Persistent, depth-intensified mixing during the Western Mediterranean Transition's initial stages

Piñeiro, S., González-Pola, C., Fernández-Díaz, J. M., Naveira-Garabato, A. C., Sánchez-Leal, R., Puig, P., et al. (2021). Persistent, depth-intensified mixing during the Western Mediterranean Transition's initial stages. Journal of Geophysical Research: Oceans, 126, e2020JC016535. https://doi.org/10.1029/2020JC016535. © 2020. American Geophysical Union. All Rights Reserved.© 2020. American Geophysical Union. All Rights Reserved. Major deep-convection activity in the northwestern Mediterranean during winter 2005 triggered the formation of a complex anomalous deep-water structure that substantially modified the properties of the Western Mediterranean deep layers. Since then, evolution of this thermohaline structure, the so-called Western Mediterranean Transition (WMT), has been traced through a regularly sampled hydrographic deep station located on the outer continental slope of Minorca Island. A rapid erosion of the WMT's near-bottom thermohaline signal was observed during 2005–2007. The plausible interpretation of this as local bottom-intensified mixing motivates this study. Here, the evolution of the WMT structure through 2005–2007 is reproduced by means of a one-dimensional diffusion model including double-diffusive mixing that allows vertical variation of the background mixing coefficient and includes a source term to represent the lateral advection of deep-water injections from the convection area. Using an optimization algorithm, a best guess for the depth-dependent background mixing coefficient is obtained for the study period. WMT evolution during its initial stages is satisfactorily reproduced using this simple conceptual model, indicating that strong depth-intensified mixing (K ∞ (z) ≈ 22 × 10−4 m2 s−1; z ⪆ 1,400 dbar) is a valid explanation for the observations. Extensive hydrographic and current observations gathered over the continental slope of Minorca during winter 2018, the first deep-convective winter intensively sampled in the region, provide evidence of topographically localized enhanced mixing concurrent with newly formed dense waters flowing along-slope toward the Algerian sub-basin. This transport-related boundary mixing mechanism is suggested to be a plausible source of the water-mass transformations observed during the initial stages of the WMT off Minorca.CTM2014-54374-R. BES-2015-074316.Versión del editor3,17

IL-4 Amplifies the Pro-Inflammatory Effect of Adenosine in Human Mast Cells by Changing Expression Levels of Adenosine Receptors

Adenosine inhalation produces immediate bronchoconstriction in asthmatics but not in normal subjects. The bronchospastic effect of adenosine is largely mediated through adenosine-induced mast cell activation, the mechanism of which is poorly understood due to limitations in culturing human primary mast cells. Here, we show that human umbilical cord blood -derived mast cells incubated with the Th2 cytokine IL-4 develop increased sensitivity to adenosine. Potentiation of anti-IgE- induced and calcium ionophore/PMA-induced degranulation was augmented in mast cells cultured with IL-4, and this effect was reduced or abolished by pre-treatment with A2BsiRNA and selective A2B receptor antagonists, respectively. IL-4 incubation resulted in the increased expression of A2B and reduced expression of A2A adenosine receptors on human mast cells. These results suggest that Th2 cytokines in the asthmatic lung may alter adenosine receptor expression on airway mast cells to promote increased responsiveness to adenosine

Recent improvements in the development of A2B adenosine receptor agonists

Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1Ki = 1050 nM, hA2AKi = 1550 nM, hA2B EC50 = 82 nM, hA3Ki > 5 μM) and its 2-chloro analogue 23 (hA1Ki = 3500 nM, hA2AKi = 4950 nM, hA2B EC50 = 210 nM, hA3Ki > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis

Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability

Prostacyclin (PGI2) modulates platelet activation to regulate haemostasis. Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI2 could reverse platelet spreading by actin cytoskeletal modulation, leading to reduced capability of platelet aggregates to withstand a high shear environment. Our data demonstrates that post-flow of PGI2 over activated and spread platelets on fibrinogen, identified a significant reduction in platelet surface area under high shear. Exploration of the molecular mechanisms underpinning this effect revealed that PGI2 reversed stress fibre formation in adherent platelets, reduced platelet spreading, whilst simultaneously promoting actin nodule formation. The effects of PGI2 on stress fibres were mimicked by the adenylyl cyclase activator forskolin and prevented by inhibitors of protein kinase A (PKA). Stress fibre formation is a RhoA dependent process and we found that treatment of adherent platelets with PGI2 caused inhibitory phosphorylation of RhoA, reduced RhoA GTP-loading and reversal of myosin light chain phosphorylation. Phospho-RhoA was localised in actin nodules with PKA type II and a number of other phosphorylated PKA substrates. This study demonstrates that PGI2 can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling thrombosis

Extracellular ATP is a pro-angiogenic factor for pulmonary artery vasa vasorum endothelial cells

Expansion of the vasa vasorum network has been observed in a variety of systemic and pulmonary vascular diseases. We recently reported that a marked expansion of the vasa vasorum network occurs in the pulmonary artery adventitia of chronically hypoxic calves. Since hypoxia has been shown to stimulate ATP release from both vascular resident as well as circulatory blood cells, these studies were undertaken to determine if extracellular ATP exerts angiogenic effects on isolated vasa vasorum endothelial cells (VVEC) and/or if it augments the effects of other angiogenic factors (VEGF and basic FGF) known to be present in the hypoxic microenvironment. We found that extracellular ATP dramatically increases DNA synthesis, migration, and rearrangement into tube-like networks on Matrigel in VVEC, but not in pulmonary artery (MPAEC) or aortic (AOEC) endothelial cells obtained from the same animals. Extracellular ATP potentiated the effects of both VEGF and bFGF to stimulate DNA synthesis in VVEC but not in MPAEC and AOEC. Analysis of purine and pyrimidine nucleotides revealed that ATP, ADP and MeSADP were the most potent in stimulating mitogenic responses in VVEC, indicating the involvement of the family of P2Y1-like purinergic receptors. Using pharmacological inhibitors, Western blot analysis, and Phosphatidylinositol-3 kinase (PI3K) in vitro kinase assays, we found that PI3K/Akt/mTOR and ERK1/2 play a critical role in mediating the extracellular ATP-induced mitogenic and migratory responses in VVEC. However, PI3K/Akt and mTOR/p70S6K do not significantly contribute to extracellular ATP-induced tube formation on Matrigel. Our studies indicate that VVEC, isolated from the sites of active angiogenesis, exhibit distinct functional responses to ATP, compared to endothelial cells derived from large pulmonary or systemic vessels. Collectively, our data support the idea that extracellular ATP participates in the expansion of the vasa vasorum that can be observed in hypoxic conditions

Нефрэктомия, тромбэктомия у больных раком почки с протяженным опухолевым венозным тромбозом: как выполнить операцию с минимальным риском для пациента?

