The increasing presence of cyanotoxin producers in several regions of the world is hazardous for humans and animals. Cylindrospermopsin (CYN) is nowadays recognized as a widely distributed freshwater ...cyanobacterial toxin. This toxin has been shown to induce protein synthesis inhibition as well as inhibition of glutathione synthesis. Given that the liver seems to be the main target of cylindrospermopsin, in this work we used cultures of primary rat hepatocytes to study the type of cell death induced by CYN nanomolar concentrations. The involvement of reactive oxygen species in toxin induced cell death, the relationship between protein synthesis inhibition and toxicity, and the cell endogenous antioxidant response regulation were studied. We show that cylindrospermopsin induces apoptosis in primary rat hepatocytes. At the concentrations used in this work, protein synthesis inhibition and oxidative stress were involved in the cytotoxic effect elicited by the toxin. Finally, activation of the cell antioxidant response was observed at the transcriptional and translational levels.
This paper is presenting a driver behaviour investigation conducted within the framework of ISi-PADAS (Integrated Human Modelling and Simulation to support Human Error Risk Analysis of Partially ...Autonomous Driver Assistance Systems) FP7 European Project (September 2008–September 2011). This research has been developed at an initial phase of the project to support the conception of a new driver assistance system, aimed at improving longitudinal driving by means of information, warning and intervention strategies. In this research, the contribution to the system conception is based on providing a knowledge base of driver behaviour through the conduction of simulator experiments. In particular, this paper is aimed at providing a thorough description of the rationale behind the investigation, as well as at describing the methodology and the procedure used for the experiments conduction. Moreover, the main results achieved through this research and how these results are linked to the modelling phase inside the ISi-PADAS project, are covered within this paper.
Objectives Shift work that involves circadian disruption has been associated with a higher cancer risk. Most epidemiological studies to date have focused on breast cancer risk and evidence for other ...common tumors is limited. We evaluated the risk for colorectal cancer (CRC) in relation to shift work history in a population-based case–control study in Spain. Methods This analysis included 1626 incident CRC cases and 3378 randomly selected population controls of both sexes, enrolled in 11 regions of Spain. Sociodemographic and lifestyle information was assessed in face-to-face interviews. Shift work was assessed in detail throughout lifetime occupational history. We estimated the risk of colon and rectal cancer associated with rotating and permanent shift work (ever, cumulative duration, age of first exposure) using unconditional logistic regression analysis adjusting for potential confounders. Results Having ever performed rotating shift work (morning, evening and/or night) was associated with an increased risk for CRC odds ratio (OR) 1.22, 95% confidence interval (95% CI) 1.04–1.43, as compared to day workers. Having ever worked permanent night shifts (≥3 nights/month) was not associated with CRC risk (OR 0.79, 95% CI 0.62–1.00). OR increased with increasing lifetime cumulative duration of rotating shift work (P-value for trend 0.005) and were highest among subjects in the top quartiles of exposure (3rd quartile, 20–34 years, OR 1.38, 95%CI 1.06–1.81; 4th quartile, ≥35 years, OR 1.36, 95% CI 1.02–1.79). Conclusions These data suggest that rotating shift work may increase the risk of CRC especially after long-term exposures.
Crambescins are guanidine alkaloids from the sponge
Crambe crambe
. Crambescin C1 (CC) induces metallothionein genes and nitric oxide (NO) is one of the triggers. We studied and compared the
in vitro
...,
in vivo, and in silico
effects of some crambescine A and C analogs. HepG2 gene expression was analyzed using microarrays. Vasodilation was studied in rat aortic rings.
In vivo
hypotensive effect was directly measured in anesthetized rats. The targets of crambescines were studied
in silico
. CC and homo-crambescine C1 (HCC), but not crambescine A1 (CA), induced metallothioneins transcripts. CC increased NO production in HepG2 cells. In isolated rat aortic rings, CC and HCC induced an endothelium-dependent relaxation related to eNOS activation and an endothelium-independent relaxation related to iNOS activation, hence both compounds increase NO and reduce vascular tone.
In silico
analysis also points to eNOS and iNOS as targets of Crambescin C1 and source of NO increment. CC effect is mediated through crambescin binding to the active site of eNOS and iNOS. CC docking studies in iNOS and eNOS active site revealed hydrogen bonding of the hydroxylated chain with residues Glu377 and Glu361, involved in the substrate recognition, and explains its higher binding affinity than CA. The later interaction and the extra polar contacts with its pyrimidine moiety, absent in the endogenous substrate, explain its role as exogenous substrate of NOSs and NO production. Our results suggest that CC serve as a basis to develop new useful drugs when bioavailability of NO is perturbed.
In regions with slow‐moving faults, the incompleteness of earthquake and fault data complicates the study of seismic hazard. The instrumental and historical seismic catalogs cover a short period ...compared with the long‐time interval between major events. Paleoseismic evidence allows us to increase the time frame of actual observations, but data is still scarce and imprecise. Physics‐based earthquake simulations overcome the limitations of actual earthquake catalogs and generate long‐term synthetic seismicity. The RSQSim earthquake simulator used in our study reproduces the earthquake physical processes based on a 3D fault model that contains the kinematics, the long‐term slip rates and the rate‐and‐state friction properties of the main seismogenic sources of a region. The application of earthquake simulations to the Eastern Betic Shear Zone, a slow fault system at southeastern Spain, allows the compilation of 100 kyr‐synthetic catalogs of MW > 4.0 events. Multisection earthquakes and complete ruptures of some faults in this region, preferentially on strike‐slip dominant ruptures, are possible according to our simulations. The largest MW > 6.5 events are likely as a result of jumping ruptures between the Carboneras and the Palomares faults, with recurrence times of < 20,000 years; and less frequently between the Alhama de Murcia and the Los Tollos faults. A great variability of interevent times is observed between successive synthetic seismic cycles, in addition to the occurrence of complex co‐ruptures between faults. Consequently, the occurrence of larger earthquakes, even MW ≥ 7.0, cannot be ruled out, contrasting with the low to moderate magnitudes recorded in the instrumental and historical earthquake catalog.
