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From 6 to 8 November 2011, a baroclinic wave moved from North Atlantic to Balearic Sea, produced a cut-off, at all altitudes, and developed into a Tropical-Like Cyclone (TLC) characterized by a deep-warm core. This TLC led to a mean sea level pressure minimum of about 987 hPa, 10 m wind speeds higher than 30 m/s around the eye, and very intense rainfall, especially in the Gulf of Lion and the surrounding areas, close to the mountain chains (floods in Genoa and Elba Island).To explore in details the effect of the sea surface temperature on the TLC development, we employed the coupled modeling system COAWST, which consists of the following models: ROMS for the hydrodynamic part, WRF for the meteorological part and SWAN for the surface wave modeling, using a 5 km horizontal grid over all Mediterranean Sea.COAWST was used with different configurations: Stand Alone (SA) approach using only the atmospheric part, atmosphere-ocean coupled mode (AO), and fully coupled version including also surface waves (AOW). Comparing the three runs, the effects of different simulations on the TLC trajectory are significant only in the later stage of the cyclone lifetime. On the other hand, wind intensity is higher in the SA case w.r.t. both coupled runs. When compared to case AO, winds are about 1 m/s larger, even though the spatial distribution is very similar (possibly because of the lower SST produced by case AO). Case AOW produces less intense winds than SA and AO case in the areas where the wave is most developed (differences are about 2-4 m/s), while winds are more intense nearby the cyclone’s eye. Moreover, the inclusion of the wave model (AOW) has implications in the water column, by increasing the mixing in the ocean, changing the depth of the ocean mixed layer along the track of the TLC, increasing the surface drag and the net heat fluxes from ocean to atmosphere, so that eventually SST in AOW run is colder than in AO.It is observed that SST of the SA case is overestimated compared to the coupled cases, and in particular the best performances are observed using the fully coupled case, with the wave motion implementation. The best description of the SST impacts the cyclone intensity and the amount of precipitation at catchment scale. The vertical profiles show that wave induced mixing modifies the mixed layer structure and cools the water column, removing much of the SST (and Ocean Heat Content) anomaly present in the mixed layer.The date chosen for the run initialization appears important: an earlier initial condition allows to properly simulate the evolution of the cyclone from the cyclogenesis between the inclusion and setting-up of air sea interaction effect, through the coupled models.Warming SST in the Mediterranean Sea induced by climate change might increase TLC frequency and/or intensity, potentially becoming more harmful for coastal populations and infrastractures. Fully coupled AOW models might be better suited for studying such aspects. Funding from the STO Office of Chief Scientist (907EUR30) is gratefully acknowledged.

Four different Marine Rapid Environmental Assessment (MREA) procedures are compared with a focus on underwater acoustic performance. Co-located oceanographic-acoustic data were collected during the summer of 2015 in the Northwestern Mediterranean in the framework of a sea trial led by the NATO Centre for Maritime Research and Experimentation. The data were used to link MREA procedures and ocean-acoustic validation in a seamless framework. The MREA procedures consider Conductivity Temperature Depth (CTD) data, operational products from the Copernicus Marine Service, and two dynamical downscaling systems (with and without data assimilation). A portion of the oceanographic data are used for the assimilation procedure, and the remaining portion is withheld from the assimilation system for use as an independent verifying dataset. The accuracy of modelled acoustic properties is evaluated using the sound speed estimates from the different MREA methodologies as inputs to an acoustic model, and then comparing the modelled and observed acoustic arrival intensities and temporal structure. In 95% of the studied cases, the assimilative dynamical downscaling approach provides acoustic results equaling or exceeding in skill those modelled with the sound speed extracted from CTD casts. Acoustic assessment results indicate that our implementation of dynamical downscaling has skill at oceanographic scales of 4 km, about ten times larger than the ocean model horizontal resolution.

Colorectal cancer (CRC) is the second leading cause of death of malignant tumors worldwide. Recent studies point to a role for adiponectin-receptor axis in colorectal carcinogenesis, and in particular to the oncosuppressive properties of T-cadherin receptor. In addition, the loss of T-cadherin expression in tumor tissues has been linked to cancer progression and attributed to aberrant methylation of its promoter. Recognizing the pivotal role of microRNAs in CRC, this work explores their possible contribution to the down-regulation of T-cadherin. A systematic bioinformatics analysis, restricted by microRNA expression data in the colon or in cultured colorectal cell lines, predicted twelve top-ranking target miRNA sites within the 3' UTR of T-cadherin. Experimental validation analyses based on luciferase reporter constructs and miRNA mimic or miRNA inhibitor transfections toward colorectal adenocarcinoma cell lines indicated that miR-377-3p was able to directly bind to the T-cadherin sequence, and thus down-regulating its expression. Given the oncogenic activity of miR-377 and the oncosuppressive activity of T-cadherin in CRC, the regulatory circuit highlighted in this work may add new insights into molecular mechanisms driving colorectal carcinogenesis, and perspectively it could be exploited to identify novel biomarkers and therapeutic targets. This article is protected by copyright. All rights reserved.

