Search

Enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Venous thrombosis and thromboembolism risks are associated with increased plasma levels of TAFI (Thrombin Activatable Fibrinolysis Inhibitor) as well as its active form TAFIa. A new TAFIa inhibitor, namely S62798 has been identified. Its ability to enhance fibrinolysis was investigated both in vitro and in vivo in a mouse model of pulmonary thromboembolism, as well as its effect on bleeding. S62798 is a highly selective human, mouse and rat TAFIa inhibitor (IC 50 = 11; 270; 178 nmol/L, respectively). It accelerates lysis of a human clot in vitro , evaluated by thromboelastometry (EC 50 = 27 nmol/L). In a rat tail bleeding model, no effect of S62798 treatment was observed up to 20 mg/kg. Enhancement of endogenous fibrinolysis by S62798 was investigated in a mouse model of Tissue Factor-induced pulmonary thromboembolism. Intravenous administration of S62798 decreased pulmonary fibrin clots with a minimal effective dose of 0.03 mg/kg. Finally, effect of S62798 in combination with heparin was evaluated. When treatment of heparin was done in a curative setting, no effect was observed whereas a significantly decreased pulmonary fibrin deposition was observed in response to S62798 alone or in combination with heparin. This study demonstrates that S62798 is a potent TAFIa inhibitor with minimal risk of bleeding. In vivo , curative S62798 intravenous treatment, alone or associated with heparin, accelerated clot lysis by potentiating endogenous fibrinolysis and thus decreased pulmonary fibrin clots. S62798 is expected to be a therapeutic option for pulmonary embolism patients on top of anticoagulants. • Venous thrombosis is associated with increased activity of fibrinolysis inhibitors. • Inhibition of TAFIa improves endogenous fibrinolysis. • TAFIa inhibition has no impact on bleeding. • TAFIa inhibition accelerates in vivo thrombus lysis. [ABSTRACT FROM AUTHOR]

Phytoplankton productivity (PP) is expected to be impacted by climate change and anthropogenic activity in freshwater ecosystems, but the effects and interactions of these environmental stressors are often complex and not clearly understood. In this research, we investigated the influences of climate change and human activity on changes in PP recorded by sedimentary organic geochemical proxies (including bulk properties, Rock-Eval parameters, n -alkanols, and sterols) in the Pearl River Delta of southern China over the past few decades. Multiple proxies suggested that PP has increased in the mesotrophic Lian'an reservoir (LA) and the eutrophic Liuhuahu lake (LHH) since the 1960s. Phytoplankton sterols revealed that the dominant algal community consisted of dinoflagellates, cyanobacteria, and green algae in LA, while cyanobacteria and green algae were the primary algae groups in LHH. Phytoplankton proxies exhibited significant positive correlation with rising temperature (r > 0.57, p < 0.05) and nutrient loadings (r > 0.80, p < 0.01), suggesting that climate warming and nutrient input have contributed to the variations in PP. Climate change has caused a rise in temperature and changes in precipitation, along with human activity such as agriculture, dam construction, and sewage input, have collectively impacted aquatic environments. The generalized additive model (GAM) was used to quantitatively analyze the impacts of climate change and anthropogenic activity on aquatic ecosystems. Results demonstrated the cumulative and synergistic effects of climate change and anthropogenic activity, and higher climatic influences observed after the 1990s. The synergistic effects led to algal blooms and restricted the growth of aquatic macrophytes, particularly in the eutrophic LHH. This has worsened eutrophication and resulted in an imbalance in aquatic ecosystems. In summary, this research emphasizes the interactions between climate change and anthropogenic activity, and PP variations in aquatic ecosystems and underscores the importance of studying these factors to comprehend the influence of environmental stressors. • The phytoplankton productivity (PP) variations were traced by organic geochemical proxies. • Aquatic PP increased as a result of climate change and anthropogenic activity. • Generalized additive model quantified the climate and human impacts on aquatic ecosystems. • The effects of environmental factors resulted in algal blooms and species imbalance. [ABSTRACT FROM AUTHOR]

