This paper introduces new insights into the hydrochemical functioning of lowland river systems using field-based spectrophotometric and electrode technologies. The streamwater concentrations of ...nitrogen species and phosphorus fractions were measured at hourly intervals on a continuous basis at two contrasting sites on tributaries of the River Thames - one draining a rural catchment, the River Enborne, and one draining a more urban system, The Cut. The measurements complement those from an existing network of multi-parameter water quality sondes maintained across the Thames catchment and weekly monitoring based on grab samples. The results of the sub-daily monitoring show that streamwater phosphorus concentrations display highly complex dynamics under storm conditions dependent on the antecedent catchment wetness, and that diurnal phosphorus and nitrogen cycles occur under low flow conditions. The diurnal patterns highlight the dominance of sewage inputs in controlling the streamwater phosphorus and nitrogen concentrations at low flows, even at a distance of 7 km from the nearest sewage treatment works in the rural River Enborne. The time of sample collection is important when judging water quality against ecological thresholds or standards. An exhaustion of the supply of phosphorus from diffuse and multiple septic tank sources during storm events was evident and load estimation was not improved by sub-daily monitoring beyond that achieved by daily sampling because of the eventual reduction in the phosphorus mass entering the stream during events. The results highlight the utility of sub-daily water quality measurements and the discussion considers the practicalities and challenges of in situ, sub-daily monitoring.
Titin, an important protein in the sarcomere, is the largest human protein. This study identified mutations in the titin gene that result in a truncated protein as important causes of dilated ...cardiomyopathy.
Gene mutation is an important cause of cardiomyopathy. Mutations in eight sarcomere-protein genes cause hypertrophic cardiomyopathy, detected in 40 to 70% of patients.
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Variations in more than 40 genes, most of which encode components of the sarcomere, the cytoskeleton, or the nuclear lamina, have been shown or posited to cause dilated cardiomyopathy.
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Clinical evaluation identifies 30 to 50% of patients with dilated cardiomyopathy as having a relative who is affected or likely to be affected,
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implicating a genetic cause. However, pathogenic mutations have been found in only 20 to 30% of patients.
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TTN,
the gene encoding titin, . . .
Aims/hypothesis Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. ...The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. Methods A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. Results A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). Conclusions/interpretation Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.
Sequence stratigraphy emphasizes facies relationships and stratal architecture within a chronological framework. Despite its wide use, sequence stratigraphy has yet to be included in any ...stratigraphic code or guide. This lack of standardization reflects the existence of competing approaches (or models) and confusing or even conflicting terminology. Standardization of sequence stratigraphy requires the definition of the fundamental model-independent concepts, units, bounding surfaces and workflow that outline the foundation of the method. A standardized scheme needs to be sufficiently broad to encompass all possible choices of approach, rather than being limited to a single approach or model.
A sequence stratigraphic framework includes genetic units that result from the interplay of accommodation and sedimentation (i.e., forced regressive, lowstand and highstand normal regressive, and transgressive), which are bounded by ‘sequence stratigraphic’ surfaces. Each genetic unit is defined by specific stratal stacking patterns and bounding surfaces, and consists of a tract of correlatable depositional systems (i.e., a ‘systems tract’). The mappability of systems tracts and sequence stratigraphic surfaces depends on depositional setting and the types of data available for analysis. It is this high degree of variability in the precise expression of sequence stratigraphic units and bounding surfaces that requires the adoption of a methodology that is sufficiently flexible that it can accommodate the range of likely expressions. The integration of outcrop, core, well-log and seismic data affords the optimal approach to the application of sequence stratigraphy. Missing insights from one set of data or another may limit the ‘resolution’ of the sequence stratigraphic interpretation.
A standardized workflow of sequence stratigraphic analysis requires the identification of all genetic units and bounding surfaces that can be delineated objectively, at the selected scale of observation, within a stratigraphic section. Construction of this model-independent framework of genetic units and bounding surfaces ensures the success of the sequence stratigraphic method. Beyond this, the interpreter may make model-dependent choices with respect to which set of sequence stratigraphic surfaces should be elevated in importance and be selected as sequence boundaries. In practice, the succession often dictates which set of surfaces are best expressed and hold the greatest utility at defining sequence boundaries and quasi-chronostratigraphic units. The nomenclature of systems tracts and sequence stratigraphic surfaces is also model-dependent to some extent, but a standard set of terms is recommended to facilitate communication between all practitioners.
The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We ...used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG).
In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent 18F-NaF and 18F-FDG PET-CT, and invasive coronary angiography. 18F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of 18F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction.
In 37 (93%) patients with myocardial infarction, the highest coronary 18F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 IQR 1·40–2·25 vs highest non-culprit 1·24 1·06–1·38, p<0·0001). By contrast, coronary 18F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 1·40–2·13 vs 1·58 1·28–2·01, p=0·34). Marked 18F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal 18F-NaF uptake (maximum tissue-to-background ratio 1·90 IQR 1·61–2·17) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 1·09–1·19 vs 1·01 0·94–1·06; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% 21–29 vs 18% 14–22, p=0·001).
18F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease.
Chief Scientist Office Scotland and British Heart Foundation.
During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction ...cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling.
Dark sectors charged under a new Abelian interaction have recently received much attention in the context of dark matter models. These models introduce a light new mediator, the so-called dark photon ...(A^{'}), connecting the dark sector to the standard model. We present a search for a dark photon in the reaction e^{+}e^{-}→γA^{'}, A^{'}→e^{+}e^{-}, μ^{+}μ^{-} using 514 fb^{-1} of data collected with the BABAR detector. We observe no statistically significant deviations from the standard model predictions, and we set 90% confidence level upper limits on the mixing strength between the photon and dark photon at the level of 10^{-4}-10^{-3} for dark photon masses in the range 0.02-10.2 GeV. We further constrain the range of the parameter space favored by interpretations of the discrepancy between the calculated and measured anomalous magnetic moment of the muon.
Films of ZnO doped with magnetic ions Mn and Co and, in some cases, with Al have been fabricated with a very wide range of carrier densities. Ferromagnetic behavior is observed in both insulating and ...metallic films, but not when the carrier density is intermediate. Insulating films exhibit variable range hopping at low temperatures and are ferromagnetic at room temperature due to the interaction of the localized spins with static localized states. The magnetism is quenched when carriers in the localized states become mobile. In the metallic (degenerate semiconductor) range, robust ferromagnetism reappears together with very strong magneto-optic signals and room temperature anomalous Hall data. This demonstrates the polarization of the conduction bands and indicates that, when ZnO is doped into the metallic regime, it behaves as a genuine magnetic semiconductor.
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