MicroRNAs (miRNA) are small-non coding RNAs endowed with great regulatory power, thus playing key roles not only in almost all physiological pathways, but also in the pathogenesis of several diseases. Surprisingly, genomic distribution analysis revealed the highest density of miRNA sequences on the X chromosome; this evolutionary conserved mammalian feature equips females with a larger miRNA machinery than males. However, miRNAs contribution to some X-related conditions, properties or functions is still poorly explored. With the aim to support and focus research in the field, this review analyzes the literature and databases about X-linked miRNAs, trying to understand how miRNAs could contribute to emerging gender-biased functions and pathological mechanisms, such as immunity and cancer. A fine map of miRNA sequences on the X chromosome is reported, and their known functions are discussed; in addition, bioinformatics functional analyses of the whole X-linked miRNA targetome (predicted and validated) were performed. The emerging scenario points to different gaps in the knowledge that should be filled with future experimental investigations, also in terms of possible implications and pathological perspectives for X chromosome aneuploidy syndromes, such as Turner and Klinefelter syndromes. Electronic supplementary material The online version of this article (10.1007/s00018-020-03526-7) contains supplementary material, which is available to authorized users.

CircRNA cargo in spermatozoa (SPZ) participates in setting cell quality, in terms of morphology and motility. Cannabinoid receptor CB1 activity is correlated with a proper spermatogenesis and epididymal sperm maturation. Despite CB1 promotes endogenous skill to circularize mRNAs in SPZ, few notions are reported regarding the functional link between endocannabinoids and spermatic circRNA cargo. In CB1 knock-out male mice, we performed a complete dataset of spermatic circRNA content by microarray strategy. Differentially expressed (DE)-circRNAs, as a function of genotype, were identified. Within DE-circRNAs, we focused the attention on circLIMA1, as putative actin-cytoskeleton architecture regulator. The validation of circLIMA1 dependent-competitive endogenous RNA (ceRNA) network (ceRNET) in in vitro cell line confirmed its activity in the regulation of the cytoskeletal actin. Interestingly, a dynamic actin regulation in SPZ nuclei was found during their epididymal maturation. In this scenario, we showed for the first time an intriguing sperm nuclear actin remodeling, regulated via a ceRNET-independent pathway, consisting in the nuclear shuttling of circLIMA1-QKI interactome and downstream in Gelsolin regulation. In particular, the increased levels of circLIMA1 in CB1 knock-out SPZ, associated with an inefficient depolymerization of nuclear actin, specifically illustrate how endocannabinoids, by regulating circRNA cargo, may contribute to sperm morpho-cellular maturation.

During the Long-Term Glider Mission for Environmental Characterization 2016 sea trial, carried out in the eastern Ligurian Sea (Northwestern Mediterranean Sea), two gliders rated to a maximum depth of 1000 m operated continuously from 3 May 2016–27 June 2016. When possible, glider tracks were synchronized with the contemporaneous footprints of the Jason-2, SARAL/AltiKa and CryoSat-2 altimeters. Temperature and salinity measured by the gliders that were co-localised with the altimeter passages were used to calculate along-track dynamic heights (DH). The latter were then compared with the altimeters’ near real-time absolute dynamic topography (ADT) measurements. ADT and DH values showed very similar, but shifted patterns, suggesting that gliders had sampled the same structures but at different times. Average surface absolute geostrophic velocities at the time of glider transit were used in a novel relocation technique to reposition glider measurements where they would have been at the time of the altimeter passage. The relocation increases the correlation between datasets to a value close to 1 and reduces the RMSE of an order of magnitude, also when the time-difference between measurements was greater than 3 days. The sea level spatial and temporal variability is attributed to the presence of meanders generated by the baroclinic instability of the Liguro- Provencal Current (LPC). These meanders are characterized by a 38 km amplitude and 0.12 m s−1 average propagation speed that are confirmed by the larger scale ocean colour measurements and are in agreement with those previously described in the literature. We found that the presence of LPC meanders in along-track ADT and DH measurements is evidenced by a decrease in sea level when profiles sampled the Modified Atlantic Water, and an increase in sea level when measurements sampled the adjacent waters of Tyrrhenian Sea origin. The relocation technique introduced here is expected to improve future altimetry-glider comparisons, as similar validation experiments were considered possible only when glider and altimetry measurements were near synoptic, and collected up to one day from each other.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel RNA virus affecting humans, causing a form of acute pulmonary respiratory disorder named COVID-19, declared a pandemic by the World Health Organization. MicroRNAs (miRNA) play an emerging and important role in the interplay between viruses and host cells. Although the impact of host miRNAs on SARS-CoV-2 infection has been predicted, experimental data are still missing. This study started by a bioinformatics prediction of cellular miRNAs potentially targeting viral RNAs; then, a number of criteria also based on experimental evidence and virus biology were applied, giving rise to eight promising binding miRNAs. Their interaction with viral sequences was experimentally validated by transfecting luciferase-based reporter plasmids carrying viral target sequences or their inverted sequences into the lung A549 cell line. Transfection of the reporter plasmids resulted in a reduction of luciferase activity for five out of the eight potential binding sites, suggesting responsiveness to endogenously expressed miRNAs. Co-transfection of the reporter plasmids along with miRNA mimics led to a further and strong reduction of luciferase activity, validating the interaction between miR-219a-2-3p, miR-30c-5p, miR-378d, miR-29a-3p, miR-15b-5p, and viral sequences. miR-15b was also able to repress plasmid-driven Spike expression. Intriguingly, the viral target sequences are fully conserved in more recent variants such as United Kingdom variant B.1.1.7 and South Africa 501Y.V2. Overall, this study provides a first experimental evidence of the interaction between specific cellular miRNAs and SARS-CoV-2 sequences, thus contributing to understanding the molecular mechanisms underlying virus infection and pathogenesis to envisage innovative therapeutic interventions and diagnostic tools.

