RATIONALE:Atherosclerosis and aneurysms are leading causes of mortality worldwide. MicroRNAs (miRs) are key determinants of gene and protein expression, and atypical miR expression has been ...associated with many cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm stability are poorly understood.
OBJECTIVE:To investigate whether miR-181b regulates tissue inhibitor of metalloproteinase-3 expression and affects atherosclerosis and aneurysms.
METHODS AND RESULTS:Here, we demonstrate that miR-181b was overexpressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms and correlated with decreased expression of predicted miR-181b targets, tissue inhibitor of metalloproteinase-3, and elastin. Using the well-characterized mouse atherosclerosis models of Apoe and Ldlr, we observed that in vivo administration of locked nucleic acid anti-miR-181b retarded both the development and the progression of atherosclerotic plaques. Systemic delivery of anti-miR-181b in angiotensin II–infused Apoe and Ldlr mice attenuated aneurysm formation and progression within the ascending, thoracic, and abdominal aorta. Moreover, miR-181b inhibition greatly increased elastin and collagen expression, promoting a fibrotic response and subsequent stabilization of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage tissue inhibitor of metalloproteinase-3 expression and vascular smooth muscle cell elastin production, both important factors in maintaining atherosclerotic plaque and aneurysm stability. Validation studies in Timp3 mice confirmed that the beneficial effects afforded by miR-181b inhibition are largely tissue inhibitor of metalloproteinase-3 dependent, while also revealing an additional protective effect through elevating elastin synthesis.
CONCLUSIONS:Our findings suggest that the management of miR-181b and its target genes provides therapeutic potential for limiting the progression of atherosclerosis and aneurysms and protecting them from rupture.
Suitable autologous conduits may be lacking when performing coronary artery bypass grafting. The aim of this review is to determine the status of nonautologous grafts in coronary artery bypass ...grafting.
We conducted a literature search on MEDLINE All, Embase Classic, and Embase through Ovid from 1960 to April 2020.
Of the 1579 records identified, 21 studies were included in the review. The following grafts were assessed for patency: 109 homologous saphenous veins (patency rates ranged from 66.7% at a median follow-up of 8.5 months to 0% at 6-12 months and 7-18 months, respectively), 29 expanded polytetrafluoroethylene grafts (from 80% at a median follow-up of 5 months to 14.3% at 45 months), 12 human umbilical veins (50% at a median follow-up of 6 months), 50 Bioflow bovine internal mammary arteries (from 15.8% to 0% at a mean follow-up of 9.5 months and 19 months, respectively), 39 Perma-Flow grafts (80% and 76.9% at 1-3 months and 12 months, respectively), 20 No-React bovine internal mammary arteries (57.1% at a median follow-up of 28 months and 23.1% at a mean follow-up of 7 months), 40 autologous venous endothelial cell–seeded expanded polytetrafluoroethylene grafts (94.7% and 81% at a mean follow-up of 27 months and 60 months, respectively), and 12 autologous venous endothelial cell–seeded cryopreserved homologous veins (83.3% at a mean follow-up of 8.5 months).
The goal of an alternative conduit with patency and attributes that match those of autografts remains elusive. Autologous endothelial cell–seeded synthetic grafts have demonstrated promising results but require further investigation.
The timing of crustal thickening in the northern Central Andean Plateau (CAP), at 13–20°S, and its relationship to surface uplift is debated. Zircon qualitatively records crustal thickness as its ...trace element chemistry is controlled by the growth of cogenetic minerals and relative uptake of light and heavy Rare Earth Elements. Jurassic to Neogene zircons from volcanic rocks, sandstones, and river sediments reveal shifts in trace element ratios suggesting major crustal thickening at 80–55 Ma and 35–0 Ma, coincident with high‐flux magmatism. An intervening magmatic lull due to shallow subduction obscures the magmatic record from 55 to 35 Ma during which thickening continued via crustal shortening. Protracted thickening since the Late Cretaceous correlates with early elevation gain of the CAP western margin, but contrasts with Miocene establishment of near modern elevation in the northern CAP and the onset of hyperaridity along the Pacific coast, highlighting their complex spatial and temporal relationship.