Nonylphenol (Noph) has garnered worldwide concern as a typical endocrine disruptor due to its toxicity, estrogenic properties, and widespread contamination. To better elucidate the interaction of Noph with ubiquitously existing microplastics (MPs) and the potential interdependence of their transport behaviors, batch adsorption and column experiments were conducted, paired with mathematical modeling. Compared with sand, MPs and soil colloids show stronger adsorption affinity for Noph due to the formation of hydrogen bonding and the larger numbers of interaction sites that are available on solid surfaces. Limited amount of soil-colloid coating on sand grains significantly influenced transport behaviors and the sensitivity to solution chemistry. These coatings led to a monotonic increase in Noph retention and a nonmonotonic MPs retention in single systems because of the altered physicochemical properties. The mobility of both MPs and Noph was enhanced when they coexisted, resulting from their association, increased electrostatic repulsion, and competition on retention sites. Limited release of MPs and Noph (under reduced ionic strength (IS) and increased pH) indicated strong interactions in irreversible retention. The retention and release of Noph were independent of IS and solution pH. A one-site model with a blocking term and a two-site kinetic model well described the transport of MPs and Noph, respectively. Our findings highlight the essential roles of coexisting MPs and Noph on their transport behaviors, depending on their concentrations, IS, and physicochemical properties of the porous media. The new knowledge from this study refreshes our understanding of the co-transport of MPs and organic contaminants such as Noph in the subsurface. [Display omitted] • The coexistence of nonylphenol (Noph) and microplastic (MP) facilitates their transport. • Soil colloids differentiate the trends of Noph/MP retention to ionic strength (IS). • Physicochemical heterogeneity from soil colloids highly influences Noph/MP transport. • MP transport is highly associated with Noph, IS, and collector surface roughness. • ●Irreversibly retention occurred for Noph and the release is independent of IS/pH. [ABSTRACT FROM AUTHOR]

Background: Bipolar voltage mapping has a role in defining endocardial-based scar in postinfarct patients undergoing ventricular tachycardia catheter ablation. The utility of bipolar and unipolar voltages in characterizing scar has not been evaluated in patients with nonischemic cardiomyopathy. Objective: To relate left ventricular (LV) endocardial bipolar and unipolar voltages in these patients to scar transmurality (endocardial vs nonendocardial) and composition (homogeneous core vs heterogeneous gray). Methods: Ten consecutive cardiomyopathy patients undergoing endocardial LV tachycardia ablation were included (age 48 ± 14 years; left ventricular ejection fraction 43% ± 15%). Preablation late gadolinium-enhanced magnetic resonance imaging was used to quantify core and gray scar by using signal-intensity thresholding. Electroanatomic LV endocardial mapping provided bipolar and unipolar voltages. Electroanatomic maps and late gadolinium-enhanced magnetic resonance imaging were rigidly registered in order to relate voltage to scar (registration error 3.6 ± 2.9 mm). Results: Bipolar voltage was lower in endocardial core than in no scar (P <.001). Unipolar voltage was lower in endocardial core and nonendocardial core than in no scar (P <.001). Endocardial and nonendocardial gray scar had an effect similar to that of core in reducing bipolar and unipolar voltages (P <.001). The mass of healthy myocardium and endocardial core scar independently predicted bipolar and unipolar voltages using general estimating equation modeling. With receiver operating characteristic curve analysis, bipolar voltage >1.9 mV and unipolar voltage <6.7 mV had a high negative predictive value (91%) for detecting nonendocardial scar from either endocardial scar or no scar. Conclusions: In patients with nonischemic cardiomyopathy, LV endocardial bipolar voltage is dependent on endocardial core and gray scar, while the unipolar voltage is influenced by core and gray scar across the LV wall as defined by late gadolinium-enhanced magnetic resonance imaging. [Copyright &y& Elsevier]

