Validation and intercomparison of two vertical-mixing schemes in the Mediterranean Sea

International audienceIn this study, two types of vertical turbulence closure models are tested in the Mediterranean Sea in a one-dimensional configuration. The numerical experiments are performed at different locations in the Mediterranean for which the year 2004 is simulated. The model results are then compared and validated with in-situ temperature observations. For the model simulations, initial profiles of temperature and salinity come from the ARGO (Array for Real-time Geostrophic Oceanography) profiles. The surface forcing (momentum, heat) is calculated from bulk formulae using 6-hourly atmospheric data from the European Center for Medium Range Weather Forecast (ECMWF). The vertical mixing schemes tested in this study are a second-order statistical model (k-?) and the non-local K-profile parameterization (KPP). Both schemes yield similar results in terms of reproducing the water column dynamics. A major source of discrepancy between model and observations comes from the uncertainties in the atmospheric forcing parameterization. At this point, net shortwave radiation data from NCEP atmospheric reanalysis has been used obtaining a more realistic Sea Surface Temperature (SST) compared with satellite observations for the summer months

Integration of Argo trajectories in the Mediterranean Forecasting System and impact on the regional analysis of the western Mediterranean circulation

The impact of Argo float trajectory assimilation on the quality of ocean analyses is studied by means of an operational oceanographic model implemented in the Mediterranean Sea and a 3D-Var assimilation scheme. For the first time, both Argo trajectories and vertical profiles of temperature and salinity (TS) together with satellite altimeter data of sea level anomaly (SLA) are assimilated to produce analyses for short-term forecasts. The study period covers 3 months during winter 2005 when four Argo trajectories were present in the northwestern Mediterranean Sea. The scheme is first assessed computing the misfits between observations and model forecast and analysis. The misfit statistics appear improved for float trajectories, while they are not degraded for the other assimilated variables (TS profiles and SLA). This indicates that the trajectory integration is consistent with the other components of the assimilation system and provides new information on horizontal pressure gradients. Comparisons between analyses obtained with and without trajectory assimilation suggest that trajectory assimilation can have an impact on the description of boundary currents and their instabilities, as well as mesoscale activity at regional scales. Changes are depicted by intermediate water mass redistributions, mesoscale eddy relocations, and net transport modulations. These impacts are detailed and assessed considering historical and simultaneous in situ data sets. The results motivate the integration of Argo trajectories in the operational Mediterranean Forecasting System

Daily oceanographic analyses by the Mediterranean basin scale assimilation system

This study presents the upgrade of the Optimal Interpolation scheme used in the basin scale assimilation scheme of the Mediterranean Forecasting System . The modifications include a daily analysis cycle, the assimilation of ARGO float profiles, the implementation of the geostrophic balance in the background error covariance matrix and the initialisation of the analyses. A series of numerical experiments showed that each modification had a positive impact on the accuracy of the analyses: The daily cycle improved the representation of the processes with a relatively high temporal variability, the assimilation of ARGO floats profiles significantly improved the salinity analyses quality, the geostrophically balanced background error covariances improved the accuracy of the surface elevation analyses, and the initialisation removed the barotropic adjustment in the forecast first time steps starting from the analysis

Integration of ARGO trajectories in the Mediterranean Forecasting System and impact on the regional analysis of the Western Mediterranean circulation

The impact of ARGO float trajectory assimilation on the quality of ocean analyses is studied by means of an operational oceanographic model implemented in the Mediterranean Sea and a 3D-var assimilation scheme. For the first time, both ARGO trajectories and vertical profiles of temperature and salinity (TS) together with satellite altimeter data of sea level anomaly (SLA) are assimilated to produce analyses for short term forecasts. The study period covers three months during winter 2005 when four ARGO trajectories were present in the northwestern Mediterranean Sea. The scheme is first assessed computing the misfits between observations and model forecast and analysis. The misfit statistics appear improved for float trajectories, while they are not degraded for the other assimilated variables (TS profiles and SLA). This indicates that the trajectory integration is consistent with the other components of the assimilation system, and provides new information on horizontal pressure gradients. Comparisons between analyses obtained with and without trajectory assimilation suggest that trajectory assimilation can impact on the description of boundary currents and their instabilities, as well as mesoscale activity at regional scales. Changes are depicted by intermediate water mass redistributions, mesoscale eddy relocations and net transport modulations. These impacts are detailed and assessed considering historical and simultaneous in-situ datasets. The results motivate the integration of ARGO trajectories in the operational Mediterranean Forecasting System

Comparative assessment of in vitro and in silico methods for aerodynamic characterization of powders for inhalation

