Revisiting the geodynamics of the Middle East region from an integrated geophysical perspective

A long-standing question in geodynamics is whether mantle flow is driven by the plate motion alone, or mantle upwelling makes a significant contribution to it. Subducting slabs and lateral variations of the continental lithosphere can further influence the asthenospheric flow and control its direction. The Middle East region (MER) is a complex continental setting where different processes such as rifting, break-up, plate collision, and tectonic escape kinematically interact with each other. In this context, the role that lithospheric structure, mantle flow, and active upwellings may play is debated. Tomographic images provide a snapshot of the current thermal conditions of a region and seismic anisotropy can also help resolve mantle convection. Here, we synthesize shear-wave splitting observations together with up-to-date tomography models of the mantle structure beneath the MER and other geophysical data. Low-velocity anomalies are seen at asthenospheric depths beneath W Arabia, NW Iran, and Anatolia, suggesting a spreading zone of warm mantle. Two deep low-velocity bodies in Afar and Levant –interpreted as hot mantle plumes– are the sources of this shallower mantle flow. Where low velocities are imaged, we observe predominantly NE–SW oriented anisotropy, anomalously high topography, and abundant basaltic volcanism. The integrated analysis suggests that a horizontal component associated with active upwelling is present in the upper-mantle flow field. The large-scale circulation flow fed by the Afar and Levant Plumes, aided by the subduction-induced forces, facilitates the lateral motion of the Anatolian microplate and affects the dynamic evolution of the Zagros orogen. The proposed scenario demonstrates that the interplay between plate-tectonic events and mantle dynamics controls the kinematics of the region and can explain the general patterns of deformation observed at the surface

Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation

Leucine-rich repeat kinase 2 (LRRK2) kinase activity is increased in several pathogenic mutations, including the most common mutation, G2019S, and is known to play a role in Parkinson’s disease (PD) pathobiology. This has stimulated the development of potent, selective LRRK2 kinase inhibitors as one of the most prevailing disease-modifying therapeutic PD strategies. Although several lines of evidence support beneficial effects of LRRK2 kinase inhibitors, many questions need to be answered before clinical applications can be envisaged. Using six different LRRK2 kinase inhibitors, we show that LRRK2 kinase inhibition induces LRRK2 dephosphorylation and can reduce LRRK2 protein levels of overexpressed wild type and G2019S, but not A2016T or K1906M, LRRK2 as well as endogenous LRRK2 in mouse brain, lung and kidney. The inhibitor-induced reduction in LRRK2 levels could be reversed by proteasomal inhibition, but not by lysosomal inhibition, while mRNA levels remained unaffected. In addition, using LRRK2 S910A and S935A phosphorylation mutants, we show that dephosphorylation of these sites is not required for LRRK2 degradation. Increasing our insight in the molecular and cellular consequences of LRRK2 kinase inhibition will be crucial in the further development of LRRK2-based PD therapies

Annual Ryegrass Pasture for Dairy Cows Receiving Total Mixed Ration

The inclusion of herbage in the diet of medium yielding dairy cows offered a total mixed ration (TMR) may be beneficial. This study, which involved mid lactation dairy cows, examined the effect of partial replacement of a TMR with annual temperate pasture. Treatments were ad libitum TMR (TMR100), 75% ad libitum TMR + ryegrass (Lolium multiflorum ‘Maximus’) (TMR75), and 50% ad libitum TMR + ryegrass (TMR50). Twelve multiparous Holstein and F1 Jersey × Holstein cows were divided into six homogeneous groups, taking account of milk production (26.6 ± 4.5 kg/day), days in milk (128 ± 50) and body weight (546 ± 31 kg). Treatments were compared in a replicated 3×3 Latin square design, comprising three 21-day periods (measurements during final 5 days). Cows on TMR75 and TMR50 strip grazed between morning and afternoon milking (7 h/day), with a target pre- and post-grazing sward height of 24 and 12 cm, respectively. Herbage DM intake was estimated as the difference between pre- and post-grazing herbage mass. The TMR and herbage had a crude protein content of 150 and 303 g/kg DM, and a NDF content of 366 and 495 g/kg DM, respectively. Herbage DM intake increased from 4.8 kg/day in TMR75 to 6.7 kg/day on TMR50. Total DM intake decreased from 19.4 kg/day (TMR100), to 18.1 and 15.9 kg/day (TMR75 and TMR50, respectively). Milk production, milk fat and milk protein content were similar between treatments, averaging 25.6 kg/day, 44.6 g/kg and 33.7 g/kg, respectively. The net energy for lactation (NEL) supply was 113, 104 and 92% of NEL requirements, for cows receiving TMR100, TMR75 and TMR50, respectively. Ryegrass pastures were able to replace up to 50% of TMR offered to mid lactation dairy cows without any adverse effects on milk production and milk composition

Revisiting the geodynamics of the Middle East region from an integrated geophysical perspective