Abstract: This paper presents two case studies in which the use of full field measurements could provide valuable information to allow the development of R&D methods having the potential of assessing industrial issues.The first example is related to the study of the fracture properties of the nuclear fuel rods after a postulated Loss of Coolant Accident (LOCA) event. It will be shown that 3-D Digital Image Correlation strain measurements performed on a non-conventional mechanical test (expansion due to compression) can help to assess failure properties and derive fracture criteria of highly oxydized and hydrided Zircaloy cladding. These fracture criteria are therefore used in the Safety Demonstrations due conducted by EDF in reply to the French Safety Authority.The second example is related to the investigation of potentially brittle failure of an irradiation aged nuclear reactor pressure vessel (RPV) during a Loss of Coolant Accident event. As a matter of fact, the reactor pressure vessel is one of the non replaceable components of a nuclear power plant. Consequently, the study of the RPV ageing is of major importance for assessing plants lifetime. One consequence of the RPV ageing is the increasing risk of brittle fracture during postulated LOCA events. As a first step to better characterize experimentally the embrittlement of RPV steel, the second example presents in-situ strain heterogeneities in the plastic response of bainitic-ferritic 16MND5 steel, with respect to crystalline phases and orientations. These local observations are then used by a specific identification procedure, in order to obtain experimentally the crystal plasticity hardening flow behaviour of RPV steel. [Copyright &y& Elsevier]

Abstract: Thepresentworkinvestigatesthemechanicalresponseofapolycrystallineaggregatebythecombineduseof3DX-raydiffractioncontrasttomography(DCT)experimentandthefastFouriertransform(FFT)numericalhomogenisationscheme.Themicrostructureofarecrystal-lizedsampleof304LausteniticsteelhasbeencharacterizedwiththeDCTtechniqueatESRF(ID11beamline)whichallowstohaveaccesstothespatialdistributionandtheindividualshapeoftheconstituentgrainstogetherwiththeircrystallineorientati.Toestimatethemechanicalbehaviourofsuchrealpolycrystallinemicrostructure,themostwidelyusedapproachisbasedonthefiniteelementtechniquewhichimpliesatediousandcomplextaskofmeshing.Tocircum-ventthisdifficulty,anattractiveapproachistheFFT-basednumericalschemewhichallowstousethedigitalimageofthemicrostructureasadirectinputtocomputethemechanicalresponseofaheterogenesmaterial.Theefficiencyofthismethodcombinedwithexperimentaltomographicdataisemphasizedandtheelasticandelastic-plasticbehaviorofthepolycrystallinesampleisinvestigated.Comparisonsaremadewithestimatesdeliveredbytheself-consistentapproach,thatrelyonpartialinformationonthemicrostructure,andfirstorderbounds [Copyright &y& Elsevier]

Abstract: Scanning acoustic microscopy (SAM) provides high-resolution mapping of acoustic impedance related to tissue stiffness. This study investigates changes in tissue acoustic impedance resulting from mechanical loading in trabecular bone cores cultured in 3-D bioreactor. Trabecular bone cores were extracted from bovine sternum (n = 15) and ulna metaphysis (n = 15). From each bone, the samples were divided in three groups. The basal control (BC) group was fixed post-extraction, the control (C) and loaded (L) groups were maintained as viable in a controlled culture-loading cell over three weeks. Samples of L group underwent a dynamic compressive strain, whereas C samples were left free from loading. After three weeks, L and C samples were embedded in polymethylmethacrylate and all samples were explored with a 200-MHz SAM. For each specimen, the acoustic impedance distribution was obtained over flat and polished section of bone blocks prepared parallel to the loading axis. Our results showed that in basal controls, the acoustic impedance varied with bone anatomical location and was 15% higher in weight-bearing ulna compared with nonweight-bearing sternum. The comparison between loaded and nonloaded groups showed that sternum-only exhibited significant change in acoustic impedance (L vs. C sternum: +9%). This result suggests that when the applied load is comparable with the stress naturally experienced by a weight-bearing bone (ulna), the tissue material properties (manifested by acoustic impedance) remained unchanged. In conclusion, SAM is a potentially relevant tool for the assessment of subtle changes in intrinsic microelastic properties of bone induced by adaptive remodeling process in response to mechanical loading. (E-mail: amena.saied@upmc.fr) [Copyright &y& Elsevier]