Key Points
The RSQSim earthquake simulator reproduces a realistic 100 kyr synthetic catalog of MW > 4.5 events based on a slow fault system
Large earthquakes, even MW ≥ 7.0, and complex multifault ruptures are possible despite their nonoccurrence in historical times
The synthetic seismic cycles have variable interseismic time periods, so the different time frames should be considered in hazard studies
In this paper, we show the effect of crambescidin-816, -800, and -830 on Saccharomyces cerevisiae viability. We determined that, of the three molecules tested, crambescidin-816 was the most potent. ...Based on this result, we continued by determining the effect of crambescidin-816 on the cell cycle of this yeast. The compound induced cell cycle arrest in G2/M followed by an increase in cell DNA content and size. When the type of cell death was analyzed, we observed that crambescidin-816 induced apoptosis. The antifungal effect indicates that crambescidins, and mostly crambescidin-816, could serve as a lead compound to fight fungal infections.
The FP7 EU project ISi-PADAS (Integrated Human Modelling and Simulation to support Human Error Risk Analysis of Partially Autonomous Driver Assistance Systems) endeavours to conceive an intelligent ...system called PADAS (Partially Autonomous Driver Assistance System) for aiding human drivers in driving safely by providing them with pertinent and accurate information in real time about the external situation and by acting as a co-pilot in emergency conditions. The system interacts with the driver through a Human–Machine Interface (HMI) installed on the vehicle using an adequate Warning and Intervention Strategy (WIS). In this paper, the design of the PADAS HMI as well as a decision-theoretic approach for deriving an optimal WIS are described.
Classical models of fault rock architecture point to a relatively simple and symmetric architecture of a fault zone, where the fault core is a narrow foliated cataclasite (few centimeters) bounded by ...a thick damage zone developed cutting through host rocks. Those models are far from the studied fault rocks developed in the Alhama de Murcia Fault (AMF), SE Spain, where fault core is in contact with an almost no deformed hosting rock at one side and to a wide damage zone towards the opposite boundary. The AMF is an active shear zone and the source of destructive recent and historical earthquakes. It has more than 10 km accumulated slip, and it develops a more than 100 meters wide shear zone with fault rocks that have been continuously sampled and analyzed combining a drill core from a 174 m deep vertical borehole, six trenches excavation, and outcrop surfaces cleaning. Hand specimen and microanalyses were used to classify the fault rock in deformation domains in a strongly heterogeneous shear zone according to its lithologies and structural features. It ranges from 10 to 30 meters wide fault core, where steady strain occurs, to an intensely deformed damage zone where strain is concentrated along discrete gouge bands. Trenching also showed a surface rupture that offsets Arabic archaeological remains related to the 1674 catastrophic event occurred in Lorca (Murcia). Steady homogeneous deformation was found in the areas closest to the hanging wall, in the fault core, where Lower Paleozoic Schists are the protolith of ultrafault gouges. As deformation increased, the shear zone involved Permian-Triassic basement rocks and Miocene sedimentary rocks in heterogeneous deformation domains. In the lower domains, strain is located in anastomosing shear bands which are spatially related with a surface seismic rupture of the 1674 destructive earthquake.
Determination of the targets of a compound remains an essential aspect in drug discovery. A complete understanding of all binding interactions is critical to recognize in advance both therapeutic ...effects and undesired consequences. However, the complete polypharmacology of many drugs currently in clinical development is still unknown, especially in the case of G protein‐coupled receptor (GPCR) ligands. In this work we have developed a chemoproteomic platform based on the use of chemical probes to explore the target profile of a compound in biological systems. As proof of concept, this methodology has been applied to selected ligands of the therapeutically relevant serotonin 5‐HT1A and 5‐HT6 receptors, and we have identified and validated some of their off‐targets. This approach could be extended to other drugs of interest to study the targeted proteome in disease‐relevant systems.
Target profile: Determination of the targets of a compound remains an essential aspect in drug discovery. Probes based on 5‐HT1A and 5‐HT6 serotonin receptor ligands reveal additional sites of action of these compounds (see figure).
In vivo, after administration by gavage to mice and rats, okadaic acid has been reported to produce lesions in liver, small intestine and forestomach. Because several reports differ in the damage ...detected in different organs, and on okadaic acid distribution after consumption, we determined the toxicity of this compound after oral administration to mice. After 24 hours, histopathological examination showed necrotic foci and lipid vacuoles in the livers of intoxicated animals. By immunohistochemical analysis, we detected this toxin in the liver and kidneys of intoxicated animals. Okadaic acid induces oxidative stress and can be activated in vitro into reactive compounds by the post-mitochondrial S9 fraction, so we studied the okadaic effect on the gene expression of antioxidant and phase II detoxifying enzymes in liver. We observed a downregulation in the expression of these enzymes and a reduction of protein expression of catalase and superoxide dismutase 1 in intoxicated animals.
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