This Letter reports the first extraction of individual antineutrino spectra from ^{235}U and ^{239}Pu fission and an improved measurement of the prompt energy spectrum of reactor antineutrinos at ...Daya Bay. The analysis uses 3.5×10^{6} inverse beta-decay candidates in four near antineutrino detectors in 1958 days. The individual antineutrino spectra of the two dominant isotopes, ^{235}U and ^{239}Pu, are extracted using the evolution of the prompt spectrum as a function of the isotope fission fractions. In the energy window of 4-6 MeV, a 7% (9%) excess of events is observed for the ^{235}U (^{239}Pu) spectrum compared with the normalized Huber-Mueller model prediction. The significance of discrepancy is 4.0σ for ^{235}U spectral shape compared with the Huber-Mueller model prediction. The shape of the measured inverse beta-decay prompt energy spectrum disagrees with the prediction of the Huber-Mueller model at 5.3σ. In the energy range of 4-6 MeV, a maximal local discrepancy of 6.3σ is observed.
Deducing mechanisms for advance and retreat of magmatic arcs is fundamental to understanding accretionary tectonics and the evolution of continents. However, first‐order explanations of large spatial ...and long temporal changes in magmatic arcs remain elusive. We present isotopic evidence that Cordilleran magmatic arc systems were controlled by spherical harmonic degree‐2 mantle convection and characterized by two antipodal upwellings bisected by a meridional downwelling. Once established, the meridional “subduction girdle” drives hemispheric slab rollback and remains the locus of Cordilleran oceanic arcs. Continual westward migration of the North and South American continents led to arc advancement and consumption of back‐arc basins, culminating in arc‐continent collisions and reversals of subduction polarity. Continental arcs initiated diachronously as North and South America arrived at the subduction girdle and oceanic arcs were accreted. Systematic patterns in radiogenic isotopes along the Cordilleran system support that slab dynamics are controlled, to first order, by long‐wavelength mantle convection.
Plain Language Summary
The migration of modern volcanic arcs has been demonstrated by geophysical methods to be controlled by mantle convection patterns. It is hypothesized that like an inverted sail, subducted oceanic slabs “blow in the mantle wind.” However, identifying geologic data supporting the long term and widespread migration patterns has remained elusive. Luckily, the geochemical signature of oceanic and continental arcs is controlled by the amount of continental material assimilated in the magmas and therefore can be distinguished by distinct signatures. We demonstrate a consistent evolution of the geochemical signature of the Cordilleran subduction system from Antarctica to northeast Russia that attests to a dramatic migration of subduction zone magmatism from a continental to oceanic position and then back to a continental position within the past ~150 Myr. These data suggest that volcanic arc migration is controlled at the first‐order by large‐scale and long‐lived mantle convection patterns.
Key Points
Migration of arc systems to meridional downwelling is driven by large‐scale mantle convection and outpaces continental drift
Radiogenic isotopic signatures suggest that arc migration to downwelling marks transition from continental to oceanic arcs
Oceanic arc accretion and beginning of renewed continental arc magmatism begins as continents override downwelling
Background
Phosphorylcholine (PC) is an important pro‐inflammatory damage‐associated molecular pattern. Previous data have shown that natural IgM anti‐PC protects against cardiovascular disease. We ...aimed to develop a monoclonal PC IgG antibody with anti‐inflammatory and anti‐atherosclerotic properties.
Methods
Using various techniques PC antibodies were validated and optimized. In vivo testing was performed in a femoral artery cuff model in ApoE3*Leiden mice. Safety studies are performed in rats and cynomolgus monkeys.
Results
A chimeric anti‐PC (PC‐mAb(T15), consisting of a human IgG1 Fc and a mouse T15/E06 Fab) was produced, and this was shown to bind specifically to epitopes in human atherosclerotic tissues. The cuff model results in rapid induction of inflammatory genes and altered expression of genes associated with ER stress and choline metabolism in the lesions. Treatment with PC‐mAb(T15) reduced accelerated atherosclerosis via reduced expression of endoplasmic reticulum stress markers and CCL2 production. Recombinant anti‐PC Fab fragments were identified by phage display and cloned into fully human IgG1 backbones creating a human monoclonal IgG1 anti‐PC (PC‐mAbs) that specifically bind PC, apoptotic cells and oxLDL. Based on preventing macrophage oxLDL uptake and CCL2 production, four monoclonal PC‐mAbs were selected, which to various extent reduced vascular inflammation and lesion development. Additional optimization and validation of two PC‐mAb antibodies resulted in selection of PC‐mAb X19‐A05, which inhibited accelerated atherosclerosis. Clinical grade production of this antibody (ATH3G10) significantly attenuated vascular inflammation and accelerated atherosclerosis and was tolerated in safety studies in rats and cynomolgus monkeys.