In vitro assessment of dry powders for inhalation (DPIs) aerodynamic performance is an inevitable test in DPI development. However, contemporary trends in drug development also implicate the use of in silico methods, e.g., computational fluid dynamics (CFD) coupled with discrete phase modeling (DPM). The aim of this study was to compare the designed CFD-DPM outcomes with the results of three in vitro methods for aerodynamic assessment of solid lipid microparticle DPIs. The model was able to simulate particle-to-wall sticking and estimate fractions of particles that stick or bounce off the inhaler’s wall; however, we observed notable differences between the in silico and in vitro results. The predicted emitted fractions (EFs) were comparable to the in vitro determined EFs, whereas the predicted fine particle fractions (FPFs) were generally lower than the corresponding in vitro values. In addition, CFD-DPM predicted higher mass median aerodynamic diameter (MMAD) in comparison to the in vitro values. The outcomes of different in vitro methods also diverged, implying that these methods are not interchangeable. Overall, our results support the utility of CFD-DPM in the DPI development, but highlight the need for additional improvements in these models to capture all the key processes influencing aerodynamic performance of specific DPIs

Integration of ARGO trajectories in the Mediterranean Forecasting System and impact on the regional analysis of the Western Mediterranean circulation

The impact of ARGO trajectory assimilation on the quality of ocean analyses is studied by means of an operational oceanographic model implemented in the Mediterranean Sea and a 3D-var assimilation scheme. For the first time, both ARGO trajectories and vertical profiles together with satellite data are assimilated to produce analyses for short term forecasts. The study period covers three months during winter 2005 when four ARGO trajectories were present in the northwestern Mediterranean Sea. It is shown that their integration is consistent with the other components of the assimilation system, and it contributes to refine the model error structure with new information on horizontal pressure gradients. So the analysis benefits of a more accurate description of the boundary currents and their instabilities that drive the mesoscale activity of regional circulations. As a consequence, the trajectory assimilation remotely and significantly influences the basin scale circulation. Changes can be depicted by intermediate water mass redistributions, mesoscale eddy relocations or net transports modulations. These impacts are detailed and assessed considering historical and contemporary datasets. The obtained qualitative and quantitative agreements motivate the integration of ARGO trajectories in the operational Mediterranean Forecasting System

Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors

Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR

Mediterranean Sea large-scale low-frequency ocean variability and water mass formation rates from 1987 to 2007: A retrospective analysis

We describe a synthesis of the Mediterranean Sea circulation structure and dynamics from a 23-year- long reanalysis of the ocean circulation carried out by Adani et al. (2011). This mesoscale permitting dynamical reconstruction of past ocean variability in the Mediterranean Sea allows the study of the time-mean circulation and its low frequency, decadal, components. It is found that the time-mean circu- lation is composed of boundary and open ocean intensified jets at the border of cyclonic and anticyclonic gyres. The large scale basin circulation is generally characterized in the northern regions by cyclonic gyres and in its southern parts by anticyclonic gyres and eddy-dominated flow fields, with the exception of the Tyrrhenian and the northern Ionian Sea. The time-mean Tyrrhenian Sea circulation is dominated by cyclonic gyres of different intensity and intermittency. The northern Ionian Sea circulation, however, reverses in sign in two ten-year periods, the first in 1987–1996 and the second in 1997–2006, which is here called the Northern Ionian reversal phenomenon. This reversal is provoked by the excursion of the Atlantic-Ionian Stream from the middle to the northern parts of the basin. The decadal variability of other parts of the basin is characterized by changes in strength of the basin scale structures. The water mass formation rates and variability are dominated by event-like periods where the intermediate and deep waters are formed for 2–3 years at higher rates. The largest deep water formation events of the past 23 years occurred separately in the western and eastern Mediterranean basin: the first coincided with the Eastern Mediterranean Transient (Roether et al., 1996) and the second with the western Mediterranean deep water formation event in 2005–2006 (Smith et al., 2008). A new schematic of the basin-scale circu- lation is formulated and commented.Published318-3324A. Oceanografia e climaJCR Journa

High motor variability in DYT1 dystonia is associated with impaired visuomotor adaptation.

For the healthy motor control system, an essential regulatory role is maintaining the equilibrium between keeping unwanted motor variability in check whilst allowing informative elements of motor variability. Kinematic studies in children with generalised dystonia (due to mixed aetiologies) show that movements are characterised by increased motor variability. In this study, the mechanisms by which high motor variability may influence movement generation in dystonia were investigated. Reaching movements in the symptomatic arm of 10 patients with DYT1 dystonia and 12 age-matched controls were captured using a robotic manipulandum and features of motor variability were extracted. Given that task-relevant variability and sensorimotor adaptation are related in health, markers of variability were then examined for any co-variance with performance indicators during an error-based learning visuomotor adaptation task. First, we confirmed that motor variability on a trial-by-trial basis was selectively increased in the homogenous and prototypical dystonic disorder DYT1 dystonia. Second, high baseline variability predicted poor performance in the subsequent visuomotor adaptation task offering insight into the rules which appear to govern dystonic motor control. The potential mechanisms behind increased motor variability and its corresponding implications for the rehabilitation of patients with DYT1 dystonia are highlighted

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

INTRODUCTION: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. METHODS: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. RESULTS: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. DISCUSSION: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD