A new model of the deglaciation history of Antarctica over the past 25 kyr has been developed, which we refer to herein as ICE-6G_C (VM5a). This revision of its predecessor ICE-5G (VM2) has been ...constrained to fit all available geological and geodetic observations, consisting of: (1) the present day uplift rates at 42 sites estimated from GPS measurements, (2) ice thickness change at 62 locations estimated from exposure-age dating, (3) Holocene relative sea level histories from 12 locations estimated on the basis of radiocarbon dating and (4) age of the onset of marine sedimentation at nine locations along the Antarctic shelf also estimated on the basis of 14C dating. Our new model fits the totality of these data well. An additional nine GPS-determined site velocities are also estimated for locations known to be influenced by modern ice loss from the Pine Island Bay and Northern Antarctic Peninsula regions. At the 42 locations not influenced by modern ice loss, the quality of the fit of postglacial rebound model ICE-6G_C (VM5A) is characterized by a weighted root mean square residual of 0.9 mm yr–1. The Southern Antarctic Peninsula is inferred to be rising at 2 mm yr–1, requiring there to be less Holocene ice loss there than in the prior model ICE-5G (VM2). The East Antarctica coast is rising at approximately 1 mm yr–1, requiring ice loss from this region to have been small since Last Glacial Maximum. The Ellsworth Mountains, at the base of the Antarctic Peninsula, are inferred to be rising at 5–8 mm yr–1, indicating large ice loss from this area during deglaciation that is poorly sampled by geological data. Horizontal deformation of the Antarctic Plate is minor with two exceptions. First, O'Higgins, at the tip of the Antarctic Peninsula, is moving southeast at a significant 2 mm yr–1 relative to the Antarctic Plate. Secondly, the margins of the Ronne and Ross Ice Shelves are moving horizontally away from the shelf centres at an approximate rate of 0.8 mm yr–1, in viscous response to the early Holocene unloading of ice from the current locations of the ice shelf centers. ICE-6G_C (VM5A) fits the horizontal observations well (wrms residual speed of 0.7 mm yr–1), there being no need to invoke any influence of lateral variation in mantle viscosity. ICE-6G_C (VM5A) differs in several respects from the recently published W12A model of Whitehouse et al. First, the upper-mantle viscosity in VM5a is 5 × 1020 Pa s, half that in W12A. The VM5a profile, which is identical to that inferred on the basis of the Fennoscandian relaxation spectrum, North American relative sea level histories and Earth rotation constraints, when coupled with the revised ICE-6G_C deglaciation history, fits all of the available constraints. Secondly, the net contribution of Antarctica ice loss to global sea level rise is 13.6 m, 2/3 greater than the 8 m in W12A. Thirdly, ice loss occurs quickly from 12 to 5 ka, and the contribution to global sea level rise during Meltwater Pulse 1B (11.5 ka) is large (5 m), consistent with sedimentation constraints from cores from the Antarctica ice shelf. Fourthly, in ICE-6G_C there is no ice gain in the East Antarctica interior, as there is in W12A. Finally, the new model of Antarctic deglaciation reconciles the global constraint upon the global mass loss during deglaciation provided by the Barbados record of relative sea level history when coupled with the Northern Hemisphere counterpart of this new model.
A new model of the last deglaciation event of the Late Quaternary ice age is here described and denoted as ICE‐6G_C (VM5a). It differs from previously published models in this sequence in that it has ...been explicitly refined by applying all of the available Global Positioning System (GPS) measurements of vertical motion of the crust that may be brought to bear to constrain the thickness of local ice cover as well as the timing of its removal. Additional space geodetic constraints have also been applied to specify the reference frame within which the GPS data are described. The focus of the paper is upon the three main regions of Last Glacial Maximum ice cover, namely, North America, Northwestern Europe/Eurasia, and Antarctica, although Greenland and the British Isles will also be included, if peripherally, in the discussion. In each of the three major regions, the model predictions of the time rate of change of the gravitational field are also compared to that being measured by the Gravity Recovery and Climate Experiment satellites as an independent means of verifying the improvement of the model achieved by applying the GPS constraints. Several aspects of the global characteristics of this new model are also discussed, including the nature of relative sea level history predictions at far‐field locations, in particular the Caribbean island of Barbados, from which especially high‐quality records of postglacial sea level change are available but which records were not employed in the development of the model. Although ICE‐6G_C (VM5a) is a significant improvement insofar as the most recently available GPS observations are concerned, comparison of model predictions with such far‐field relative sea level histories enables us to identify a series of additional improvements that should follow from a further stage of model iteration.