Abstract: The increased risk of thrombotic events associated with disease states such as diabetes and hypertension has been correlated with elevated circulating levels of Plasminogen Activator Inhibitor type-1 (PAI-1). In the present study we evaluate the benzothiophene derivative S35225 in comparison with two recently described inhibitors of PAI-1 activity Tiplaxtinin and WAY140312 on a panel of PAI-1 activity assays in vitro and in vivo. In a direct chromogenic assay, S35225 has an IC50 value of 44±0.9 μM similar to that of Tiplaxtinin (34±7 μM) and of WAY140312 (39±1 μM). In a clot lysis assay however, S35225 has a significantly lower IC50 value than Tiplaxtinin and WAY140312 (0.6±0.3 versus 22±5 and 16±2 μM respectively). Using a tPA capture assay to quantify active PAI-1 in rat or human plasma, neither WAY140312, nor Tiplaxtinin attained 50% inhibition of PAI-1 activity at the highest concentration tested (1 mM); S35225 has an IC50 value of 194±30 μM against active rat PAI-1 and 260±41 μM against active human PAI-1. The ability of the compounds to inhibit endogenous active PAI-1 in the rat following intravenous administration was also tested using the tPA capture assay. Only S35225 reduced circulating active PAI-1 levels in vivo (maximum inhibition of 76±5% at 10 mg/kg and 53±5% at 3 mg/kg). In contrast to Tiplaxtinin and WAY140312, S35225 is a direct inhibitor of PAI-1 activity in vitro in rat and human plasmas where vitronectin is constitutively present as well as in vivo in the blood after an intravenous administration in the rat. [Copyright &y& Elsevier]

Abstract: In statistical process control (SPC) methodology, quantitative standard control charts are often based on the assumption that the observations are normally distributed. In practice, normality can fail and consequently the determination of assignable causes may result in error. After pointing out the limitations of hypothesis testing methodology commonly used for discriminating between Gaussian and non-Gaussian populations, a very flexible family of statistical distributions is presented in this paper and proposed to be introduced in SPC methodology: the generalized lambda distributions (GLD). It is shown that the control limits usually considered in SPC are accurately predicted when modelling usual statistical laws by means of these distributions. Besides, simulation results reveal that an acceptable accuracy is obtained even for a rather reduced number of initial observations (approximately a hundred). Finally, a specific user-friendly software have been used to process, using the SPC Western Electric rules, experimental data originating from an industrial production line. This example and the fact that it enables us to avoid choosing an a priori statistical law emphasize the relevance of using the GLD in SPC. [Copyright &y& Elsevier]

The inducible form of nitric oxide synthase (iNOS) is present in advanced atherosclerotic lesions. The aim of the present paper was to compare the functionality of iNOS in rabbits fed a 0.3% cholesterol-diet for 24 weeks (Baseline), and 36 weeks, with l-arginine (l-Arg) or vehicle supplementation (Saline) for the last 12 weeks. N-iminoethyl-l-lysine (l-NIL; 10 μM), a selective inhibitor of iNOS, potentiated the contractions to phenylephrine in aortas from Baseline, Saline and l-Arg rabbits confirming the presence of a functional iNOS. In l-Arg rabbits, the contractions induced by l-NIL were less pronounced than those noted in Baseline and Saline rabbits; superoxide dismutase (150 U/ml) significantly increased the phenylephrine-induced contractions only in the l-Arg rabbits. In the presence of NADPH, aortas from l-Arg rabbits produced more superoxide anions than aortas from saline rabbits as evidenced by the lucigenin-enhanced chemiluminescence technique. In conclusion, our results show functional and biochemical evidence for an increased superoxide anion production in atherosclerotic aortas from hypercholesterolemic rabbits treated with l-Arg for 12 weeks. These data may thus help to explain the lack of beneficial effects of l-Arg on atherosclerosis progression in long-term experimental hypercholesterolemia as well as in severely atherosclerotic humans. [Copyright &y& Elsevier]