Plain Language Summary
Detailed relationships between crustal thickening, surface uplift, and climate remain unresolved. Although most mountains seem to be in isostatic equilibrium today, there is an imperfect correlation between elevation and crustal thickness in the modern continental lithosphere globally. We report trace element geochemical data of zircons extracted from volcanic rocks, sandstones, and modern river sediments collected in the northern Central Andean Plateau. Our analysis suggests that crustal thickness significantly increased from 80 to 55 Ma and from 35 Ma to present. The magmatic record between these two periods is obscured because the subducting slab shallowed, causing a decrease in magmatic activity; despite this, crustal thickening continued due to crustal shortening. The ∼80 Myr history of crustal shortening correlates with an early phase of surface uplift on the western side of the orogenic system, but contrasts with the main phase of plateau uplift and establishment of hyperaridity along the Pacific coast.
Key Points
New zircon trace element data record thin crust at 200–80 Ma and major phases of crustal thickening at 80–55 and 35 Ma to present
Thickening at 55–35 Ma is obscured by a magmatic lull due to shallow subduction, during which thickening continued via crustal shortening
Results highlight the complex spatiotemporal relationship of late Cenozoic Central Andean crustal thickening, surface uplift, and climate
One billion people worldwide experience intermittent water supply (IWS), in which piped water is delivered for limited durations. Households with IWS must invest in water storage infrastructure and ...often rely on multiple sources of water; therefore, these household-level purchasing and infrastructure decisions is a critical component of water access. Informed by interviews with IWS households, we use radial basis function networks, a type of artificial neural network, to determine optimal household water management decisions that maximize reliability of water supply while minimizing costs for a representative household in Mexico City that uses municipal piped water, trucked water, and rainwater. We find that securing reliable water supply for IWS households is greatly assisted by installation of household storage tanks of at least 2500 L. In the case of IWS households with limited storage options, the overall cost for water supply is reduced by scheduling water deliveries on nonconsecutive days. Rainwater harvesting systems were shown to be economically viable for households with limited water supply. This study demonstrates the importance of considering the management of multiple sources and household storage infrastructure when evaluating water investments in cities with IWS.
Summary
Plaque rupture underlies most myocardial infarctions. Plaques vulnerable to rupture have thin fibrous caps, an excess of macrophages over vascular smooth muscle cells, large lipid cores, and ...depletion of collagen and other matrix proteins form the cap and lipid core. Production of matrix metalloproteinases from macrophages is prominent in human plaques, and studies in genetically modified mice imply a causative role for metallopro teinases in plaque vulnerability. Recent in-vitro studies on human monocyte-derived macrophages and on foam-cell macrophages generated
in vivo
suggest the existence of several macrophage phenotypes with distinct patterns of metalloproteinase expression. These phenotypes could play differing roles in cap, core and aneurysm formation.
AbstractTranslation of a system’s performance goals into measurable quantities is fundamental for water systems planning. Frequently, the selected metrics are the same threshold-based metrics that ...have been common in water systems analysis for four decades. These are single statistic measures that characterize failure characteristics (e.g., frequency, duration, and magnitude) for a given simulation period where the failure threshold is a target delivery. At the same time, our systems are increasingly challenged by shifting water availability due to climate change and other anthropogenic pressures. Preparing our water systems to be resilient to such changes is a major challenge faced by water resources planners and managers. In particular, shifting mismatches between availability and target deliveries mean that for optimal design and control problems, metric choice implicitly becomes a statement of preference of failure type (i.e., the magnitude and/or duration of failure events). This usually occurs without explicit discussion of failure preference, resulting in unintended consequences that are not well understood. This study addresses the issue of unintended consequences in two ways. First, we introduce an approach to detect the threshold at which the balance between availability and delivery is no longer stable. Second, we characterize the consequences of metric choice when this threshold is exceeded. We find that early warning signals, and specifically the L moment estimator of variance, are able to detect the system’s entry into a state of increasing failure. We also find that for target deliveries greater than this threshold there are increasing tradeoffs between failure frequency, duration, and magnitude and that the distributional characteristics of failure magnitude and duration are driven by metric selection, objective formulation, and where on the Pareto front the solution sets lies. This study establishes a way to detect critical system thresholds and characterizes the effects of metric and threshold selection on failure, both of which are requisite for analysts and decision makers to avoid unintended consequences of planning and management decisions in an uncertain and changing world.
Practical ApplicationsMetrics form the basis of comparison for water resources planning and management decisions. When availability and demand are mismatched, the use of the standard threshold-based metrics in optimization problems can easily lead to unintended consequences. This is of fundamental concern for water resources planning and management in a changing world. This study helps analysts and decision makers avoid unintended consequence of poor metric selection by (1) characterizing the influence of metric selection on the types of failure events the system may endure; and (2) introducing a measure to detect the threshold at which analysts and decision makers should begin to be cautious of such consequences.