Key Points
Space geodetic data are employed to constrain a global model of glacial isostasy
The GPS‐refined model is verified using GRACE time‐dependent gravity data
The spherically symmetric model of the GIA process is confirmed
NADPH oxidases are a family of enzymes that generate reactive oxygen species (ROS). The NOX1 (NADPH oxidase 1) and NOX2 oxidases are the major sources of ROS in the artery wall in conditions such as ...hypertension, hypercholesterolaemia, diabetes and ageing, and so they are important contributors to the oxidative stress, endothelial dysfunction and vascular inflammation that underlies arterial remodelling and atherogenesis. In this Review, we advance the concept that compared to the use of conventional antioxidants, inhibiting NOX1 and NOX2 oxidases is a superior approach for combating oxidative stress. We briefly describe some common and emerging putative NADPH oxidase inhibitors. In addition, we highlight the crucial role of the NADPH oxidase regulatory subunit, p47phox, in the activity of vascular NOX1 and NOX2 oxidases, and suggest how a better understanding of its specific molecular interactions may enable the development of novel isoform-selective drugs to prevent or treat cardiovascular diseases.
Influenza A virus pandemics and emerging anti-viral resistance highlight the urgent need for novel generic pharmacological strategies that reduce both viral replication and lung inflammation. We ...investigated whether the primary enzymatic source of inflammatory cell ROS (reactive oxygen species), Nox2-containing NADPH oxidase, is a novel pharmacological target against the lung inflammation caused by influenza A viruses. Male WT (C57BL/6) and Nox2(-/y) mice were infected intranasally with low pathogenicity (X-31, H3N2) or higher pathogenicity (PR8, H1N1) influenza A virus. Viral titer, airways inflammation, superoxide and peroxynitrite production, lung histopathology, pro-inflammatory (MCP-1) and antiviral (IL-1β) cytokines/chemokines, CD8(+) T cell effector function and alveolar epithelial cell apoptosis were assessed. Infection of Nox2(-/y) mice with X-31 virus resulted in a significant reduction in viral titers, BALF macrophages, peri-bronchial inflammation, BALF inflammatory cell superoxide and lung tissue peroxynitrite production, MCP-1 levels and alveolar epithelial cell apoptosis when compared to WT control mice. Lung levels of IL-1β were ∼3-fold higher in Nox2(-/y) mice. The numbers of influenza-specific CD8+D(b)NP(366)+ and D(b)PA(224)+ T cells in the BALF and spleen were comparable in WT and Nox2(-/y) mice. In vivo administration of the Nox2 inhibitor apocynin significantly suppressed viral titer, airways inflammation and inflammatory cell superoxide production following infection with X-31 or PR8. In conclusion, these findings indicate that Nox2 inhibitors have therapeutic potential for control of lung inflammation and damage in an influenza strain-independent manner.
Hypertension is a complex condition and is the most common cardiovascular risk factor, contributing to widespread morbidity and mortality. Approximately 90% of hypertension cases are classified as ...essential hypertension, where the precise cause is unknown. Hypertension is associated with inflammation; however, whether inflammation is a cause or effect of hypertension is not well understood. The purpose of this review is to describe evidence from human and animal studies that inflammation leads to the development of hypertension, as well as the evidence for involvement of oxidative stress and endothelial dysfunction—both thought to be key steps in the development of hypertension. Other potential proinflammatory conditions that contribute to hypertension—such as activation of the sympathetic nervous system, aging, and elevated aldosterone—are also discussed. Finally, we consider the potential benefit of anti-inflammatory drugs and statins for antihypertensive therapy. The evidence reviewed suggests that inflammation can lead to the development of hypertension and that oxidative stress and endothelial dysfunction are involved in the inflammatory cascade. Aging and aldosterone may also both be involved in inflammation and hypertension. Hence, in the absence of serious side effects, anti-inflammatory drugs could potentially be used to treat hypertension in the future.
Real-time quantitative polymerase chain reaction (qPCR) of complementary DNA is now a standard method for studies of gene expression. However, qPCR can identify genuine variation only when transcript ...quantities are accurately normalized to an appropriate reference. To identify the most reliable reference genes for transcript quantification by qPCR, we describe a systematic evaluation of candidate reference genes of Arabidopsis thaliana ecotype Columbia-0 (Col-0). Twelve genes were selected for transcript stability studies by qPCR of complementary DNA prepared from Arabidopsis leaf tissue infected with one of five plant viruses (Cauliflower mosaic virus, Tobacco mosaic virus, Tomato spotted wilt virus, Turnip mosaic virus, and Turnip yellow mosaic virus). The F-box family protein, elongation factor 1-α, sand family protein, and protodermal factor 2 gene transcripts showed the most stable accumulation, whereas a traditionally used reference gene, Actin8, showed the least stable accumulation as measured by the geNorm algorithm. The data furnish plant virologists with reference genes for normalization of qPCR-derived gene expression in virus-infected Arabidopsis and will be beneficial to the selection and design of primers targeting orthologous genes in other plant species.
