusions inferred by magnetic anomalies and by δ3He enrichment in the discharged fluids at the CVR summit. Our results add new insights on the southern Tyrrhenian Sea arc-related magmatism and on the Calabrian inner-arc tectonic setting dissected by seismogenic faults able to trigger high-destructive earthquakes.

Exceptional discovery of a shallow-water hydrothermal site in the SW area of Basiluzzo islet (Aeolian archipelago, South Tyrrhenian Sea): An environment to preserve.

The geological, biological and geochemical features of a particular field of hydrothermal vents, discovered in the Panarea Volcanic Complex during a research survey carried out in 2015, are described for the first time. The site, located at 70-80 m depth off the South-western coast of the islet of Basiluzzo, was named Smoking Land for the presence of a large number of wide and high active chimneys and was characterized in terms of dissolved benthic fluxes, associated macrofauna and megafauna communities and preliminary mineralogy and geochemistry of chimney structures. On the whole field, a total of 39 chimneys, different in size and shape, were closely observed and described; 14 of them showed emission of low temperature hydrothermal fluids of marine origin characterized by acidified chemical conditions. The CTD and benthic chamber measurements highlighted that the Smoking Land is able to form a sea water bottom layer characterized by variable acidity and high DIC and trace elements concentrations; these characteristics weaken moving away from the chimney mouths. The SEM-EDS analysis of the collected solid samples revealed a chimney structure principally composed by amorphous and low crystalline Fe-oxyhydroxides of hydrothermal origins. The ROV explorations revealed a wide coverage of red algae (Peyssonnelia spp.) colonized by the green algae Flabiella petiolata and by suspension feeders, mainly sponges, but also bryozoans, and tubicolous polychaetes. Although novent-exclusive species were identified, the benthic communities found in association to the chimneys included more taxa than those observed in the surrounding no-vent rocky areas. These first findings evidence a submarine dynamic habitat where geological, chemical and biological processes are intimately connected, making the Smoking Land an important site in terms of marine heritage that should be safeguarded and protected.

Detecting long-term temporal trends in sediment-bound metals in the western Adriatic (Mediterranean Sea).

Major and trace metal concentrations were determined in western Adriatic sediment cores. Based on sediment chronology, the earliest anthropogenic influence appeared as a Zn and Pb increase in the Po River prodelta starting from ~1914. The increasing contamination signal of these trace metals propagated southward as far as 450km with a growing delay, taking ~10years to reach the south Adriatic Sea. Although greater inventories of excess trace metals in the northern sector pointed to the influence of the intense human activities in the Po River drainage basin and Venice lagoon system, we observed a reduction of excess trace metals from mid-1980s, related to the implementation of stricter environmental regulations on chemical wastewaters. In contrast, an increase in trace metal accumulation in surficial sediment from the 2000s in front of the cities of Ancona and Bari suggested a recent local input of trace metals, probably due to harbor activities.

Spatial patterns and temporal trends of trace metal mass budgets in the western Adriatic sediments (Mediterranean Sea).

Spatial patterns of major (Al, Fe and Ti) and trace metals (Cu, Cr, Mn, Ni, Pb and Zn) measured in surficial sediments collected within the Late-Holocene mud-wedge in the western Adriatic Sea were analyzed to elucidate their sources, transport and mass budgets. Distributions of sedimentary trace metals, their fluvial inputs and accumulation loads reveal along-shore transport towards the southern Adriatic. Pb and to a lower extent Zn accumulation loads over time decreased significantly since 1988 in the North Adriatic, consistently with the implementation of regulations in the Western Europe, whereas Zn accumulation in the Po River prodelta remained unchanged since 1995. The Po River fluvial inputs accounted for half of Cr, Ni, Pb and Zn of the fluvial inputs into the western Adriatic Sea, contributing for the delivery of important amounts of Cr and Ni into the sediments, probably related to the natural occurrence of ultramafic rocks in the North sector. Collectively, ~30% of trace metal fluvial inputs discharged into the North sector are exported to the Central and South sectors. The Po River acts as both a bypass and an accumulation zone. In contrast, trace metal accumulation in the Central sector far exceed trace metal fluvial inputs, which suggested that this area is a preferential sink for particle-reactive river-borne material from the North Adriatic. The North sector shows moderate enrichment of Zn and Pb mainly related to the Po River influence. The anthropogenic fraction of Pb shows a large drop of ~30% from the North sector southwards, whereas Zn proportions remain fairly the same up to the Central sector only decreasing in the South sector.

Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding.

Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.

Polyfluorinated amino acids for sensitive 19F NMR-based screening and kinetic measurements.

Two novel series of polyfluorinated amino acids (PFAs) were designed and synthesized according to a very short and scalable synthetic sequence. The advantages and limitations of these moieties for screening purposes are presented and discussed. The potential applications of these PFAs were tested with their incorporation into small arginine-containing peptides that represent suitable substrates for the enzyme trypsin. The enzymatic reactions were monitored by 19F NMR spectroscopy, using the 3-FABS (three fluorine atoms for biochemical screening) technique. The high sensitivity achieved with these PFAs permits a reduction in substrate concentration required for 3-FABS. This is relevant in the utilization of 3-FABS in fragment-based screening for identification of small scaffolds that bind weakly to the receptor of interest. The large dispersion of 19F isotropic chemical shifts allows the simultaneous measurement of the efficiency of the different substrates, thus identifying the best substrate for screening purposes. Furthermore, the knowledge of KM and Kcat for the different substrates allows the identification of the structural motifs responsible for the binding affinity to the receptor and those affecting the chemical steps in enzymatic catalysis. This enables the construction of suitable pharmacophores that can be used for designing nonpeptidic inhibitors with high affinity for the enzyme or molecules that mimic the transition state. The novel PFAs can also find useful application in the FAXS (fluorine chemical shift anisotropy and exchange for screening) experiment, a 19F-based competition binding assay for the detection of molecules that inhibit the interaction between two proteins.

Sensitivity improvement in 19F NMR-based screening experiments: theoretical considerations and experimental applications.

NMR-based binding and functional screening performed with FAXS (fluorine chemical shift anisotropy and exchange for screening) and 3-FABS (three fluorine atoms for biochemical screening) represents a potential alternative approach to high-throughput screening for the identification of novel potential drug candidates. The major limitation of this method in its current status is its intrinsic low sensitivity that limits the number of tested compounds. One approach for overcoming this problem is the use of a cryogenically cooled (19)F probe that reduces the thermal noise in the receiver circuitry. Sensitivity improvement in the two screening techniques achieved with the novel cryogenic (19)F probe technology permits an increased throughput, detection of weaker binders and inhibitors (relevant in a fragment-based lead discovery program), detection of slow binders, and reduction in protein and substrate consumption. These aspects are analyzed with theoretical simulations and experimental quantitative performance evaluation. Application of 3-FABS combined with the cryogenic (19)F probe technology to rapid screening at very low enzyme concentrations and the current detection limits reached with this approach are also presented.

Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition.

Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of protein kinases. The most potent compound reported in this study had an IC(50) of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between 0.05 microM and 0.5 microM for the inhibition of proliferation of different tumor cell lines.

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.

Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.