Objective: to evaluate the outcomes of thrombectomy performed using different surgical techniques in renal cell carcinoma (RCC) patients with extensive tumor venous thrombosis.Materials and methods. This study included 345 RCC patients with extensive tumor venous thrombosis who underwent surgical treatment.The median age was 57 years (range: 16—79 years); the male-to-female ratio was 1:1.9. Two hundred and sixty patients (75.4 %) had their tumor thrombus originating from the right renal vein, 85 patients (24.6 %) — from the left renal vein. In 169 patients (49.0 %), the thrombus spread to the retrohepatic inferior vena cava (IVC), while in 176 patients (51.0 %), it spread above the diaphragm (to the intrapericardial IVC in 59 patients (17.1 %) and to the right heart cameras in 117 patients (33.9 %)). Regional metastases were found in 90 individuals (26.1 %), while distant metastases were observed in 124 patients (35.9 %). All patients underwent surgical treatment (radical in 251 patients (72.8 %) and cytoreductive — in 94patients (27.2 %)); the technique of vascular control and circulatory support was chosen individually. In 97 patients (28.1 %), the control over the cranial thrombus boarder did not require opening of the chest cavity; eleven patients (3.2 %) were operated on with cardiopulmonary bypass.Results. The median surgery time was 215 minutes; the median blood loss was 4500 mL. Intraoperative complications were registered in 209 patients (60.6 %) and postoperative complications were observed in 118 patients (35.1 %) (including those of grade I—II in 43 individuals (12.8 %) and grade III—V in 75 individual (22.3 %)). The in-hospital mortality rate was 10.7 % (37/345). At a median follow-up of 32.3 months, overall and diseasespecific survival rates among all patients were 51.9 % and 68.3 %, respectively; relapse-free survival rate in 226patients who have undergone radical surgeries and discharged from the hospital was 61.5 %; progression-free survival rate in 82 patients who have undergone cytoreductive surgery was 33.0 %. The method ofIVC control and circulatory support had no effect on both short-term and long-term treatment outcomes (p >0.05 for both).Conclusion. The use of minimally invasive techniques of vascular control and avoidance of cardiopulmonary bypass in carefully selected RCC patients with extensive tumor venous thrombosis do not worsen the outcomes of nephrectomy and thrombectomy.Цель исследования — оценить результаты применения различных методик тромбэктомии у больных почечно-клеточным раком с протяженным опухолевым венозным тромбозом.Материалы и методы. В исследование отобраны данные 345 больных почечно-клеточным раком с протяженным опухолевым венозным тромбозом, подвергнутых хирургическому лечению. Медиана возраста — 57 (16—79) лет, соотношение мужчин и женщин — 1:1,9. Опухолевый тромб исходил из правой почечной вены у 260 (75,4 %), из левой — у 85(24,6 %) пациентов. У 169 (49,0 %) больных тромб распространялся до ретропеченочного сегмента нижней полой вены, у 176 (51,0 %) — выше диафрагмы (до интра-перикардиального сегмента нижней полой вены — 59 (17,1 %), в правые камеры сердца — 117 (33,9 %)). Регионарные метастазы имели место у 90 (26,1 %), отдаленные — у 124 (35,9 %) пациентов. Всем больным выполнено хирургическое лечение (радикальное — 251 (72,8 %), циторедуктивное — 94 (27,2 %)), методика сосудистого контроля и циркуляторной поддержки определялась индивидуально. В 97 (28,1 %) случаях контроль краниальной границы тромба осуществлялся без вскрытия грудной полости, циркуляторная поддержка использовалась у 11 (3,2 %) больных.Результаты. Медиана операционного времени — 215 мин, медиана объема кровопотери — 4500 мл. Интраоперационные осложнения зарегистрированы в 209 (60,6 %), послеоперационные — в 118 (35,1 %) случаях (I—IIстепеней тяжести — 43 (12,8 %), III—V степеней тяжести — 75(22,3 %)). Госпитальная летальность составила 10,7 % (37/345). При медиане наблюдения 32,3 мес общая и специфическая выживаемость всех больных составила 51,9 и 68,3 %; безрецидивная выживаемость 226 радикально оперированных больных, выписанных из стационара, равнялась 61,5 %, беспрогрессивная выживаемость 82 пациентов, перенесших циторедуктивную операцию, — 33,0 %. Независимого влияния метода контроля нижней полой вены и циркуляторной поддержки на непосредственные и отдаленные результаты лечения не выявлено (р >0,05 для всех).Заключение. Использование малотравматичных методов сосудистого контроля и отказ от циркуляторной поддержки у отобранных больных почечно-клеточным раком с опухолевым венозным тромбозом не ухудшают результаты нефрэктомии, тромбэктомии

