From ductile to brittle: evolution and localization of deformation below a crustal detachment (Tinos, Cyclades, Greece)

International audienceThe Cycladic Oligo-Miocene detachment of Tinos island is an example of a flat-lying extensional shear zone evolving into a low-angle brittle detachment. A clear continuum of extensional strain from ductile to brittle regime is observed in the footwall. The main brittle structures marking extension are shallow- and steeply dipping normal faults associated with subvertical extensional joints and veins. The earliest brittle structures are lowangle normal faults which commonly superimpose on, and reactivate, earlier (precursory) ductile shear bands, but newly formed low-angle normal faults could also be observed. Low-angle normal faults are cut by late steeply dipping normal faults. The inversion of fault slip data collected within, and away from, the main detachment zone shows that the direction of the minimum stress axis is strictly parallel to the NE-SW stretching lineation and that the maximum principal stress axis remained subvertical during the whole brittle evolution, in agreement with the subvertical attitude of veins throughout the island. The high angle of s1 to the main detachment suggests that the detachment was weak. This observation, together with the presence of a thick layer of cataclasites below the main detachment and the kinematic continuum from ductile to brittle, leads us to propose a kinematic model for the formation of the detachment. Boudinage at the crustal scale induces formation, near the brittle-ductile transition, of ductile shear zones near the edges of boudins. Shear zones are progressively exhumed and replaced by shallowdipping cataclastic shear zones when they reached the brittle field. Most of the displacement is achieved through cataclastic flow in the upper crust and only the last increment of strain gives rise to the formation of brittle faults. The formation of the low-angle brittle detachment is thus ''prepared'' by the ductile shear zone and the cataclasites and favored by the circulation of surface-derived fluids in the shear zone

In vitro anti-malarial interaction and gametocytocidal activity of cryptolepine

YesBackground: Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, cryptolepine. This study also investigates the anti-malarial interaction of cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues. Methods: The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7. Results: Cryptolepis sanguinolenta ( IC50 = 49.65 nM) and its major alkaloid, cryptolepine ( IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine. Conclusions: The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for cryptolepine in the development of novel fixed dose combinations

2020 Clinical practice guidelines for Myocarditis in adults

Russian Society of Cardiology (RSC)With the participation: Eurasian Association of Therapists (EUAT), Society of Specialists in Heart Failure (OSSN), Russian Scientific Medical Society of Therapists (RNMOT), Russian Society of Pathologists, Russian Society of Radiologists and Radiologists (RSR)Endorsed by: Research and Practical Council of the Ministry of Health of the Russian Federatio

The treatment of

Ferriprotoporphyrin IX (FPIX) is a potentially toxic product of hemoglobin digestion by intra-erythrocytic malaria parasites. It is detoxified by biomineralization or through degradation by glutathione. Both processes are inhibited by the antimalarial drug chloroquine, leading to the accumulation of FPIX in the membranes of the infected cell and their consequent permeabilization. It is shown here that treatment of Plasmodium falciparum-infected erythrocytes with chloroquine also leads to the binding of FPIX to a subset of parasite proteins. Parasite enzymes such as aldolase, pyrimidine nucleoside monophosphate kinase and pyrimidine 5'- nucleotidase were inhibited by FPIX in vitro, but only the activity of 6-phosphogluconate dehydrogenase was reduced significantly in cells after drug treatment. Additional proteins were extracted from parasite cytosol by their ability to bind FPIX. Sequencing of these proteins identified heat shock proteins 90 and 70, enolase, elongation factor 1-α, phoshoglycerate kinase, glyceraldehyde 3- phosphate dehydrogenase, L-lactate dehydrogenase and gametocytogenesis onset-specific protein. The possible involvement of these proteins in the antimalarial mode of action of chloroquine is discussed. It is concluded that drug-induced binding of FPIX to parasite glycolytic enzymes could underlie the demonstrable inhibition of glycolysis by chloroquine. The inhibition of 6- phosphogluconate dehydrogenase could explain the reduction of the activity of the hexose monophosphate shunt by the drug. Inhibition of both processes is deleterious to parasite survival. Binding of FPIX to other proteins is probably inconsequential to the rapid killing of the parasite by chloroquine

The treatment of Plasmodium falciparum-infected erythrocytes with chloroquine leads to accumulation of ferriprotoporphyrin IX bound to particular parasite proteins and to the inhibition of the parasite's 6-phosphogluconate dehydrogenase