A long-standing question in geodynamics is whether mantle flow is driven by the plate motion alone, or mantle upwelling makes a significant contribution to it. Subducting slabs and lateral variations of the continental lithosphere can further influence the asthenospheric flow and control its direction. The Middle East region (MER) is a complex continental setting where different processes such as rifting, break-up, plate collision, and tectonic escape kinematically interact with each other. In this context, the role that lithospheric structure, mantle flow, and active upwellings may play is debated. Tomographic images provide a snapshot of the current thermal conditions of a region and seismic anisotropy can also help resolve mantle convection. Here, we synthesize shear-wave splitting observations together with up-to-date tomography models of the mantle structure beneath the MER and other geophysical data. Low-velocity anomalies are seen at asthenospheric depths beneath W Arabia, NW Iran, and Anatolia, suggesting a spreading zone of warm mantle. Two deep low-velocity bodies in Afar and Levant –interpreted as hot mantle plumes– are the sources of this shallower mantle flow. Where low velocities are imaged, we observe predominantly NE–SW oriented anisotropy, anomalously high topography, and abundant basaltic volcanism. The integrated analysis suggests that a horizontal component associated with active upwelling is present in the upper-mantle flow field. The large-scale circulation flow fed by the Afar and Levant Plumes, aided by the subduction-induced forces, facilitates the lateral motion of the Anatolian microplate and affects the dynamic evolution of the Zagros orogen. The proposed scenario demonstrates that the interplay between plate-tectonic events and mantle dynamics controls the kinematics of the region and can explain the general patterns of deformation observed at the surface

Relationships between energy balance during early lactation and cow performance, blood metabolites, and fertility: A meta-analysis of individual cow data

Publication history: Accepted - 15 January 2021; Published online - 6 March 2021This study was designed to contribute to the understanding of the relationships between energy balance (EB) in early lactation [4 to 21 d in milk (DIM)] and fertility traits [interval to start of luteal activity (SLA), interval to first observed heat (FOH), and conception to first artificial insemination (AI)], and their associated relationships with cow performance and blood metabolites between 4 to 150 DIM. Individual cow data (488 primiparous and 1,020 multiparous lactations) from 27 experiments was analyzed. Data on cow performance, EB (on a metabolizable energy basis), and fertility traits were available for all cows, whereas milk progesterone data (to determine SLA) and periodic blood metabolite data were available for 1,042 and 1,055 lactations, respectively. Data from primiparous and multiparous cows were analyzed separately, with the data sets for the 2 parity groups divided into quartiles (Q1–Q4) according to the average EB during 4 to 21 DIM (EB range for Q1 to Q4: primiparous, −120 to −49, −49 to −24, −24 to −3, and −3 to 92 MJ/d, respectively: multiparous, −191 to −79, −79 to −48, −48 to −22, and −22 to 93 MJ/d, respectively). Differences between EB quartiles for production and fertility traits were compared. In early lactation (4 to 21 DIM), moving from Q1 to Q4 mean DMI and metabolizable energy intake increased whereas mean ECM decreased. During the same period, moving from Q1 to Q4 milk fat content, milk fat-to-protein ratio, and plasma nonesterified fatty acid and β-hydroxybutyrate concentrations decreased, whereas milk protein content and plasma glucose concentrations increased in both primiparous and multiparous cows. When examined over the entire experimental period (4 to 150 DIM), many of the trends in intakes and milk production remained, although the magnitude of the difference between quartiles was much reduced, whereas milk fat content did not differ between quartiles in primiparous cows. The percentage of cows with FOH before 42 DIM increased from Q1 to Q4 (from 46 to 72% in primiparous cows, and from 41 to 58% in multiparous cows). Interval from calving to SLA and to FOH decreased with increasing EB during 4 to 21 DIM, with these occurring 9.8 and 10.2 d earlier, respectively, in Q4 compared with Q1 (primiparous cows), and 7.4 and 5.9 d earlier, respectively, in Q4 compared with Q1 (multiparous cows). For each 10 MJ/d decrease in mean EB during 4 to 21 DIM, FOH was delayed by 1.2 and 0.8 d in primiparous and multiparous cows, respectively. However, neither days to first AI nor the percentage of cows that conceived to first AI were affected by daily EB during 4 to 21 DIM in either primiparous or multiparous cows, and this is likely to reflect a return to a less metabolically stressed status at the time of AI. These results demonstrate that interval from calving to SLA and to FOH were reduced with increasing EB in early lactation, whereas early lactation EB had no effect on conception to the first service.This work was supported by the Department of Agriculture and Rural Development for Northern Ireland (DAERA, Northern Ireland, UK) as part of the Department of Agriculture, Food, and the Marine (DAFM, Republic of Ireland) NutriGen project. Maurício Civiero was in receipt of a scholarship from Programa de Bolsas Universitárias de Santa Catarina (UNIEDU/FUMDES, Florianópolis, SC, Brazil) and thanks Centro Universitário Vale do Iguaçu (UNIGUAÇU, União da Vitória, PR, Brazil) for providing time to complete this wo