MicroRNAs (miRNA), and more recently long non-coding RNAs (lncRNA), are emerging as a driving force for hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death. In this work, we investigated a possible RNA regulatory network involving two oncosuppressive miRNAs, miR-125a and let-7e, and a long non-coding antisense RNA, SPACA6P-AS (SP-AS), all transcribed from the same locus, with SP-AS in the opposite direction and thus carrying complementary sequences to the miRNAs. In vitro experiments validated the binding of the miRNAs to SP-AS. Then, the boosting of either the miRNAs or SP-AS levels demonstrated their reciprocal inhibition. In addition, overexpression of SP-AS resulted in a reduced silencing activity of miR-125a and let-7e toward their key oncogenic targets, i.e., Lin28b, MMP11, SIRT7, Zbtb7a, Cyclin D1, CDC25B, HMGA2, that resulted significantly upregulated. Finally, the analysis of 374 HCC samples in comparison to 50 normal liver tissues showed an upregulation of SP-AS and a reverse expression of miR-125a, not observed for let-7e; consistently, miR-125a oncogenic targets were upregulated. Overall, the data depict a novel competing endogenous RNA (ceRNA) network, ceRNET, whereby miR-125a can regulate the expression of SP-AS, which in turn regulates the miRNA by competing with the binding to the mRNA targets. We speculate that the unbalancing of any network component may contribute to hepatocarcinogenesis.

Zbtb7a is a transcription factor whose dysfunction is correlated to the development of several types of cancer, including hepatocellular carcinoma (HCC). It generally acts as a repressor of transcription downregulating the expression of several target genes including oncosuppressors ARF and Rb. In this study, Zbtb7a was found to suppress the expression of miR-125a, an oncosuppressive miRNA that is often downregulated in HCC. This effect is mediated by the binding of the transcription factor to a regulatory sequence in the promoter of the transcription unit of miR-125a located 14bp upstream of the transcription start site. Consistent with this observation, the analysis of 370 HCC samples showed an upregulation of Zbtb7a compared to 50 normal liver tissues and a reverse correlation with miR-125a expression. These data suggest that miR-125a may support the oncogenic potential of Zbtb7a.

Background: Although the breakage of a Sachse's knife blade is already a rare event while performing optical internal urethrotomy, a double failure appears to be at the same time a unique and a challenging complication to manage since no reference has emerged from literature review. Case Presentation: A male patient, 80 years of age, underwent retreatment of recurrent urethral stricture that occurred after transurethral resection of the prostate. The latter was complicated by severe intraoperative urethrorrhagia; this is the reason he was transferred from another institution where at first a suprapubic cystostomy was carried out, followed by urethral recanalization through internal urethrotomy and finally he underwent intracavernous Sachse's knife blade discharge. Preoperative evaluation included combined retrograde and voiding urethrography and CT to evaluate the complete resolution of the urethral stenosis and to establish the correct location of the blades inside the corpus cavernosum. A transperineal approach to the left corpus cavernosum was carried out with manageable removal of the foreign body and postoperative assessment showed no early considerable complications for the patient. Conclusion: To our knowledge, this is the first case of double breakage of Sachse's knife blade performing optical internal urethrotomy reported in literature. Although it may appear to be an easy procedure, close attention to its execution must always be paid to prevent major complications. A transperineal approach has proven to be effective and safe without creating any further outcomes to the patient.

The Misa River on the Italian Adriatic coast is typical of the rivers that drain the Apennine Mountain range. The focus of this study, conducted in the late summer of 2013 and mid-winter of 2014, was to contrast the general wintertime-summertime dynamics in the Misa River estuarine system rather than investigate specific dynamical features (e.g. offshore sediment transport, channel seiche, and flocculation mechanisms). Summertime conditions of the Misa River estuary are characterized by low freshwater discharge and net sediment deposition whereas, in the wintertime, the Misa River and estuary is characterized by high episodic freshwater discharge and net erosion and sediment export. Major observed differences between wintertime-summertime dynamics in the Misa River and estuary are a result of seasonal-scale differences in regional precipitation and forcing conditions driven largely by the duration and intensity of prevailing wind patterns that frequently change direction in summertime while keep almost constant directions for much longer periods in wintertime, thus generating major sea storms. Sediment deposition was observed in the final reach of the Misa River and estuary in the summertime. However, in the wintertime, large flood events led to sediment erosion and export in the final reach of the Misa River and estuary that, in conjunction with storm-wave-induced mud transport, led to sediment deposition at the river entrance and in the adjacent nearshore region. The seasonal cyclic pattern of erosion and deposition was confirmed with bathymetric surveys of the final reach of the estuarine region. A critical component for the balance between summertime deposition and wintertime erosion was the presence of an underlying mat of organic deposits that limited the availability of sediments for erosion in winter, when massive debris transport occurs. Further, suspended cohesive sediments flocs were subjected to smaller hydrodynamic stresses in the summertime favoring deposition within the estuary. Conversely, during wintertime storms, flocs were subjected to larger hydrodynamic stresses favoring breakup into smaller flocs and deposition outside the estuary.