Ischemic heart disease is the most common cause of death in patients with chronic kidney disease (CKD). Patients with CKD who develop an acute coronary syndrome (ACS) have a poor prognosis, with >70% mortality at 2 years. Despite this heavy burden of disease, the optimal management of ACS in this patient population is unknown. Our goal was to compare the effect of coronary revascularization or medical therapy alone on the long-term survival of patients with CKD presenting with ACS. From 1990 to 1998, data were prospectively collected on 4,758 patients admitted to a coronary care unit with the diagnosis of ACS. Of these, 3,104 had preserved renal function, and 1,654 had significant renal dysfunction, as defined by the National Kidney Foundation in the Kidney Disease Outcomes Quality Initiative classification of kidney function as an estimated glomerular filtration rate of <60 ml/min/1.73 m2. Long-term survival was assessed and outcomes were compared according to whether patients were treated with medical therapy alone or if they underwent a percutaneous or surgical revascularization procedure. Follow-up information was available in 99% of the patients up to 8 years after the index hospitalization. Of the 1,654 patients with significant renal dysfunction, 64 underwent coronary artery bypass surgery, 232 underwent percutaneous coronary revascularization, 280 underwent a diagnostic cardiac catheterization and were subsequently treated medically, whereas 1,078 were treated with medical therapy alone. Percutaneous coronary revascularization was associated with superior long-term survival. In conclusion, patients with severe CKD and ACS had improved long-term survival when treated with percutaneous coronary revascularization. [Copyright &y& Elsevier]

Atrial fibrillation (AF) is the most frequent cardiac arrhythmia, which is characterized by a high risk of stroke due to increased thrombogenesis and thrombin formation in poorly contractile atria. In addition to its role in the coagulation cascade, thrombin has pleiotropic effects on cardiovascular system through the activation of protease activated receptor 1 (PAR 1). Here we examined whether thrombin contributes to the atrial myocardial remodeling that occurs during heart failure (HF) and whether direct thrombin inhibitors can prevent this remodeling process and AF progression. The study was conducted in a well established rat model of atrial dilation and susceptibility to AF associated with ischemic HF secondary to myocardial infarction (MI). The endogenous thrombin potential increased in plasma after MI, and remained elevated in HF rats. Treating MI rats for one or two months with direct thrombin inhibitors reduced the area and diameter of left atria. After two months, there was also a reduction of the duration of burst pacing induced AF and a downregulation of the expression of hypertrophic markers such as brain natriuretic peptide and β myosin heavy chain. The transcription factor NFATc3, known to be activated in cardiac hypertrophy, and the plasminogen activator inhibitor 1, which has both thrombotic and fibrogenic activities were also downregulated. Treating rats with a PAR 1 antagonist reproduced the effect of thrombin inhibitors. To study the role of thrombin on atrial myocardium in absence of other cardiac stimuli, atrial explant cultures were performed. In cultured atria, thrombin upregulated hypertrophic markers and plasminogen activator inhibitor 1 through PAR 1 and the Rho/Rho kinase pathway. These results indicate that thrombin is a potent hypertrophic factor for atrial myocardium; they point to chronic inhibition of thrombin/PAR1 pathways as a potential therapeutic option to prevent atrial remodeling and AF substrate formation. The author hereby declares no conflict of interest [ABSTRACT FROM AUTHOR]

In SHR-SP, oxidative stress participates to altered relaxation in response to acetylcholine (ACh) and sodium-nitroprusside (SNP). The aim of this study was to evaluate the effects of the activator of soluble guanylate cyclase (sGC) BAY 58-2667 on SHR-SP in comparison to control Wistar-Kyoto rats (WKY). Aortas from 15 week-old SHRSP and WKY were removed and isometric tension as well as cGMP generation were determined in response to ACh, SNP and BAY 58-2667. After contraction of aortic rings by phenylephrine (10-6 M), the relaxations of SHR-SP rings were smaller in response to ACh (60 % vs. 90 % maximal relaxation, n=15), to SNP (EC50 : 6.4 vs. 0.9nM, n=20) and to BAY 58-2667 (EC50 : 95 vs. 9nM, n=6). In contrast, cGMP generation (in the presence of the PDE inhibitor IBMX, 2mM) caused by 10-8M BAY 58-2667 was not significantly altered in SHR-SP vs. WKY (34¡Ó11 vs. 64¡Ó23 pmol/mg protein, ns t-test, n=7) whereas that caused by 10-5M ACh and 10-6M SNP were significantly smaller (−90 % and −60 % vs. WKY, respectively, p,,T0.05, t-test, n=9). Moreover, the amount of (fÑf¡fyfÒf¡)-sGC subunits, quantified by western-blot, was decreased by 35 % in SHR-SP aorta (n=12). Interestingly, an oral chronic treatment of rats with 1 mg/kg/day of BAY 58-2667 for 5 days (mini-pump Alzet, IP, n=11-13) decreased SHR-SP systolic blood pressure by 15¡Ó4 mmHg, proteinuria by 50¡Ó5 % and was associated with a aortic and urinary cGMP increase (20¡Ó2 vs. 9¡Ó1.3pmol/mg proteins and 11¡Ó1 vs. 7.6¡Ó1.4nmol/24h, respectively, t-test). These results demonstrate that BAY 58-2667 activates sGC in SHRSP aorta, even if the enzyme amount is decreased and suggest the presence of oxidized and/or heme free form of sGC unresponsive to NO in SHR-SP. In conclusion, activators of sGC may constitute an alternative treatment of resistant hypertension associated to vascular complications. [Copyright &y& Elsevier]