BEL \u3b2-TREFOIL. A NOVEL LECTIN WITH ANTITUMORAL PROPERTIES IN KING BOLETE (BOLETUS EDULIS) MUSHROOMS

A novel lectin completely different from the formerly described member of the saline soluble family of mushroom specific lectins (named BEL, Boletus edulis lectin, Bovi et al., 2011) was purified from the fruiting bodies of king bolete mushrooms (also called porcino, cep or penny bun). The lectin was structurally characterized: its amino acid sequence and three dimensional structure were determined. The protein is a homodimer and each protomer folds as \u3b2-trefoil domain and therefore we propose the name BEL \u3b2-trefoil to distinguish it from the other lectin that has been described in these mushrooms: BEL. The new lectin has potent anti-proliferative effects on human epithelial cancer cells which confers to it an interesting therapeutic potential as an antineoplastic agent. Several crystal forms of the apoprotein and of complexes with different carbohydrates were studied by X-ray diffraction. The interaction of the lectin with lactose, galactose, N-acetylgalactosamine, T-antigen disaccharide (Gal\u3b21-3GalNAc) and T-antigen (Ser-Gal\u3b21-3GalNAc) was examined in detail. All the three potential binding sites present in the \u3b2-trefoil fold are occupied in at least one crystal form. No important conformational changes are observed in the lectin when comparing its co-crystals with carbohydrates with those of the ligand free protein

PAK6 Phosphorylates 14-3-3 gamma to Regulate Steady State Phosphorylation of LRRK2

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson’s disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain

RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits

Mutations in the LRRK2 kinase are the most common cause of familial Parkinson's disease, and variants increase risk for the sporadic form of the disease. LRRK2 phosphorylates multiple RAB GTPases including RAB8A and RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which may interfere with ciliogenesis in a disease-relevant context. Our previous studies indicate that the centrosomal accumulation of phosphorylated RAB8A causes centrosomal cohesion deficits in dividing cells, including in peripheral patient-derived cells. Here, we show that both RAB8 and RAB10 contribute to the centrosomal cohesion deficits. Pathogenic LRRK2 causes the centrosomal accumulation not only of phosho-RAB8 but also of phospho-RAB10, and the effects on centrosomal cohesion are dependent on RAB8, RAB10 and RILPL1. Conversely, the pathogenic LRRK2-mediated ciliogenesis defects correlate with the centrosomal accumulation of both phospho-RAB8 and phospho-RAB10. LRRK2-mediated centrosomal cohesion and ciliogenesis alterations are observed in patient-derived peripheral cells, as well as in primary astrocytes from mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibition. These data suggest that the LRRK2-mediated centrosomal cohesion and ciliogenesis defects are distinct cellular readouts of the same underlying phospho-RAB8/RAB10/RILPL1 nexus and highlight the possibility that either centrosomal cohesion and/or ciliogenesis alterations may serve as cellular biomarkers for LRRK2-related PD

GTP binding and intramolecular regulation by the ROC domain of Death Associated Protein Kinase 1

The ROCO proteins are a family of large, multidomain proteins characterised by the presence of a Ras of complex proteins (ROC) domain followed by a COR, or C-terminal of ROC, domain. It has previously been shown that the ROC domain of the human ROCO protein Leucine Rich Repeat Kinase 2 (LRRK2) controls its kinase activity. Here, the ability of the ROC domain of another human ROCO protein, Death Associated Protein Kinase 1 (DAPK1), to bind GTP and control its kinase activity has been evaluated. In contrast to LRRK2, loss of GTP binding by DAPK1 does not result in loss of kinase activity, instead acting to modulate this activity. These data highlight the ROC domain of DAPK1 as a target for modifiers of this proteins function, and casts light on the role of ROC domains as intramolecular regulators in complex proteins with implications for a broad range of human diseases

Thermal Nature of Mantle Upwellings Below the Ibero-Western Maghreb Region Inferred From Teleseismic Tomography

©2019. American Geophysical Union. All Rights Reserved. Independent models of P wave and S wave velocity anomalies in the mantle derived from seismic tomography help to distinguish thermal signatures from those of partial melt, volatiles, and compositional variations. Here we use seismic data from SW Europe and NW Africa, spanning the region between the Pyrenees and the Canaries, in order to obtain a new S-SKS relative arrival-time tomographic model of the upper mantle below Iberia, Western Morocco, and the Canaries. Similar to previous P wave tomographic results, the S wave model provides evidence for (1) subvertical upper-mantle low-velocity structures below the Canaries, Atlas Ranges, and Gibraltar Arc, which are interpreted as mantle upwellings fed by a common lower-mantle source below the Canaries; and (2) two low-velocity anomalies below the eastern Rif and Betics that we interpret as the result of the interaction between quasi-toroidal mantle flow induced by the Gibraltar slab and the mantle upwelling behind it. The analysis of teleseismic P wave and S wave arrival-time residuals and the conversion of the low-velocity anomalies to temperature variations suggest that the upwellings in the upper mantle below the Canaries, Atlas Ranges, and Gibraltar Arc system may be solely thermal in nature, with temperature excesses in the range ~100–350 °C. Our results also indicate that local partial melting can be present at lithospheric depths, especially below the Atlas Ranges. The locations of thermal mantle upwellings are in good agreement with those of thinned lithosphere, moderate to high heat-flow measurements, and recent magmatic activity at the surface