// Nicola Coppola 1 , Giorgio de Stefano 2 , Marta Panella 3 , Lorenzo Onorato 1 , Valentina Iodice 2 , Carmine Minichini 1 , Nicola Mosca 3 , Luisa Desiato 3 , Nunzia Farella 2 , Mario Starace 1 , Giulia Liorre 2 , Nicoletta Potenza 3 , Evangelista Sagnelli 1 , Aniello Russo 3 1 Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy 2 IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy 3 Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy Correspondence to: Aniello Russo, email: aniello.russo@unina2.it Keywords: microRNA, gene regulation, cell proliferation, tumor, hepatocellular carcinoma Received: November 08, 2016 Accepted: February 07, 2017 Published: February 28, 2017 ABSTRACT Human microRNA-125a-5p (miR-125a) is expressed in most tissues where it downregulates the expression of membrane receptors or intracellular transductors of mitogenic signals, thus limiting cell proliferation. Expression of this miRNA generally increases with cell differentiation whereas it is downregulated in several types of tumors, such as breast, lung, ovarian, gastric, colon, and cervical cancers, neuroblastoma, medulloblastoma, glioblastoma, and retinoblastoma. In this study, we focused on hepatocellular carcinoma and used real-time quantitative PCR to measure miR-125a expression in 55 tumor biopsies and in matched adjacent non-tumor liver tissues. This analysis showed a downregulation of miR-125a in 80 % of patients, with a mean decrease of 4.7-fold. Comparison of miRNA downregulation with clinicopathological parameters of patients didn’t yield significant correlations except for serum bilirubin. We then evaluated the expression of known targets of miR-125a and found that sirtuin-7, matrix metalloproteinase-11, and c-Raf were up-regulated in tumor tissue by 2.2-, 3-, and 1.7-fold, respectively. Overall, these data support a tumor suppressor role for miR-125a and encourage further studies aimed at the comprehension of the molecular mechanisms governing its expression, eventually leading to treatments to restore its expression in tumor cells.

Sorafenib is an antitumor drug for treatment of advanced hepatocellular carcinoma (HCC). It acts as a multikinase inhibitor suppressing cell proliferation and angiogenesis. Human microRNA-125a-5p (miR-125a) is endowed with similar activities and is frequently downregulated in HCC. Looking for a potential microRNA-based mechanism of action of the drug, we found that sorafenib increases cellular expression of miR-125a in cultured HuH-7 and HepG2 HCC cells. Upregulation of the microRNA inhibited cell proliferation by suppression of sirtuin-7, a NAD(+)-dependent deacetylase, and p21/p27-dependent cell cycle arrest in G1. Later, recruitment of miR-125a in the antiproliferative activity of sorafenib was inquired by modulating its expression in combination with the drug treatment. This analysis showed that intracellular delivery of miR-125a had no additive effect on the antiproliferative activity of sorafenib, whereas a miR-125a inhibitor could counteract it. Finally, evaluation of other oncogenic targets of miR-125a revealed its ability to interfere with the expression of matrix metalloproteinase-11, Zbtb7a proto-oncogene, and c-Raf, possibly contributing to the antiproliferative activity of the drug. J. Cell. Physiol. 232: 1907-1913, 2017. © 2016 Wiley Periodicals, Inc.

International audience; Quantile mapping (QM) represents a common post-processing technique used to connect climate simulations to impact studies at different spatial scales. Depending on the simulation-observation spatial scale mismatch, QM can be used for two different applications. The first application uses only the bias correction component, establishing transfer functions between observations and simulations at similar spatial scales. The second application includes a statistical downscaling component when point-scale observations are considered. However, knowledge of alterations to climate change signal (CCS) resulting from these two applications is limited. This study investigates QM impacts on the original temperature and precipitation CCSs when applied according to a bias correction only (BC-only) and a bias correction plus downscaling (BC + DS) application over reference stations in Central Italy. BC-only application is used to adjust regional climate model (RCM) simulations having the same resolution as the observation grid. QM BC + DS application adjusts the same simulations to point-wise observations. QM applications alter CCS mainly for temperature. BC-only application produces a CCS of the median ~ 1 °C lower than the original (~ 4.5 °C). BC + DS application produces CCS closer to the original, except over the summer 95th percentile, where substantial amplification of the original CCS resulted. The impacts of the two applications are connected to the ratio between the observed and the simulated standard deviation (STD) of the calibration period. For the precipitation, original CCS is essentially preserved in both applications. Yet, calibration period STD ratio cannot predict QM impact on the precipitation CCS when simulated STD and mean are similarly misrepresented.

Silybin is a flavonolignan extracted from Silybum marianum (milk thistle) with hepatoprotective, antioxidant, and anti-inflammatory activity. Several studies have shown that silybin is highly effective to prevent and treat different types of cancer and that its antitumor mechanisms involve the arrest of the cell cycle and/or apoptosis. An MTT assay was performed to study cell viability, lipid peroxidation, extracellular NO production, and scavenger enzyme activity were studied by Thiobarbituric Acid-Reactive Species (TBARS) assay, NO assay, and MnSOD assay, respectively. Cell cycle and apoptosis analysis were performed by FACS. miRNA profiling were evaluated by real time PCR. In this study, we demonstrated that Silybin induced growth inhibition blocking the Hepg2 cells in G1 phase of cell cycle and activating the process of programmed cell death. Moreover, the antiproliferative effects of silybin were paralleled by a strong increase of the number of ceramides involved in the modulation of miRNA secretion. In particular, after treatment with silybin, miR223-3p and miR16-5p were upregulated, while miR-92-3p was downregulated (p &lt, 0.05). In conclusion, our results suggest that silybin-Induced apoptosis occurs in parallel to the increase of ceramides synthesis and miRNAs secretion in HepG2 cells.