The synthesis and activity of novel benzothiophene derivatives are described. In the t-Pa-induced fibrin clot lysis assay, several compounds inhibit the formation of the tPa–PAI-1 complex with submicromolar IC50. This class of compounds potentially represents a new generation of antithrombotic-fibrinolytic agents. [Copyright &y& Elsevier]

In many basins, hydrogen-emitting structures are now observed, but the estimation of the H 2 flow leading to their formation remains poorly constrained since all data show that the H 2 emissions are variable in space and time. We present here the data of a long-term monitoring campaign with a high density of permanent hydrogen detectors installed in 2 structures in the Minas Gerais State (Brazil). Results show that two kinds of signals are recorded, large sporadic pulses that affect the H 2 content of the soil for one or two days and smaller ones, with a daily periodicity, that last 6 h and during which the near surface soil concentration usually does not exceed 200 ppm. This last signal is very regular in frequency, less in amount, and the daily maximum happens around noon or in the early afternoon. We interpret the large pulses as evidences of a deep hydrogen flux, leaking either from a reservoir located in the subsurface, from an aquifer which is degassing or, although it seems unlikely, directly from the H 2 generation area. The time correlation between the pulse and the increase of the daily signal suggests that this last one corresponds to the slow release of the gas that has been captured by the soil during its transport towards the surface. This daily signal is most likely influenced by external factors such as atmospheric pressure and sub-surface bacterial activity. In map view, the lack of correlation between the highest hydrogen concentrations over time suggests that the soil is very heterogeneous and that preferential pathways exist. The results confirm that long-term monitoring, over a few months, is mandatory to catch a certain number of high pulses and so to have a better estimation of the real flow. Data also suggests that sensors with a large concentration range should be used (from 10 to several 104 ppm). Even if quantification of leakage doesn't help to quantify the subsurface reserves, these new data allow a more precise evaluation of the quantity of H 2 released in surface by these structures, few hundred of kilo per day, and confirm the high H 2 prospectivity of this basin. • Large quantities of H 2 are leaking from the Sao Francisco basin. • Few hundred kg of H 2 per day/km2 escape from the emitting structures. • High Pulses are emitted sporadically and part of the H 2 remains trapped in the soil. • Remaining H 2 is then slowly released following daily changes in temperature and pressure. [ABSTRACT FROM AUTHOR]