Abstract
Despite substantial promise, the use of antioxidant therapy to improve cardiovascular outcomes has been disappointing. Whilst the fundamental biology supporting their use continues to build, ...the challenge now is to differentially target dysregulated redox signalling domains and to identify new ways to deliver antioxidant substances. Looking further afield to other disciplines, there is an emerging ‘tool-kit’ containing sophisticated molecular and drug delivery applications. Applying these to the cardiovascular redox field could prove a successful strategy to combat the increasing disease burden. Excessive reactive oxygen species production and protein modifications in the mitochondria has been the target of successful drug development with several positive outcomes emerging in the cardiovascular space, harnessing both improved delivery mechanisms and enhanced understanding of the biological abnormalities. Using this as a blueprint, similar strategies could be applied and expanded upon in other redox-hot-spots, such as the caveolae sub-cellular region, which houses many of the key cardiovascular redox proteins such as NADPH oxidase, endothelial nitric oxide synthase, angiotensin II receptors, and beta adrenoceptors. The expanded tool kit of drug development, including gene and miRNA therapies, nanoparticle technology and micropeptide targeting, can be applied to target dysregulated redox signalling in subcellular compartments of cardiovascular cells. In this review, we consider the opportunities for improving cardiovascular outcomes by utilizing new technology platforms to target subcellular ‘bonfires’ generated by dysregulated redox pathways, to improve clinical outcomes.
Abstract
Aims
Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic ...diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension.
Methods and results
C57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25–40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206+ (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, Na+, and albuminuria (each by 20–25%). None of the above parameters were altered by MCC950 in normotensive mice.
Conclusion
MCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy.
The endothelium is essential for the maintenance of vascular homeostasis. Central to this role is the production of endothelium-derived nitric oxide (EDNO), synthesized by the endothelial isoform of ...nitric oxide synthase (eNOS). Endothelial dysfunction, manifested as impaired EDNO bioactivity, is an important early event in the development of various vascular diseases, including hypertension, diabetes, and atherosclerosis. The degree of impairment of EDNO bioactivity is a determinant of future vascular complications. Accordingly, growing interest exists in defining the pathologic mechanisms involved. Considerable evidence supports a causal role for the enhanced production of reactive oxygen species (ROS) by vascular cells. ROS directly inactivate EDNO, act as cell-signaling molecules, and promote protein dysfunction, events that contribute to the initiation and progression of endothelial dysfunction. Increasing data indicate that strategies designed to limit vascular ROS production can restore endothelial function in humans with vascular complications. The purpose of this review is to outline the various ways in which ROS can influence endothelial function and dysfunction, describe the redox mechanisms involved, and discuss approaches for preventing endothelial dysfunction that may highlight future therapeutic opportunities in the treatment of cardiovascular disease.
Improved medical care over more than five decades has markedly increased life expectancy, from 12 years to approximately 60 years, in people with Down syndrome (DS). With increased survival into late ...adulthood, there is now a greater need for the medical care of people with DS to prevent and treat aging-related disorders. In the wider population, acquired cardiovascular diseases such as stroke and coronary heart disease are common with increasing age, but the risks of these diseases in people with DS are unknown. There are no population-level data on the incidence of acquired major cerebrovascular and coronary diseases in DS, and no data examining how cardiovascular comorbidities or risk factors in DS might impact on cardiovascular event incidence. Such data would be also valuable to inform health care planning for people with DS. Our objective was therefore to conduct a population-level matched cohort study to quantify the risk of incident major cardiovascular events in DS.
A population-level matched cohort study compared the risk of incident cardiovascular events between hospitalized patients with and without DS, adjusting for sex, and vascular risk factors. The sample was derived from hospitalization data within the Australian state of Victoria from 1993-2010. For each DS admission, 4 exact age-matched non-DS admissions were randomly selected from all hospitalizations within a week of the relevant DS admission to form the comparison cohort. There were 4,081 people with DS and 16,324 without DS, with a total of 212,539 person-years of observation. Compared to the group without DS, there was a higher prevalence in the DS group of congenital heart disease, cardiac arrhythmia, dementia, pulmonary hypertension, diabetes and sleep apnea, and a lower prevalence of ever-smoking. DS was associated with a greater risk of incident cerebrovascular events (Risk Ratio, RR 2.70, 95% CI 2.08, 3.53) especially among females (RR 3.31, 95% CI 2.21, 4.94) and patients aged ≤ 50 years old. The association of DS with ischemic strokes was substantially attenuated on adjustment for cardioembolic risk (RR 1.93, 95% CI 1.04, 3.20), but unaffected by adjustment for atherosclerotic risk. DS was associated with a 40-70% reduced risk of any coronary event in males (RR 0.58, 95% CI 0.40, 0.84) but not in females (RR 1.14, 95% CI 0.73, 1.77).
DS is associated with a high risk of stroke, expressed across all ages. Ischemic stroke risk in DS appears mostly driven by cardioembolic risk. The greater risk of hemorrhagic stroke and lower risk of coronary events (in males) in DS remain unexplained.
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