Repeated slip along a major decoupling horizon between crustal-scale nappesof the Central Western Carpathians documented in the Ochtinà tectonicmélange

International audienceThe Ochtiná Unit is situated in the ENE-WSW-trending contact zone between two crustal-scale nappes, the upper Gemer Unit and the lower Vepor Unit, in the Central Western Carpathians, Slovakia. The Ochtiná Unit consists mainly of Carboniferous phyllitic schists and sandstones enclosing lenses of diverse lithological nature and contrasting metamorphic history. Peak PT conditions obtained by means of phase equilibrium modelling from lenses of amphibolite and chloritoid schist in this unit indicate 500-600 °C and 4-6.5 kbar and 500-520 °C and 9-11 kbar, respectively. These PT conditions contrast not only with the greenschist-facies metamorphism of dominant phyllite but also with each other documenting two distinct metamorphic field gradients related to Variscan and Alpine metamorphic events. Geochemical data reveal an affinity of the amphibolite lenses to similar Variscan rocks in the basement of the upper Gemer Unit and of the chloritoid schist to similar Alpine rocks in the cover of the lower Vepor Unit. Such heterogeneous lithological and metamorphic record is consistent with a block-in-matrix rock arrangement and the Ochtiná Unit is interpreted as deep seated tectonic mélange. The mélange evolved via repeated slip along the rheologically weak sediments of the Ochtiná Unit during the building and collapse of the Eo-Alpine orogenic wedge of the Central Western Carpathians. Deformation record indicates that the mélange separates two distinct structural domains marked by a decoupled behaviour, i.e. the orogenic suprastructure represented by the Gemer Unit and the infrastructure represented by the Vepor Unit. With this respect, the Ochtiná Unit represents an unusual example of a suprastructure-infrastructure transition zone with its position being controlled by the mechanical weakness of this sedimentary horizon and not by the temperature-dependent rheological transition

Expression patterns of protein C inhibitor in mouse development

Proteolysis of extracellular matrix is an important requirement for embryonic development and is instrumental in processes such as morphogenesis, angiogenesis, and cell migration. Efficient remodeling requires controlled spatio-temporal expression of both the proteases and their inhibitors. Protein C inhibitor (PCI) effectively blocks a range of serine proteases, and recently has been suggested to play a role in cell differentiation and angiogenesis. In this study, we mapped the expression pattern of PCI throughout mouse development using in situ hybridization and immunohistochemistry. We detected a wide-spread, yet distinct expression pattern with prominent PCI levels in skin including vibrissae, and in fore- and hindgut. Further sites of PCI expression were choroid plexus of brain ventricles, heart, skeletal muscles, urogenital tract, and cartilages. A strong and stage-dependent PCI expression was observed in the developing lung. In the pseudoglandular stage, PCI expression was present in distal branching tubules whereas proximal tubules did not express PCI. Later in development, in the saccular stage, PCI expression was restricted to distal bronchioli whereas sacculi did not express PCI. PCI expression declined in postnatal stages and was not detected in adult lungs. In general, embryonic PCI expression indicates multifunctional roles of PCI during mouse development. The expression pattern of PCI during lung development suggests its possible involvement in lung morphogenesis and angiogenesis

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Distinct metasomatic events and their relation to a crustal-scaledeformation zone (Gemer-Vepor Contact Zone, CentralWesternCarpathians)

International audienceNumerous talc, magnesite and siderite ore deposits occur in the Central Western Carpathians (Slovakia) along theso-called Gemer-Vepor Contact Zone, which marks the contact between two major blocks of Variscan basement,the Vepor and Gemer units. During the polyphase deformation of Cretaceous age, the Gemer Unit was first thrustover the Vepor Unit. This is well documented by the development of subhorizontal and prograde metamorphic foliationreaching up to amphibolite facies conditions in the Vepor and by the development of subvertical greenschistfacies cleavages in the Gemer Unit. The subsequent exhumation of the Vepor Unit along large-scale detachmentzone is documented by the development of subhorizontal lower grade cleavage in the Vepor Unit. Finally, the ongoingnorthward propagating convergence with the Gemer Unit led to the development of the sinistral transpressionalTrans-Gemer Shear zone. Two types of shear zones with contrasting metasomatic record have been recognized inthe Vepor Unit. Mg-enriched shear zones heterogeneously develop within the Carboniferous granitoids resulting information of Mg-chlorite–muscovite–quartz phyllonites as well as Mg-chlorite–kyanite-bearing schists. Comparedto the composition of granitoids, these mylonites-phyllonites are depleted in alkalies and enriched in magnesium,iron and manganese, which is most likely related to the influx of fluids along the shear zones. The equilibriummineral assemblage chlorite, kyanite, muscovite, rutile and quartz corresponds to 420C at 4 kbar. In contrast,the second type of shear zones developed within chloritoid-kyanite schists of the Veporic Permian cover. Theseshear zones display metasomatic alteration characterized by a strong Fe-enrichment resulting in formation of Fechlorite-muscovite-quartz phyllonite. The unusual enrichment in either Mg or Fe suggests either heterogenous fluidcomposition or two separate metasomatic events in the studied area. Indeed, the two types of shear zones are associatedwith two distinct deformation events. The Mg-enriched first type shear zones are associated with progrademetamorphic evolution related to burial of the Vepor Unit whereas the Fe-enriched second type shear zones arerelated to the Vepor exhumation. Therefore, the formation of these metasomatic rocks reflects different stages ofthe polyphase Cretaceous evolution, rather than heterogenous composition of fluids. The sources of metasomaticfluids are discussed in relation to the nearby ore deposits