•Peru hosts a 1300 km long flat slab region and active aseismic ridge subduction.•We examine the role of flat slab versus ridge subduction in inducing exhumation.•Thermochronology/geomorphology show ...elevated exhumation in areas of ridge passage.•The subducting ridge induces transient uplift & exhumation in the overriding plate.•Our findings reconcile paleoflat slab regions with corridors of focused exhumation.
Subduction of aseismic ridges and flat slab subduction are important processes that punctuate Cordilleran orogenesis and may enhance exhumation and rock uplift in the overriding plate. Distinguishing between the two drivers is often challenging, as many modern flat slabs spatially coincide with subducting buoyant ridges. The Peruvian flat slab is the largest region of active flat slab subduction on Earth, spanning over 1300 km of the subducting Nazca plate along the western margin of South America. The flat slab is associated with two seafloor ridges: the Nazca Ridge at the southern terminus and the fully subducted Inca Plateau in the north. These aseismic ridges are spatially confined with respect to the flat slab, allowing assessment of the relative roles of aseismic ridge interactions and flat slab subduction in driving upper plate exhumation. We present: (1) a regional compilation of geochronologic ages of Andean igneous rocks, which track the spatio-temporal evolution of Neogene magmatic arc cessation and hence slab flattening; (2) calculated geomorphic indices, which document landscape perturbations and climatic or lithologic changes, (3) a summary of erosion rates from river catchments on the western Andean slope, and; (4) a regional synthesis of thermochronologic ages that reflect the timing and magnitude of upper crustal cooling.
Thermochronometric cooling ages systematically track the progressive passage of the Nazca Ridge, suggesting that the buoyant ridge focused exhumation in the overriding plate. Geomorphic indices demonstrate enhanced topography and steeper channels closer to the position of the subducted ridge. The spatial progression of basement block uplifts in Peru also coincides with the timing of ridge passage. In hinterland regions, >2 km of exhumation occurred since ca. 15 Ma above the Peruvian flat slab. For individual locations within the orogen, active rock uplift declines after ridge passage, suggesting that increased coupling is not maintained across the entirety of the flat slab. We argue that above broad zones of flat slab subduction, focused areas of aseismic ridge subduction concentrate upper-plate exhumation and uplift. These observations may be relevant to other flat slab systems, which exhibit a broad zone of arc shutoff with corridors of focused exhumation.
The subduction of bathymetric highs, such as aseismic ridges, leads to far‐reaching changes in the dynamics of subduction zones with increased plate coupling and deformation in the upper plate. ...Subduction of the submarine Carnegie Ridge on the Nazca Plate has fundamentally impacted late Cenozoic magmatism and tectonic activity in the northern Andes. However, the timing of onset of Carnegie Ridge subduction has been a matter of debate. Time‐temperature inverse modeling of new thermochronological data from the Western Cordillera of Ecuador reveals two phases of cooling separated by isothermal conditions. The first cooling phase postdates early and middle Miocene magmatism in the Western Cordillera and is attributed to post‐magmatic thermal relaxation. The second cooling phase started after 6 Ma. Inferred to record the onset of tectonically controlled rock uplift and exhumation in the Western Cordillera, this phase is coeval with the last cooling phase recorded in the Eastern Cordillera. Based on these findings, we suggest that the onset of subduction of the Carnegie Ridge at ∼6–5 Ma increased plate coupling at the subduction interface, promoting shortening, regional rock uplift, and exhumation in the northern Andes. Overall, our results highlight the essential role of bathymetric highs in driving regional upper‐plate deformation at non‐collisional convergent plate margins.
Plain Language Summary
Topographic growth and morphology of the Andes have been influenced by subduction processes, tectonic inheritance, and climate. Here, we investigate the role of subduction of high topography on the ocean floor in driving deformation in the upper plate at the Nazca‐South America ocean‐continent plate margin. The subduction of the Carnegie Ridge, a linear, topographically high sector on the Nazca Plate, has impacted magmatism and deformation processes in the Ecuadorian Andes. However, the timing of onset of ridge subduction is debated. We employed radioisotopic dating techniques to evaluate the uplift of the Andes. These techniques record the cooling of rocks as mountain ranges are uplifted and eroded. The thermal histories of rocks from the Western Cordillera in Ecuador reveal two distinct cooling phases. The first cooling phase occurred shortly after Miocene magmatic bodies were emplaced in the Western Cordillera. The second cooling phase began at ∼6–5 Ma, coeval with the last cooling phase in the Eastern Cordillera. We attribute this cooling phase to the onset of uplift and erosion in the Western Cordillera. Based on these findings, we suggest that the onset of subduction of the Carnegie Ridge increased plate coupling and promoted shortening and rock uplift in the northern Andes.