Conclusions
Chimeric anti‐PCs can prevent accelerated atherosclerosis by inhibiting vascular inflammation directly and through reduced macrophage oxLDL uptake resulting in decreased lesions. PC‐mAb represents a novel strategy for cardiovascular disease prevention.
Several fast solar wind streams and stream interaction regions (SIRs) were observed by the Parker Solar Probe (PSP) during its first orbit (2018 September-2019 January). During this time, several ...recurring SIRs were also seen at 1 au at both L1 (Advanced Composition Explorer (ACE) and Wind) and the location of the Solar Terrestrial Relations Observatory-Ahead (STEREO-A). In this paper, we compare four fast streams observed by PSP at different radial distances during its first orbit. For three of these fast stream events, measurements from L1 (ACE and Wind) and STEREO-A indicated that the fast streams were observed by both PSP and at least one of the 1 au monitors. Our associations are supported by simulations made by the ENLIL model driven by GONG-(ADAPT-)WSA, which allows us to contextualize the inner heliospheric conditions during the first orbit of PSP. Additionally, we determine which of these fast streams are associated with an SIR and characterize the SIR properties for these events. From these comparisons, we find that the compression region associated with the fast-speed streams overtaking the preceding solar wind can form at various radial distances from the Sun in the inner heliosphere inside 0.5 au, with the suprathermal ion population (energies between 30 and 586 keV) observed as isolated enhancements suggesting localized acceleration near the SIR stream interface at ∼0.3 au, which is unlike those seen at 1 au, where the suprathermal enhancements extend throughout and behind the SIR. This suprathermal enhancement extends further into the fast stream with increasing distance from the Sun.
Whether reperfusion into infarcted tissue exacerbates cerebral edema has treatment implications in patients presenting with extensive irreversible injury. We investigated the effects of endovascular ...thrombectomy and reperfusion on cerebral edema in patients presenting with radiological evidence of large hemispheric infarction at baseline.
In a systematic review and individual patient-level meta-analysis of 7 randomized controlled trials comparing thrombectomy versus medical therapy in anterior circulation ischemic stroke published between January 1, 2010, and May 31, 2017 (Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration), we analyzed the association between thrombectomy and reperfusion with maximal midline shift (MLS) on follow-up imaging as a measure of the space-occupying effect of cerebral edema in patients with large hemispheric infarction on pretreatment imaging, defined as diffusion-magnetic resonance imaging or computed tomography (CT)-perfusion ischemic core 80 to 300 mL or noncontrast CT-Alberta Stroke Program Early CT Score ≤5. Risk of bias was assessed using the Cochrane tool.
Among 1764 patients, 177 presented with large hemispheric infarction. Thrombectomy and reperfusion were associated with functional improvement (thrombectomy common odds ratio =2.30 95% CI, 1.32–4.00; reperfusion common odds ratio =4.73 95% CI, 1.66–13.52) but not MLS (thrombectomy β=−0.27 95% CI, −1.52 to 0.98; reperfusion β=−0.78 95% CI, −3.07 to 1.50) when adjusting for age, National Institutes of Health Stroke Score, glucose, and time-to-follow-up imaging. In an exploratory analysis of patients presenting with core volume >130 mL or CT-Alberta Stroke Program Early CT Score ≤3 (n=76), thrombectomy was associated with greater MLS after adjusting for age and National Institutes of Health Stroke Score (β=2.76 95% CI, 0.33–5.20) but not functional improvement (odds ratio, 1.71 95% CI, 0.24–12.08).
In patients presenting with large hemispheric infarction, thrombectomy and reperfusion were not associated with MLS, except in the subgroup with very large core volume (>130 mL) in whom thrombectomy was associated with increased MLS due to space-occupying ischemic edema. Mitigating cerebral edema-mediated secondary injury in patients with very large infarcts may further improve outcomes after reperfusion therapies.
