A new microtubule-stabilizing agent shows potent antiviral effects against African swine fever virus with no cytotoxicity

© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.African swine fever virus (ASFV) is the causal agent of a fatal disease of domestic swine for which no effective antiviral drugs are available. Recently, it has been shown that microtubule-targeting agents hamper the infection cycle of different viruses. In this study, we conducted in silico screening against the colchicine binding site (CBS) of tubulin and found three new compounds with anti-ASFV activity. The most promising antiviral compound (6b) reduced ASFV replication in a dose-dependent manner (IC50 = 19.5 μM) with no cellular (CC50 > 500 μM) and animal toxicity (up to 100 mg/kg). Results also revealed that compound 6b interfered with ASFV attachment, internalization and egress, with time-of-addition assays, showing that compound 6b has higher antiviral effects when added within 2-8 h post-infection. This compound significantly inhibited viral DNA replication and disrupted viral protein synthesis. Experiments with ASFV-infected porcine macrophages disclosed that antiviral effects of the compound 6b were similar to its effects in Vero cells. Tubulin polymerization assay and confocal microscopy demonstrated that compound 6b promoted tubulin polymerization, acting as a microtubule-stabilizing, rather than a destabilizing agent in cells. In conclusion, this work emphasizes the idea that microtubules can be targets for drug development against ASFV.This work of E. A., A. H., and H. Z. was supported by the RA MESCS Science Committee, Armenia [grant number 19YR-1F039]; the work of F. F. was supported by the FCT – Fundação para a Ciência e a Tecnologia, Portugal [grant number UIDB/00276/2020].info:eu-repo/semantics/publishedVersio

Cenozoic Strike-Slip Tectonics and Structural Controls of Porphyry Cu-Mo and Epithermal Deposits During Geodynamic Evolution of the Southernmost Lesser Caucasus, Tethyan Metallogenic Belt

The Zangezur-Ordubad mining district of the southernmost Lesser Caucasus is located in the central segment of the Tethyan metallogenic belt, and consists of porphyry Cu-Mo and epithermal systems hosted by the composite Cenozoic Meghri-Ordubad pluton. Ore-hosting structures and magmatic intrusions are predominantly confined to a central north-south oriented corridor 40 km long and 10 to 12 km wide, located between two regional north-northwest oriented right-lateral faults, the Khustup-Giratagh and Salvard-Ordubad faults. The anatomy and kinematics of the main fault network is consistent with dextral strike-slip tectonics controlled by the north-northwest oriented Khustup-Giratagh and Salvard-Ordubad faults. Dextral strike-slip tectonics was initiated during the Eocene, concomitantly with final subduction of the Neotethys, and controlled the emplacement of the Agarak, Hanqasar, Aygedzor, and Dastakert porphyry Cu-Mo and the Tey-Lichkvaz epithermal deposits. The Eocene structures were repeatedly reactivated during subsequent Neogene evolution in transition to a post-subduction geodynamic setting. Ore-bearing structures at the Oligocene world-class Kadjaran porphyry Cu-Mo deposit were also controlled by dextral strike-slip tectonics, as well as porphyry mineralization and its epithermal overprint hosted by an early Miocene intrusion at Lichk. Eocene to early Miocene dextral strike-slip tectonics took place during northeast to north-northeast oriented compression related to Paleogene Eurasia-Arabia convergence and subsequent Neogene post-collision evolution. Paleostress reconstruction indicates major re-organization of tectonic plate kinematics since the early Miocene, resulting in north-south to northwest oriented compression. Early Miocene epithermal overprint at the Kadjaran porphyry deposit and left-lateral reactivation of faults and mineralized structures are linked to this late Neogene tectonic plate reorganization

The World-Class Kadjaran Mo-Cu-Porphyry Deposit, Southern Armenia, Lesser Caucasus: Structural Controls, Mineral Paragenesis and Fluid Evolution

This paper investigates the structural controls of the Kadjaran deposit, the evolution of hydrothermal fluids with variable salinity, temperature and pressure, based on a detailed field mapping, petrographic and fluid inclusion microthermometry. Detailed structural mapping and interpretation of stereonets compiling ore-bearing fractures within stockwork and vein zones allow us to define the main ore-controlling structures and main orientations of veins of the different mineralization stages of the Kadjaran deposit. The ore-enriched areas are zones sub-parallel to eastwest-oriented fractures. In particular, they are located in areas where they crosscut steeplydipping (70-85°) eastwest-, northsouth- and northeastoriented fractures. Five types of fluid inclusions were distinguished according to their nature, bubble size, and daughter mineral content. Cathodoluminescence (SEMCL) images reveal four generations of quartz. Molybdenite is associated with a dark luminescent quartz generation (Q2), which contains typical brine and aqueous-carbonic fluid inclusions, with some of them coexisting locally as boiling assemblages. Final homogenization of all brine inclusions occurs by halite dissolution. Dissolution of halite between 356±8 and 422±10°C in brine (B1) inclusions of quartz - molybdenite veins indicates salinities between about 42.6 to 50.7 wt % NaCl equiv. The vapor bubbles homogenized between 278±4°C and 327±5°C

Structural control of the Cenozoic porphyry Cu-Mo, epithermal and skarn deposits and prospects, Central Tethyan belt, Lesser Caucasus

The Cenozoic evolution of the central segment of the Tethyan metallogenic belt is dominated by the oblique convergence and final collision of Gondwana-derived terranes and the Arabian plate with Eurasia, which created a favorable setting for the formation of the highly mineralized Meghri-Ordubad pluton inthe southernmost Lesser Caucasus, in the Zangezur-Ordubad mining district. Paleostress reconstructions indicate anti-clockwise rotation from NE-oriented compression during the early and middle Eocene to NNW-oriented compression during the Pliocene. During the Eocene the N-S oriented faults are consistent with dextral strike-slip tectonics, correspond to synthetic faults and control the main porphyry Cu-Mo and epithermal deposits and prospects. The sinistral E-W oriented en- échelon faults correspond to antithetic faults. This strike-slip kinematics is consistent with the regional NE-oriented compression in the Zangezur-Ordubad district and concomitant with final subduction of the Neotethys along the Eurasian margin. Sinistral strike-slip kinematics along the E-W oriented faults resulted in clockwise rotation of the individual blocks of the Zangezur-Ordubad district. During the Oligocene and Miocene anti-clockwise rotation of the main paleostress compressional orientation resulted in reactivation of existing ore-controlling structures in a sinistral strike-slip tectonic regime, which is consistent with the re-orientation of the tectonic plate kinematics and re- organization of the Arabia-Eurasia collision

Zircon Petrochronology of the Meghri-Ordubad Pluton, Lesser Caucasus: Fingerprinting Igneous Processes and Implications for the Exploration of Porphyry Cu-Mo Deposits

The trace element composition of zircon, especially in tandem with U-Pb geochronology, has become a powerful tool for tracing magmatic processes associated with the formation of porphyry copper deposits. However, the use of the redox-sensitive Eu and Ce anomalies as a potential mineral exploration proxy is controversial. This study presents a comprehensive, temporally constrained data set of zircon trace element compositions (n = 645) for three compositionally distinct magmatic series identified in the Meghri-Ordubad pluton, southernmost Lesser Caucasus. The 30 million years of Cenozoic magmatism in the Meghri-Ordubad pluton are associated with several ore-forming pulses leading to the formation of porphyry copper deposits and epithermal-style mineralization. Our zircon geochemical data constrain the thermal and chemical evolution of this complex intrusive suite and allow an evaluation of the usefulness of zircon as a mineral exploration proxy for porphyry copper deposits. Our results combined with Rayleigh fractionation modeling indicate that the trace element composition of zircon (Th/U, Hf, Ti, YbN/DyN, Eu anomalies) is influenced by the composition and the water concentration of the parental magma, as well as by co-crystallizing titanite and apatite. In contrast, the variations of Ce anomalies remain difficult to explain by magmatic processes and could rather be ascribed to relative fluctuations of the redox conditions. In the Meghri-Ordubad pluton, we do not observe any systematic patterns between the trace element composition in zircons and the different ore-forming pulses. This questions the reliability of using the trace element composition in zircon as an exploration mineral proxy, and it rather emphasizes that a good knowledge of the entire magmatic evolution of a metallogenic province is required

30 Myr of Cenozoic magmatism along the Tethyan margin during Arabia–Eurasia accretionary orogenesis (Meghri–Ordubad pluton, southernmost Lesser Caucasus)

Three magmatic series of substantially different ages and compositions were successively emplaced to form the composite Meghri-Ordubab pluton (MOP), southernmost Lesser Caucasus. The protracted incremental assembly during 30 Myr, from Middle Eocene to Early Miocene, renders this location particularly suitable to characterize the petrogenetic evolution of Cenozoic magmatism within the realm of the final stage of the Neotethyan subduction. Based on whole-rock geochemistry, two main transitions tightly constrained in time are recognized. The first transition from Middle Eocene medium-K calc-alkaline to Late Eocene - Middle Oligocene shoshonitic magmatism corresponds to a marked increase in LREE and MREE and more juvenile 87Sr/86Sr and 143Nd/144Nd ratios. The second transition to Late Oligocene - Early Miocene high-K calc-alkaline «adakite-like» magmatism is coeval to a marked increase in Mg#, and Ni and Cr contents together with a depletion in HREE. Although the three differentiation series are derived from lower to mid-crustal hydrous magma fractionation, temporal variations of the magmatic source conditions are required to explain the contrasting chemistry of the parental magmas over time. Medium-K calc-alkaline parental magmas were generated by garnet lherzolite high degree of partial melting (~15%). The shoshonitic and adakitic magmatic series represent magmas produced by garnet lherzolite low degree (1-5%) partial melting, but higher amount of residual garnet is required for the adakitic magmatism. The timing of the two main geochemical transitions in the MOP is correlated with a progressive evolution from compressional to extensional stress regime linked to (1) the final stage of the Neotethyan subduction and by the Arabia-Eurasia continental collision during the Eocene-Oligocene, and (2) the transition toward a post-collisional magmatism combined with a switch toward extensional tectonics during the Late Oligocene – Early Miocene

Pulsed Porphyry Cu-Mo Formation during Protracted Pluton Emplacement in Southern Armenia, Lesser Caucasus: the Potential Role of Crustal Melting for Ore Recycling

The southern part of the Lesser Caucasus records a long lasting geological and metallogenic evolution from the Jurassic to the Cenozoic. The composite Meghri-Ordubad pluton, which hosts porphyry Cu-Mo deposits, includes Eocene to Miocene intrusive rocks over an area of 1400 km2. Based on LA-ICP-MS UPb zircon dating of thirty samples, we document three main magmatic events: (1) mid-Eocene from 46 to 43 Ma, (2) Eocene-Oligocene from 38 to 31 Ma, and (3) Oligocene-early Miocene from 27 to 21 Ma. Based on Re-Os molybdenite dating, each magmatic event is associated with porphyry Cu-Mo (or Mo-Cu) formation, including the giant Kadjaran porphyry Mo-Cu deposit. We propose an evolution from subduction-related calcalkaline magmas to collisional alkaline magmas followed by bi-modal magmatism over time. Preliminary Nd and Sr isotopic compositions of the magmatic rocks broadly indicate an increasing mantle-derived component with younger magmatic events. Hf isotopic compositions of zircons range from +8 to +11 for Jurassic, Cretaceous, Eocene, Oligocene and Miocene rocks. Based on Hf isotopic composition mixing models involving a depleted mantle and Jurassic to Miocene crustal rocks, we propose that an important volume of crustal rocks can be re-melted. We suggest an ore recycling process by crustal melting leading to the metal enrichment of younger magmas, especially during ore-forming protracted pluton emplacement