Abstract Hydrogen escaping from sedimentary basins has already been described in various parts of the world. Some of these leakages have been identified by superficial circular depressions, also called "fairy circles". Gas detection measurements, randomly repeated after a few months have shown that the amount of hydrogen present in soils is not constant neither versus time nor versus position in a given structure. Permanent monitoring gas analyzers were installed in the ground to estimate hydrogen flow outgassing from a topographical circular depression located in Brazil. Data show that a hydrogen flux occurs during the hottest moment of the day, as shown with permanent sensors set at a regular spacing. The process may look like a soil evaporation. In that same structure, other detectors show much higher and irregular gas output which present an unclear correlation as a function of ambient temperature and atmospheric pressure. The relationship with temperature suggests a role of water saturation driving the overall hydrogen fluxes. The reported geochemical data imply that (1) one measurement taken at a given hour on a structure cannot be considered as quantitative, as it varies too much with time and is also probably related to the soil perturbation induced by the shallow drilling, (2) hydrogen released through the soils of the studied structure is recharged daily, (3) hydrogen flux is high enough to reach the surface without being buffered by water or bacterial activity within the soil and (4) soil cannot be solely considered as a hydrogen sink but also, at least in some areas, as a hydrogen emitter. This appears to highlight that the subsurface may be considered in this site as a source of natural hydrogen, clearly differentiated from a biochemical system of atmospheric H 2 consumed by bacteria. Highlights • Hydrogen monitoring of a continental circular structure in sediments. • Periodicity of hydrogen seeping out of the soils. • Soil in the studied area is a hydrogen emitter and not a hydrogen sink. • Daily periodicity of hydrogen leakage out of the ground. • Tentative estimate of hydrogen flux in a continental area. [ABSTRACT FROM AUTHOR]

Black phosphorus nanosheets/nanoparticles (BPNs) are widely applied in many fields. However, the transport of BPNs in the subsurface still has not yet been reported and there is increasing concern about potential adverse impacts on ecosystems. Roles of median grain size and surface roughness, BPN concentration, and solution chemistries (pH, ionic strength, and cation types) on the retention and release of BPNs in column experiments were therefore investigated. The mobility of BPNs significantly increased with increasing grain size and decreasing surface roughness due to their influence on the mass transfer rate, number of deposition sites and retention capacity, and straining processes. Transport of BPNs was enhanced with an increase in pH and a decrease in ionic strength because of surface deprotonation and stronger repulsion that tends to reduce aggregation. The BPN transport was significantly sensitive to ionic strength, compared with other engineered nanoparticles. Additionally, charge heterogeneity and cation-bridging played a critical role in the retention of BPNs in the presence of divalent cations. Higher input concentrations increased the retention of BPNs, probably because collisions, aggregation at pore throat locations, and hydrodynamic bridging were more pronounced. Small fractions of BPNs can be released under decreasing IS and increasing pH due to the expansion of the electrical double layer and increased repulsion at convex roughness locations. A mathematical model that includes provisions for advective dispersive transport and time-dependent retention with blocking or ripening terms well described the retention and release of BPNs. These findings provide fundamental information that helps to understand the transport of BPNs in the subsurface environments. [Display omitted] • Transport of black phosphorus nanoparticles (BPNs) is sensitive to environmental factors. • Increased ionic strength/roughness and decreased grain size/pH increase retention. • The Ca2+ increases aggregation, charge heterogeneity and cation bridging for BPNs. • Larger C o increases retention via collisions, faster aggregation on surfaces, and bridging. • The BPN release is limited and associated with shallow primary minimum at convex site. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Plasminogen Activator Inhibitor-1 (PAI-1) is the most potent endogenous inhibitor of fibrinolysis which is implicated in the pathogenesis of myocardial infarction and metabolic syndrome. The formation of reactive oxygen species (ROS) plays an important role in the pathology of vascular disorders and has been shown to increase PAI-1 expression by endothelial cells. Growing evidence indicates that NADPH oxidase and in particular the constitutively active Nox4-p22phox complexes are major sources of ROS in endothelial cells. The aim of the present study was to characterize the role of NADPH oxidase and in particular Nox4 in the regulation of PAI-1 expression in cultured Human Umbilical Venous Endothelial Cells (HUVECs). Methods and Results: N-acetylcysteine (NAC, scavenger of ROS), diphenylene iodonium chloride (DPI, inhibitor of flavoproteins), M40403 (superoxyde dismutase mimic) and S17834 (inhibitor of NADPH oxidase) inhibited PAI-1 release and promoter activity in HUVECs. Specific knock down of Nox4 mRNA by siRNA caused a decrease in ROS production and NADPH oxidase activity. Moreover, Nox4 silencing decreased PAI-1 expression, release and activity as well as p38 MAPK pathways and NFκB activation. These signalling pathways are also involved in PAI-1 release. Conclusions: The NADPH oxidase inhibitors DPI and S 17834 as well as Nox4 silencing decreased PAI-1 synthesis in human cultured endothelial cells demonstrating the involvement of the constitutively active Nox4-containing NADPH oxidase in ROS-mediated PAI-1 transcription via p38 MAPK pathways. NADPH oxidase targeting with inhibitors such as S17834 could be an interesting strategy to decrease both oxidative stress and PAI-1 synthesis. [Copyright &y& Elsevier]