Key Points
Thermochronological data reveal two cooling phases in the Western Cordillera of Ecuador, during the Miocene and after 6 Ma
The onset of cooling at 6 Ma was associated with shortening, rock uplift, and exhumation in the Western Cordillera
Mio‐Pliocene exhumation was related to stronger coupling of the subduction interface due to the initial subduction of the Carnegie Ridge
OBJECTIVE:Galectin-3 (formerly known as Mac-2), encoded by the LGALS3 gene, is proposed to regulate macrophage adhesion, chemotaxis, and apoptosis. We investigated the role of galectin-3 in ...determining the inflammatory profile of macrophages and composition of atherosclerotic plaques.
APPROACH AND RESULTS:We observed increased accumulation of galectin-3–negative macrophages within advanced human, rabbit, and mouse plaques compared with early lesions. Interestingly, statin treatment reduced galectin-3–negative macrophage accrual in advanced plaques within hypercholesterolemic (apolipoprotein E deficient) Apoe mice. Accordingly, compared with Lgals3:Apoe mice, Lgals3:Apoe mice displayed altered plaque composition through increased macrophage:smooth muscle cell ratio, reduced collagen content, and increased necrotic core area, characteristics of advanced plaques in humans. Additionally, macrophages from Lgals3 mice exhibited increased invasive capacity in vitro and in vivo. Furthermore, loss of galectin-3 in vitro and in vivo was associated with increased expression of proinflammatory genes including MMP (matrix metalloproteinase)-12, CCL2 (chemokine C-C motif ligand 2), PTGS2 (prostaglandin-endoperoxide synthase 2), and IL (interleukin)-6, alongside reduced TGF (transforming growth factor)-β1 expression and consequent SMAD signaling. Moreover, we found that MMP12 cleaves macrophage cell-surface galectin-3 resulting in the appearance of a 22-kDa fragment, whereas plasma levels of galectin-3 were reduced in Mmp12:Apoe mice, highlighting a novel mechanism where MMP12-dependent cleavage of galectin-3 promotes proinflammatory macrophage polarization. Moreover, galectin-3–positive macrophages were more abundant within plaques of Mmp12:Apoe mice compared with Mmp12:Apoe animals.
CONCLUSIONS:This study reveals a prominent protective role for galectin-3 in regulating macrophage polarization and invasive capacity and, therefore, delaying plaque progression.
In part A, the aim was to define the maximum tolerated dose (MTD) of the hydrogen sulfate (Hyd-Sulfate) oral capsule formulation of the mitogen-activated protein kinase kinase inhibitor AZD6244 ...(ARRY-142886). In part B, the aim was to compare the pharmacokinetic profile of the new Hyd-Sulfate capsule with the initial AZD6244 free-base suspension and further characterize the pharmacodynamic profile and efficacy of the new formulation.
In part A, 30 patients received escalating doses of AZD6244 Hyd-Sulfate twice daily. In part B, 29 patients were randomized to a single dose of the Hyd-Sulfate capsule or free-base suspension, followed by a washout, then a single dose of the alternative formulation. Patients received the Hyd-Sulfate capsule twice daily at MTD of part A thereafter.
The MTD of the Hyd-Sulfate capsule was 75 mg twice daily. Dose limiting toxicities were Common Terminology Criteria for Adverse Events grade 3 acneiform rash and pleural effusion. Fatigue (65.7%) and acneiform dermatitis (60.0%) were the most frequent adverse events at the MTD. Based on area under curve(0-24), exposure of the 75 mg Hyd-Sulfate capsule relative to the 100 mg free-base suspension was 197% (90% confidence interval, 161-242%). Pharmacodynamic analysis showed that inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced extracellular signal-regulated kinase phosphorylation in peripheral blood lymphocytes was related to plasma concentrations of AZD6244, with an estimated IC(50) of 352 ng/mL and maximum inhibition (E(max)) of approximately 91%, showing target inhibition. A patient with metastatic melanoma bearing a V600E BRAF mutation achieved a complete response persisting after 15 months of therapy.
The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials.
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