Incremental growth of mid- to upper-crustal magma bodies during Arabia-Eurasia convergence and collision: A petrological study of the calc-alkaline to shoshonitic Meghri- Ordubad pluton (Southern Armenia and Nakhitchevan, Lesser Caucasus)

The composite Meghri-Ordubad pluton (MOP) is located in the southernmost Lesser Caucasus and outcrops over ~1000 km2 in southern Armenia and Nakhitchevan. It is characterized by nested intrusions incrementally emplaced over ~30 Myr from the Middle Eocene to Early Miocene, coeval with the closure of the Neotethyan Ocean and the regional Arabia-Eurasia continental collision. We recognize three compositionally distinct intrusive series in the MOP: a medium- to high-K calc-alkaline series 1 dominated by gabbro, quartz diorite and tonalite, a shoshonitic to high-K calc-alkaline series 2 including gabbro, monzogabbro, monzodiorite, monzonite and syenite, and a high-K calc-alkaline adakitic series 3 characterized by the emplacement of lamprophyre dikes followed by porphyritic granodioritic intrusions and dikes. Thermobarometry calculations together with detailed petrography, mineral chemistry and experimental mineral stability P-T diagrams indicate a polybaric crystallization history and magma emplacement at mid- to upper crustal levels (0.1-0.3 GPa). Mineral textures and compositions reveal open-system magmatic processes such as mafic magma replenishment and reactivation of crystal mushes prior to transport towards shallower crustal levels in the MOP. The evolution of magma chemistry (calc-alkaline vs shoshonitic) and mineral assemblages (amphibole-bearing vs amphibole-free) indicate fluctuation in primary melt alkali and water contents over time. Such chemical evolution is ascribed to a decrease in the degree of partial melting of a chemically heterogeneous, but isotopically homogeneous, mantle source. Overall, the MOP is characterized by the successive emplacement of hydrous magma batches in the mid- to upper crust and petrological processes that were dominated by fractional crystallization (± crustal assimilation) upon cooling and, or, decompression (± degassing). We propose a new temporal and spatial petrogenetic model for the MOP, encompassing three long-lived, chemically distinct magmatic series incrementally assembled over 30 Myr within a pre-, syn- and post-collisional geodynamic setting

Structural control and tectonic environment of the Cenozoic giant Kadjaran porphyry Cu-Mo and epithermal system, southern Armenia, Lesser Caucasus

In this contribution, we focus on the Oligocene to Miocene structural evolution of the giant Kadjaran porphyry Cu-Mo deposit and its epithermal overprint. This evolution was controlled by long-lived regional faults during the Cenozoic tectonic and magmatic evolution of the Meghri-Ordubad composite pluton located in the southernmost Lesser Caucasus. We discuss the ore-bearing fracture network characteristics related with the deposit-scale ore-controlling structures in the frame of regional strike-slip faults. Stereonets summarizing the orientations of different generations of mineralized veins allow us to constrain the favorable fracture network environment for ore-formation at the giant Kadjaran deposit. During the middle - late Oligocene, NNE-oriented shortening created the major ~N-S- and NE-oriented steeply dipping ore-controlling deposit-scale faults under dextral strike-slip tectonics. The gently to moderately dipping NE-, ~N-S- and ~E-W-oriented fracture networks along the steeply dipping deposit-scale faults were the most important structural control for the emplacement of the main porphyry stockwork mineralization. These deposit-scale ore-controlling faults were reactivated during the early Miocene under WNW-oriented shortening and NNE-oriented extension. The progressive anticlockwise rotation of paleostress orientations from middle - late Oligocene to early Miocene was linked to re-organization of tectonic plates during Arabia-Eurasia collision