Adenosine A2A receptors: localization and function

Adenosine is an endogenous purine nucleoside present in all mammalian tissues, that originates from the breakdown of ATP. By binding to its four receptor subtypes (A1, A2A, A2B, and A3), adenosine regulates several important physiological functions at both the central and peripheral levels. Therefore, ligands for the different adenosine receptors are attracting increasing attention as new potential drugs to be used in the treatment of several diseases. This chapter is aimed at providing an overview of adenosine metabolism, adenosine receptors localization and their signal transduction pathways. Particular attention will be paid to the biochemistry and pharmacology of A2A receptors, since antagonists of these receptors have emerged as promising new drugs for the treatment of Parkinson's disease. The interactions of A2A receptors with other nonadenosinergic receptors, and the effects of the pharmacological manipulation of A2A receptors on different body organs will be discussed, together with the usefulness of A2A receptor antagonists for the treatment of Parkinson's disease and the potential adverse effects of these drugs

Ephrin-A5 and EphA5 Interaction Induces Synaptogenesis during Early Hippocampal Development

Synaptogenesis is a fundamental step in neuronal development. For spiny glutamatergic synapses in hippocampus and cortex, synaptogenesis involves adhesion of pre and postsynaptic membranes, delivery and anchorage of pre and postsynaptic structures including scaffolds such as PSD-95 and NMDA and AMPA receptors, which are glutamate-gated ion channels, as well as the morphological maturation of spines. Although electrical activity-dependent mechanisms are established regulators of these processes, the mechanisms that function during early development, prior to the onset of electrical activity, are unclear. The Eph receptors and ephrins provide cell contact-dependent pathways that regulate axonal and dendritic development. Members of the ephrin-A family are glycosyl-phosphatidylinositol-anchored to the cell surface and activate EphA receptors, which are receptor tyrosine kinases.Here we show that ephrin-A5 interaction with the EphA5 receptor following neuron-neuron contact during early development of hippocampus induces a complex program of synaptogenic events, including expression of functional synaptic NMDA receptor-PSD-95 complexes plus morphological spine maturation and the emergence of electrical activity. The program depends upon voltage-sensitive calcium channel Ca2+ fluxes that activate PKA, CaMKII and PI3 kinase, leading to CREB phosphorylation and a synaptogenic program of gene expression. AMPA receptor subunits, their scaffolds and electrical activity are not induced. Strikingly, in contrast to wild type, stimulation of hippocampal slices from P6 EphA5 receptor functional knockout mice yielded no NMDA receptor currents.These studies suggest that ephrin-A5 and EphA5 signals play a necessary, activity-independent role in the initiation of the early phases of synaptogenesis. The coordinated expression of the NMDAR and PSD-95 induced by eprhin-A5 interaction with EphA5 receptors may be the developmental switch that induces expression of AMPAR and their interacting proteins and the transition to activity-dependent synaptic regulation

P1 receptors and cytokine secretion

Evidence has accumulated in the last three decades to suggest tissue protection and regeneration by adenosine in multiple different cell types. Adenosine produced in hypoxic or inflamed environments reduces tissue injury and promotes repair by receptor-mediated mechanisms. Among other actions, regulation of cytokine production and secretion by immune cells, astrocytes and microglia (the brain immunocytes) has emerged as a main mechanism at the basis of adenosine effects in diseases characterized by a marked inflammatory component. Many recent studies have highlighted that signalling through A1 and A2A adenosine receptors can powerfully prevent the release of pro-inflammatory cytokines, thus inhibiting inflammation and reperfusion injury. However, the activation of adenosine receptors is not invariably protective of tissues, as signalling through the A2B adenosine receptor has been linked to pro-inflammatory actions which are, at least in part, mediated by increased release of pro-inflammatory cytokines from epithelial cells, astrocytes and fibroblasts. Here, we discuss the multiple actions of P1 receptors on cytokine secretion, by analyzing, in particular, the role of the various adenosine receptor subtypes, the complex reciprocal interplay between the adenosine and the cytokine systems, their pathophysiological significance and the potential of adenosine receptor ligands as new anti-inflammatory agents