Ferriprotoporphyrin IX (FPIX) is a potentially toxic product of hemoglobin digestion by intra-erythrocytic malaria parasites. It is detoxified by biomineralization or through degradation by glutathione. Both processes are inhibited by the antimalarial drug chloroquine, leading to the accumulation of FPIX in the membranes of the infected cell and their consequent permeabilization. It is shown here that treatment of Plasmodium falciparum-infected erythrocytes with chloroquine also leads to the binding of FPIX to a subset of parasite proteins. Parasite enzymes such as aldolase, pyrimidine nucleoside monophosphate kinase and pyrimidine 5'- nucleotidase were inhibited by FPIX in vitro, but only the activity of 6-phosphogluconate dehydrogenase was reduced significantly in cells after drug treatment. Additional proteins were extracted from parasite cytosol by their ability to bind FPIX. Sequencing of these proteins identified heat shock proteins 90 and 70, enolase, elongation factor 1-α, phoshoglycerate kinase, glyceraldehyde 3- phosphate dehydrogenase, L-lactate dehydrogenase and gametocytogenesis onset-specific protein. The possible involvement of these proteins in the antimalarial mode of action of chloroquine is discussed. It is concluded that drug-induced binding of FPIX to parasite glycolytic enzymes could underlie the demonstrable inhibition of glycolysis by chloroquine. The inhibition of 6- phosphogluconate dehydrogenase could explain the reduction of the activity of the hexose monophosphate shunt by the drug. Inhibition of both processes is deleterious to parasite survival. Binding of FPIX to other proteins is probably inconsequential to the rapid killing of the parasite by chloroquine

Sheared sheet intrusions as a mechanism for lateral flank displacement on basaltic volcanoes: Applications to Réunion Island volcanoes.

Field work carried out on the Piton des Neiges volcano (R\ue9union Island) suggests that the injection of magma along detachments could trigger flank failure by conjugate opening and shear displacement. We use 3-D numerical models to compare the ability of purely opened sheet intrusions, sheared sheet intrusions, and normal faults to induce flank displacement on basaltic volcanoes. We assume that shear stress change on fractures results from stress anisotropy of the host rock under gravity. Exploring a large range of stress anisotropies, fracture dips, and fracture depth over length ratios, we determine that the amount of shear displacement is independent of the proximity to the ground surface. Sheared sheet intrusions are the most efficient slip medium on volcanoes. Consequently, the largest flank displacement is induced by the longest, deepest sheared intrusion dipping closest to 45\ub0 in a host rock with the highest stress anisotropy. Using our model in a forward way, we provide shear and normal displacements for buried fractures. Applying the model to a pile of sills at the Piton des Neiges volcano, we determine that the mean shear displacement caused by each intrusion was 3.7 m, leading to a total of a 180\u2013260 m of lateral displacement for the 50 m high pile of sills. Using our model in an inverse way, we formulate a decision tree to determine some fracture characteristics and the host rock stress anisotropy from ratios of maximum surface displacements. This procedure provides a priori models, which can be used to bound the parameter space before it is explored through a formal inversion. Applying the decision tree to the 1.4 m coeruptive flank displacement recorded at Piton de la Fournaise in 2007, we find that it probably originated from a shallow eastward dipping subhorizontal normal fault

Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum

BACKGROUND Malaria invasion of red blood cells involves multiple parasite-specific targets that are easily accessible to inhibitory compounds, making it an attractive target for antimalarial development. However, no current antimalarial agents act against host cell invasion. RESULTS Here, we demonstrate that the clinically used macrolide antibiotic azithromycin, which is known to kill human malaria asexual blood-stage parasites by blocking protein synthesis in their apicoplast, is also a rapid inhibitor of red blood cell invasion in human (Plasmodium falciparum) and rodent (P. berghei) malarias. Multiple lines of evidence demonstrate that the action of azithromycin in inhibiting parasite invasion of red blood cells is independent of its inhibition of protein synthesis in the parasite apicoplast, opening up a new strategy to develop a single drug with multiple parasite targets. We identified derivatives of azithromycin and erythromycin that are better invasion inhibitors than parent compounds, offering promise for development of this novel antimalarial strategy. CONCLUSIONS Safe and effective macrolide antibiotics with dual modalities could be developed to combat malaria and reduce the parasite’s options for resistance.Danny W Wilson, Christopher D Goodman, Brad E Sleebs, Greta E Weiss, Nienke WM de Jong, Fiona Angrisano, Christine Langer, Jake Baum, Brendan S Crabb, Paul R Gilson, Geoffrey I McFadden, and James G Beeso