Abstract: The 1,5-benzothiazepine-4-one scaffold was earlier shown to provide efficient protease inhibitors. In this contribution, we describe its use in the design of factor VIIa/tissue factor inhibitors. A series containing a scaffold non-substituted on its aryl part led to compound 20 with an IC50 of 2.16μM. Following molecular modelling studies of this compound, a second series was prepared, which necessitated the synthesis of protected 7- or 8-substituted 1,5-benzothiazepine-4-one derivatives. [Copyright &y& Elsevier]

Abstract: A series of urea analogues related to SA6817 and a GSK phosphonic acid with reported ACE inhibitory activity were prepared and tested for dual ACE and ECE activities. Although excellent ACE and NEP inhibition was achieved, only modest ECE inhibition was observed with one analogue. [Copyright &y& Elsevier]

Abstract: Dealing with fatigue lifetime prediction, this paper aims to report on a new statistical method combining the Lambda Distributions and the Bootstrap technique. This method is first applied for determining the Probability Density Function (PDF) of the C and n coefficients in the Paris relationship of a fatigue crack propagation curve. Then, introducing the initial crack''s length distribution, the fatigue lifetime prediction is obtained and discussed considering various standard deviations of the initial crack''s length. It is shown that the scattering of the initial crack''s length needs to be taken into account in predicting lifetime, and that the stochastic nature of the crack''s propagation is not self-sufficient to explain completely the experimental asymmetry of the PDF lifetime. This paper shows that the Lambda Distributions are a powerful tool for modelling the PDF lifetime, compared with traditional Gaussian or lognormal PDF. [Copyright &y& Elsevier]

A series of 2-substituted 3,7-dihydroimidazolo[1,2-a]pyrazine-3-ones has been synthesized and evaluated for their antioxidant activity. Compounds 1–8 are inhibitors of AAPH-induced lipid peroxidation (in vitro) and excellent protectors against microvascular damages in ischemia/reperfusion (in vivo). Hence, the bicyclic structure typical of coelenterazine (luciferin) could be considered as a useful lead in medicinal chemistry. [Copyright &y& Elsevier]

Ageing and atherosclerosis (ATH) are well-known risk factors for erectile dysfunction (ED). To identify the mechanisms implicated in ATH-induced ED, independently of its ageing-associated component, we studied (i) erectile responses in vivo, and, (ii) endothelium-dependent and independent relaxations of corporal strips from young adult (YAD, n=6), adult (AD, n=6), and cholesterol-fed (ATH, n=8) New-Zealand white rabbits. Measurement of Intima/Media (I/M) ratio on iliac arteries from ATH rabbits determined those with moderate (Mod ATH, 0.5±0.3) or severe (Sev ATH, 1.5±0.4, P<0.05 Mann–Whitney) atherosclerotic lesions. Erectile responses were reduced in AD compared with YAD rabbits (at 6 V to 10 Hz: 51.6±4.6% vs. 57.5±1.4%); they were similar in AD and mod ATH rabbits (48.1±4.6%) but drastically impaired in Sev ATH rabbits (34.8±5.4%, P<0.05, two-way analysis of variance (ANOVA)). Corporal endothelium-dependent and -independent relaxations were comparable in YAD and AD rabbits (maximal relaxation to acetylcholine: 51.3±9.5 vs. 56.1±9.3%) but decreased in ATH rabbits (37.1±1.6%, P<0.001, two-way ANOVA). These results suggest that the mechanisms implicated in ATH-induced ED are distinct from the ageing-related process in rabbits. Thus, future therapeutic targets to treat or prevent ATH-induced ED may include the reduction of the atherosclerotic plaque size or progression, as well as an improvement of the smooth muscle and endothelial reactivity of the corpus cavernosum. [Copyright &y& Elsevier]