MicroRNAs (miRNA) are small-non coding RNAs endowed with great regulatory power, thus playing key roles not only in almost all physiological pathways, but also in the pathogenesis of several diseases. Surprisingly, genomic distribution analysis revealed the highest density of miRNA sequences on the X chromosome; this evolutionary conserved mammalian feature equips females with a larger miRNA machinery than males. However, miRNAs contribution to some X-related conditions, properties or functions is still poorly explored. With the aim to support and focus research in the field, this review analyzes the literature and databases about X-linked miRNAs, trying to understand how miRNAs could contribute to emerging gender-biased functions and pathological mechanisms, such as immunity and cancer. A fine map of miRNA sequences on the X chromosome is reported, and their known functions are discussed; in addition, bioinformatics functional analyses of the whole X-linked miRNA targetome (predicted and validated) were performed. The emerging scenario points to different gaps in the knowledge that should be filled with future experimental investigations, also in terms of possible implications and pathological perspectives for X chromosome aneuploidy syndromes, such as Turner and Klinefelter syndromes.

Surface drifters and virtual particles are used to investigate transport between seven coastal regions in the central and southern Adriatic Sea to estimate the degree to which these regions function as a network. Alongshore coastal currents and cyclonic gyres are the primary circulation features that connected regions in the Adriatic Sea. The historical drifter observations span 25 years and, thus, provide estimates of transport between regions realized by the mean surface circulation. The virtual particle trajectories and a dedicated drifter experiment show that southeasterly Sirocco winds can drive eastward cross-Adriatic transport from the Italian coast near the Gargano Promontory to the Dalmatian Islands in Croatia. Southeasterly winds disrupt alongshore transport on the west coast. Northwesterly Mistral winds enhanced east-to-west transport and resulted in stronger southeastward coastal currents in the western Adriatic current (WAC) and export to the northern Ionian Sea. The central Italian regions showed strong connections from north to south, likely realized by alongshore transport in the WAC. Alongshore, downstream transport was weaker on the east coast, likely due to the more complex topography introduced by the Dalmatian Islands of Croatia. Cross-Adriatic connection percentages were higher for east-to-west transport. Cross-Adriatic transport, in general, occurred via the cyclonic sub-gyres, with westward (eastward) transport observed in the northern (southern) arms of the central and southern gyres. (C) 2016 Elsevier Ltd. All rights reserved.

Downscaling broadscale ocean model information to resolve the fine-scale swash-zone dynamics has a number of applications, such as improved resolution of coastal flood hazard drivers, modeling of sediment transport and seabed morphological evolution. A new method is presented, which enables wave-averaged models for the nearshore circulation to include short-wave induced swash zone dynamics that evolve at the wave group scale (i.e. averaged over the short waves). Such dynamics, which cannot be described, by construction through wave-averaged models, play a fundamental role in nearshore hydrodynamics and morphodynamics. The method is based on the implementation of a set of Shoreline Boundary Conditions (SBCs) in wave-averaged models. The chosen set of SBCs allows for proper computation of the short-wave properties at a mean shoreline ( x l ) taken as the envelope of the actual shoreline. The suitability of the approach is assessed through implementation of the SBCs into the Regional Ocean Modeling System (ROMS) coupled to a spectral wave model (InWave for IG waves and SWAN for wind waves). As the aim is to assess the viability of the approach, the SBCs are implemented only through a one-way coupling to ROMS (i.e. ROMS forcing the SBCs). Four different test cases – with constant, periodic and bichromatic offshore forcing – are run to assess the model performances. The main results of the analysis are: (a) the proposed SBCs can well reproduce the shoreline motion and swash zone dynamics in there for all chosen tests (RMSE and BIAS less than 20 % up to a cross-shore resolution of 4.0 m ( L 0 ∕ 3 or L 0 ∕ 5 )) and (b) implementation of the SBCs allows ROMS to accurately simulate the swash zone flows even at a resolution 40 times coarser than that needed by ROMS with its own wet–dry routine to properly describe the same flows. The latter result clearly demonstrates the major computational advantage of using the proposed SBCs. We also show that most of the swash zone dynamics is due to the mean flow (i.e. incoming Riemann variable) and the local (at x l ) wave height. However, especially in the case of bichromatic waves, the swash zone water volume content also seems to play a crucial role.

A hybrid variational-ensemble data assimilation scheme to estimate the vertical and horizontal parts of the background error covariance matrix for an ocean variational data assimilation system is presented and tested in a limited-area ocean model implemented in the western Mediterranean Sea. An extensive data set collected during the Recognized Environmental Picture Experiments conducted in June 2014 by the Centre for Maritime Research and Experimentation has been used for assimilation and validation. The hybrid scheme is used to both correct the systematic error introduced in the system from the external forcing (initialisation, lateral and surface open boundary conditions) and model parameterisation, and improve the representation of small-scale errors in the background error covariance matrix. An ensemble system is run offline for further use in the hybrid scheme, generated through perturbation of assimilated observations. Results of four different experiments have been compared. The reference experiment uses the classical stationary formulation of the background error covariance matrix and has no systematic error correction. The other three experiments account for, or not, systematic error correction and hybrid background error covariance matrix combining the static and the ensemble-derived errors of the day. Results show that the hybrid scheme when used in conjunction with the systematic error correction reduces the mean absolute error of temperature and salinity misfit by 55 and 42 % respectively, versus statistics arising from standard climatological covariances without systematic error correction.