Ghrelin Receptor Antagonism of Methamphetamine-Induced Conditioned Place Preference and Intravenous Self-Administration in Rats

Methamphetamine abuse imposes a significant burden on individuals and society worldwide, and an effective therapy of methamphetamine addiction would provide distinguished social benefits. Ghrelin significantly participates in reinforcing neurobiological mechanisms of stimulants, including amphetamines; thus, ghrelin antagonism is proposed as a promising addiction treatment. The aim of our study was to elucidate whether the pretreatment with growth hormone secretagogue receptor (GHS-R1A) antagonist, substance JMV2959, could reduce the methamphetamine intravenous self-administration (IVSA) and the tendency to relapse, and whether JMV2959 could reduce or prevent methamphetamine-induced conditioned place preference (CPP) in rats. Following an adequate maintenance period, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 180 min sessions of methamphetamine IVSA under a fixed ratio FR1, which significantly reduced the number of active lever-pressings, the number of infusions, and the amount of the consumed methamphetamine dose. Pretreatment with JMV2959 also reduced or prevented relapse-like behavior tested in rats on the 12th day of the abstinence period. Pretreatment with JMV2959 significantly reduced the expression of methamphetamine-induced CPP. Simultaneous administration of JMV2959 with methamphetamine during the conditioning period significantly reduced the methamphetamine-CPP. Our results encourage further research of the ghrelin antagonism as a potential new pharmacological tool for methamphetamine addiction treatment

Alterations in Rat Accumbens Endocannabinoid and GABA Content during Fentanyl Treatment: The Role of Ghrelin

The opioid-induced rise of extracellular dopamine, endocannabinoid anandamide and γ-aminobutyric acid (GABA) concentrations triggered by opioids in the nucleus accumbens shell (NACSh) most likely participate in opioid reward. We have previously demonstrated that systemic administration of ghrelin antagonist (JMV2959) significantly decreased morphine-induced dopamine and anandamide (N-arachidonoylethanolamine, AEA) increase in the NACSh. Fentanyl is considered as a µ-receptor-selective agonist. The aim of this study was to test whether JMV2959, a growth hormone secretagogue receptor (GHS-R1A) antagonist, can influence the fentanyl-induced effects on anandamide, 2-arachidonoylglycerol (2-AG) and GABA in the NACSh and specify the involvement of GHS-R1A located in the ventral tegmental area (VTA) and nucleus accumbens (NAC). Using in vivo microdialysis in rats, we have found that pre-treatment with JMV2959 reversed dose dependently fentanyl-induced anandamide increases in the NACSh, resulting in a significant AEA decrease and intensified fentanyl-induced decreases in accumbens 2-AG levels, with both JMV2959 effects more expressed when administered into the NACSh in comparison to the VTA. JMV2959 pre-treatment significantly decreased the fentanyl-evoked accumbens GABA efflux and reduced concurrently monitored fentanyl-induced behavioural stimulation. Our current data encourage further investigation to assess if substances affecting GABA or endocannabinoid concentrations and action, such as GHS-R1A antagonists, can be used to prevent opioid-seeking behaviour

Unprecedented plasmon-induced nitroxide-mediated polymerization (PI-NMP): a method for preparation of functional surfaces

WOS:000472219400057A plasmon as a stimulus opens up new opportunities for selective and regulated "from-surface" polymerization and functionalization of surfaces. Here, the first example of plasmon-assisted nitroxide-mediated polymerization (NMP) of stimuli-responsive block copolymers poly(N-isopropylacrylamide)-co-4-vinylboronic acid is reported. The growth of a polymer film at room temperature was achieved via plasmon-induced homolysis of alkoxyamines covalently attached to the surface of plasmon-active gold gratings at room temperature. Control of temperature, finite-difference time-domain method simulation of plasmon intensity distribution shift during polymerization, electron paramagnetic resonance experiments and other assays provide strong support for the plasmon-initiated mechanism of NMP. We demonstrated not only the control of the resulting polymer thickness but also the preparation of a surface-enhanced Raman spectroscopy chip for the detection of glycoproteins as a powerful example of plasmon-assisted NMP potential