The discovery of bioactive compounds from natural sources entails an extremely lengthy process due to the timescale and complexity of traditional methodologies. In our study, we used a rapid NMR based metabolomic approach as tool to identify secondary metabolites with anti-proliferative activity against a panel of human colorectal cancer cell lines with different mutation profiles. For this purpose, fourteen Fabaceae species of Mediterranean vegetation were investigated using a double screening method: 1H NMR profiling enabled the identification of the main compounds present in the mixtures, whilst parallel biological assays allowed the selection of two plant extracts based on their strong anti-proliferative properties. Using high-resolution 2D NMR spectroscopy, putative active constituents were identified in the mixture and isolated by performing a bio-guided fractionation of the selected plant extracts. As a result, we found two active principles: a cycloartane glycoside and protodioscin derivative. Interestingly, these metabolites displayed a preferential anti-proliferative effect on colon cancer cell lines with an intrinsic resistance to anti-EGFR therapies. Our work provides an NMR-based metabolomic approach as a powerful and efficient tool to discover natural products with anticancer activities circumventing time-consuming procedures.

MicroRNA-125a exhibits an antiproliferative activity and is downregulated in several types of tumors, including hepatocellular carcinoma where it targets sirtuin-7, matrix metalloproteinase-11, and c-Raf. Another target of miR-125a is Lin28, a pluripotency factor that is generally undetectable in differentiated cells but is often upregulated/reactivated in tumors where it acts as an oncogenic factor promoting cell proliferation and tumor progression. In this study we show that downregulation of Lin28b by miR-125a partially accounts for its antiproliferative activity toward hepatocellular carcinoma cells. We also found that Lin28b is able to bind a conserved GGAG motif of pre-miR-125a and to inhibit its maturation in hepatocellular carcinoma cells. Reciprocal inhibition between miR-125a and Lin28b reasonably generates a positive feedback loop where reactivation of Lin-28b inhibits the expression of both miR-125a and let-7, reinforcing its own expression and leading to a marked overexpression of the mitogenic targets of the two miRNAs. On the other hand, perturbation of these circuits by overexpression of miR-125a suppresses Lin28b leading to a decreased cell proliferation. Overall, these data support a tumor suppressive role for miR-125a and contribute to the elucidation of its molecular targets.

Background:MicroRNA-125a is present in all animals with bilateral symmetry and displays a conserved nucleotide sequence with a section of 11 bases including the seed region that is identical in all considered species. It primarily downregulates the expression of LIN28, thereby promoting cell differentiation and larval phase transitions in nematodes, mammals and insects.Objective:In this review, we focus on the cellular control of miR-125a expression and its antiproliferative activity.Results:In mammalians, microRNA-125a is present in most adult organs and tissues in which it targets proteins involved in the mitogenic response, such as membrane receptors, intracellular signal transducers, or transcription factors, with the overall effect of inhibiting cell proliferation. Tissue levels of miR-125a generally raise during differentiation but it is often downregulated in cancers, e.g. colon, cervical, gastric, ovarian, lung, and breast cancers, osteosarcoma, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma and hepatocellular carcinoma.Conclusion:The antiproliferative activity of miR-125a, demonstrated in many cell types, together with the notion that this miRNA is downregulated in several kinds of cancers, give a substantial support to the concept that miR-125a plays an oncosuppressive role.

Submarine canyons are large geomorphological features that incise continental margins and act as highly dynamic conduits of sediments from shallow to the deep-sea regions. They are often regarded as biodiversity and biomass hotspots, but their role in influencing plankton communities is still poorly known. We studied the ecology of planktonic deep-sea microbes in a submarine canyon system (Polcevera and Bisagno canyons) in the Ligurian Sea (NW Mediterranean Sea), aiming at testing whether these large-scale incisions are peculiar systems, in comparison to the overlying water and the adjacent uncarved slope, in terms of biogeochemical and biological features. We analysed microbial communities’ composition by high-throughput sequencing of 16S and 18S rRNA genes and their functional attributes by measuring heterotrophic carbon production, dissolved inorganic carbon fixation, respiration and the activity of the exoenzymes leucine aminopeptidase, alkaline phosphatase, beta-glucosidase and lipase. We found that both prokaryotic and eukaryotic communities were not significantly different inside the canyons (if compared to the close slope and overlying water), but they were rather shaped by the water masses dynamics in the area. The shallowest Modified Atlantic Waters, Levantine Intermediate Waters and Winter Intermediate Waters hosted higher percentages of Alphaproteobacteria, Bacteroidetes and Dinophyta, while the deepest Western Mediterranean Deep Waters hosted a higher fraction of Gammaproteobacteria, Chloroflexi, Discoba and Fungi. Among the functional measurements, only leucine aminopeptidase activity showed higher rates within the canyons. However, local hotspots within the canyons characterised by high particulate matter loads and high C:N ratio (interpreted as refractory material from sediment local resuspension) displayed pronounced degradation activities.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, characterized by chronic inflammation, demyelination and scarring as well as a broad spectrum of signs and symptoms. MicroRNA plays pivotal roles in cellular and developmental processes by regulating gene expression at the post-transcriptional level. Increasing evidence suggests the involvement of microRNAs in the pathogenesis of neurodegenerative diseases, including MS. We have already found that the expression of a specific miRNA, hsa-mir-26a-5p (miR-26a), changed during INF-β treatment in responder Relapsing-Remitting MS patients. Functional annotations of mir-26a targets revealed that a number of genes were implicated in Glutamate Receptor Signaling pathway, which is notoriously altered in neurodegenerative diseases as MS. In this study, the different potential targets were subjected to a validation test based on luciferase reporter constructs transfected in an oligodendroglial cell line. In this functional screening, miR-26a was able to interact with SLC1A1 3' UTR suppressing the reporter activity. Transfection of a miR-26a mimic was then shown to decrease the endogenous SLC1A1 mRNA. Afterward, we have evaluated in blood platelets from interferon-β treated Multiple Sclerosis patients the expression of miR-26a and SLC1A1, finding not only their converse expression, but also a responsiveness to interferon-β therapy. Overall, these data suggest that mir-26a and SLC1A1 may play a role in the MS pathogenesis, and may be potential targets for the development of new biomarkers and/or therapeutic tools.

Between 19-22 January 2014 a baroclinic wave from the Atlantic region goes in cutoff over the Strait of Gibraltar. The resulting depression remains active for approximately 80 hours, passing off shore of the north African coast, crossing the Tyrrhenian Sea and the Adriatic Sea, before turning south. During the first phase (close to the Balearic islands) and when passing over the Adriatic, the depression assumes the characteristics of a TLC (Tropical Like Cyclones). Sea Surface Temperature (SST) is a very important factor for a proper numerical simulation of these events hence we chose to model this TLC event using the COAWST suite (Coupled Ocean Atmosphere Wave Sediment Transport Modelling System). In the first phase of our work we identified the best model configuration to reproduce the phenomenon, extensively testing different microphysics and PBL (Planetary Boundary Layer) schemes available in the numerical model WRF (Weather Research for Forecasting). In the second phase, in order to evaluate the impact of SST, we used the best physical set-up that reproduces the phenomenon in terms of intensity, trajectory and timing, using four different methods of implementation of the SST in the model: i)from a spectrum-radiometer at 8.3 km resolution and updated every six hours; ii) from a dataset provided by "MyOcean" at 1 km resolution and updated every 6 hours; iii) from COAWST suite run in coupled atmosphere-ocean configuration; iv) from COAWST suite in fully coupled atmosphere-ocean- wave configuration). Results show the importance of the selected microphysics scheme in order to correctly reproduce the TLC trajectory, and of the use of high-resolution and high-frequency SST fields, updated every hour in order to reproduce the diurnal cycles. Coupled numerical runs produce less intense heat fluxes which on turn result in better TLC trajectories, more realistic timing and intensity when compared with standalone simulations, even if the latter use a high resolution SST. Last, a temporary increase of the mixed layer depth along the trajectory of the TLC was exhibited by the fully coupled run during the two phases of maximum intensity of the phenomenon, when the wave field is more developed and acts more intensely on the vertical mixing. We will discuss how these results can be improved or further validated in proximity of land by using satellite information that will be available within the framework of H2020 CEASELESS project.

The hepatitis B virus (HBV) is a widespread human pathogen and chronic HBV infection is a major risk factor for hepatocellular carcinoma (HCC). Some cellular microRNAs are emerging as important regulators of virus-host interaction, indirectly or directly modulating HBV replication and pathogenesis. miR-125a binds the viral transcript encoding the surface antigen and interferes with its expression, thus inhibiting viral replication. Intriguingly, liver miR-125a expression has been found increased in patients with high levels of hepatic HBV-DNA. The present study investigates the mechanism by which liver exposure to HBV induces the expression of miR-125a. The analyses were first performed on liver biopsies from HBV patients, showing that the expression of the viral transactivator X protein (HBx) paralleled the increase of miR-125a expression. Then, transfection of HCC cell lines with an HBx-expressing vector showed a substantial increase of miR-125a expression. Overall, the available data depict a self-inhibitory feedback loop in which HBV, through HBx, increases the expression of miR-125a, that in turn interferes with expression of HBV surface antigen, thus repressing viral replication. © 2014 Elsevier Inc. All rights reserved. The hepatitis B virus (HBV) is a widespread human pathogen and chronic HBV infection is a major risk factor for hepatocellular carcinoma (HCC). Some cellular microRNAs are emerging as important regulators of virus-host interaction, indirectly or directly modulating HBV replication and pathogenesis. miR-125a binds the viral transcript encoding the surface antigen and interferes with its expression, thus inhibiting viral replication. Intriguingly, liver miR-125a expression has been found increased in patients with high levels of hepatic HBV-DNA. The present study investigates the mechanism by which liver exposure to HBV induces the expression of miR-125a. The analyses were first performed on liver biopsies from HBV patients, showing that the expression of the viral transactivator X protein (HBx) paralleled the increase of miR-125a expression. Then, transfection of HCC cell lines with an HBx-expressing vector showed a substantial increase of miR-125a expression. Overall, the available data depict a self-inhibitory feedback loop in which HBV, through HBx, increases the expression of miR-125a, that in turn interferes with expression of HBV surface antigen, thus repressing viral replication. © 2014 Elsevier Inc. All rights reserved.

Objectives To investigate the impact on biochemical and objective response and on pain improvement of gemcitabine, prednisone, and zoledronic acid in patients with hormone-refractory prostate cancer (HRPC), previously treated with docetaxel-based regimens. Methods The patients were treated with gemcitabine 1000 mg/m2 every 14 days, prednisone 10 mg orally on days 1 to 7 and 14 to 21, and zoledronic acid every 4 weeks. Changes in prostate-specific antigen levels, tumor response, and toxicity were evaluated every month. The pain response, based on pain reduction and analgesic drug reduction, was assessed during therapy. Results A total of 22 men (median age 65 years) were treated. Overall, 5 patients (23%) achieved a 50% or greater reduction in prostate-specific antigen level after two cycles; a partial response was observed in 1 (14%) of 7 patients with measurable disease, and 3 (43%) of 7 had stable disease. Of the 22 men, 23% had pain improvement. The most important hematologic toxicity was neutropenia (grade 3 in 18%). Conclusions The combination of gemcitabine, prednisone, and zoledronic acid appears to be associated with biochemical response, pain improvement, and good safety in pretreated patients with HRPC.

In this paper we document dense water formation throughout the Adriatic shelf and coastal area in January/February 2012, resulting in record-breaking densities observed during and after the event. The unprecedented dense water generation was preconditioned by a dry and warm year which resulted in a significant reduction of coastal freshwaters, superimposed on a long-term basin-wide salinity increase. The final event that triggered the dense water formation was an extended period of cold weather with strong and severe winds. Record-breaking potential density anomalies (above 30 kg m−3) were measured at several formation sites. Accumulated surface net heat and water losses in some coastal regions exceeded 1.5 GJ m−2 and 250 kg m−2 over 21 days, respectively. Excessiveness, importance of shelf-type dense water formation and effects on the thermohaline circulation and deep aquatic systems are discussed.

The active components of the RNAi are 21 nucleotides long dsRNAs containing a 2 nucleotide overhang at the 3'-end, carrying 5'-phosphate and 3'-hydroxyl groups (siRNAs). Structural analysis revealed the siRNA is functionally bound at both ends to RISC. Terminal modifications are considered with interest as the introduction of chemical moieties interferes with the 3’overhang recognition by the PAZ domain and the 5’-phosphate recognition by the MID and PIWI domains of RISC. Herein, we report the synthesis of modified siRNAs containing terminal amide linkages by introducing hydroxyethylglycine PNA (hegPNA) moieties at 5’, at 3’ positions and on both terminals. Results of gene silencing studies highlight that some of these modifications are compatible with the RNAi machinery and markedly increase the resistance to serum-derived nucleases even after 24 h of incubation. Molecular docking simulations were attained to give at atomistic level a clearer picture of the effect of the most performing modifications on the interactions with the human Argonaute 2 PAZ, MID and PIWI domains. This study adds another piece to the puzzle of the heterogeneous chemical modifications that can be attained to enhance the silencing efficiency of siRNAs. The active components of the RNAi are 21 nucleotides long dsRNAs containing a 2 nucleotide overhang at the 3′ end, carrying 5′-phosphate and 3′-hydroxyl groups (siRNAs). Structural analysis revealed that the siRNA is functionally bound at both ends to RISC. Terminal modifications are considered with interest as the introduction of chemical moieties interferes with the 3′ overhang recognition by the PAZ domain and the 5′-phosphate recognition by the MID and PIWI domains of RISC. Herein, we report the synthesis of modified siRNAs containing terminal amide linkages by introducing hydroxyethylglycine PNA (hegPNA) moieties at 5′, and at 3′ positions and on both terminals. Results of gene silencing studies highlight that some of these modifications are compatible with the RNAi machinery and markedly increase the resistance to serum-derived nucleases even after 24 h of incubation. Molecular docking simulations were attained to give at atomistic level a clearer picture of the effect of the most performing modifications on the interactions with the human Argonaute 2 PAZ, MID, and PIWI domains. This study adds another piece to the puzzle of the heterogeneous chemical modifications that can be attained to enhance the silencing efficiency of siRNAs. © 2014 Maria Gaglione et al.

Hepatocellular carcinoma (HCC) is a multi-factorial cancer with a very poor prognosis; therefore, there are several investigations aimed at the comprehension of the molecular mechanisms leading to development and progression of HCC and at the definition of new therapeutic strategies. We have recently evaluated the expression of selenoproteins in HCC cell lines in comparison with normal hepatocytes. Recent results have shown that some of them are down- and others up-regulated, including the selenoprotein K (SELK), whose expression was also induced by sodium selenite treatment on cells. However, so far very few studies have been dedicated to a possible effect of microRNAs on the expression of selenoproteins and their implication in HCC. In this study, the analysis of SELK 3'UTR by bioinformatics tools led to the identification of eight sites potentially targeted by human microRNAs. They were then subjected to a validation test based on luciferase reporter constructs transfected in HCC cell lines. In this functional screening, miR-544a was able to interact with SELK 3'UTR suppressing the reporter activity. Transfection of a miR-544a mimic or inhibitor was then shown to decrease or increase, respectively, the translation of the endogenous SELK mRNA. Intriguingly, miR-544a expression was found to be modulated by selenium treatment, suggesting a possible role in SELK induction by selenium.