One of the biggest risk factors for developing Alzheimer’s disease is advanced age. Despite several studies examining changes to phospholipids in the hippocampus during the pathogenesis of ...Alzheimer’s disease, little is known regarding changes to phospholipids in this region during normal adult aging. This study examined the phospholipid composition of the mitochondrial and microsomal membranes of the human hippocampus from post-mortem tissue of neurologically normal subjects aged between 18 and 104 years. Many of the age-related changes found were in low-to-moderately abundant phospholipids in both membrane fractions, with decreases with age being seen in many phospholipids containing either adrenic or arachidonic acid. The most abundant phospholipid of this type was phosphatidylethanolamine 18:0_22:4, which decreased in both the mitochondrial and microsomal membranes by approximately 20 % from ages 20 to 100. Subsequent decreases with age were seen in total adrenic and arachidonic acid in the phospholipids of both membrane fractions, but not in either fatty acid specifically within the phosphatidylethanolamine class. Increases with age were seen in the hippocampus for mitochondrial phosphatidylserine 18:0_22:6. This is the first report of changes to molecular phospholipids of the human hippocampus over the adult lifespan, with this study also providing a comprehensive profile of the phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine phospholipids of the human hippocampus.
Little is known about the regional extent and variability of nitrate from atmospheric deposition that is transported to streams without biological processing in forests. We measured water chemistry ...and isotopic tracers (δ18O and δ15N) of nitrate sources across the Northern Forest Region of the U.S. and Canada and reanalyzed data from other studies to determine when, where, and how unprocessed atmospheric nitrate was transported in catchments. These inputs were more widespread and numerous than commonly recognized, but with high spatial and temporal variability. Only 6 of 32 streams had high fractions (>20%) of unprocessed atmospheric nitrate during baseflow. Seventeen had high fractions during stormflow or snowmelt, which corresponded to large fractions in near-surface soil waters or groundwaters, but not deep groundwater. The remaining 10 streams occasionally had some (<20%) unprocessed atmospheric nitrate during stormflow or baseflow. Large, sporadic events may continue to be cryptic due to atmospheric deposition variation among storms and a near complete lack of monitoring for these events. A general lack of observance may bias perceptions of occurrence; sustained monitoring of chronic nitrogen pollution effects on forests with nitrate source apportionments may offer insights needed to advance the science as well as assess regulatory and management schemes.
Summary Background In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of ...the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included. Methods We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation. Findings We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2·49, 95% CI 1·76–3·53; p<0·0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2·6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction =0·43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3·68, 95% CI 1·95–6·92), those randomised more than 300 min after symptom onset (1·76, 1·05–2·97), and those not eligible for intravenous alteplase (2·43, 1·30–4·55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations. Interpretation Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion. Funding Medtronic.
(1) Background: Changes in phospholipid (phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine, i.e., PC, PE and PS) composition with age in the mitochondrial and microsomal membranes ...of the human cerebellum and motor cortex were examined and compared to previous analyses of the prefrontal cortex, hippocampus and entorhinal cortex. (2) Methods: Nano-electrospray ionization on a hybrid triple quadrupole−linear ion trap mass spectrometer was used to analyse the brain regions of subjects aged 18−104 years. (3) Results: With age, the cerebellum showed many changes in the major phospholipids (>10% of the phospholipid class). In both membrane types, these included increases in PE 18:0_22:6 and PS 18:0_22:6, decreases in PE 18:0_20:4 and PS 18:0_18:1 and an increase in PC 16:0_16:0 (microsomal membrane only). In addition, twenty-one minor phospholipids also changed. In the motor cortex, only ten minor phospholipids changed with age. With age, the acyl composition of the membranes in the cerebellum increased in docosahexaenoic acid (22:6) and decreased in the arachidonic (20:4) and adrenic (22:4) acids. A comparison of phospholipid changes in the cerebellum, motor cortex and other brain areas is provided. (4) Conclusions: The cerebellum is exceptional in the large number of major phospholipids that undergo changes (with consequential changes in acyl composition) with age, whereas the motor cortex is highly resistant to change.
Exercising in the heat induces thermoregulatory and other physiological strain that can lead to impairments in endurance exercise capacity. The purpose of this consensus statement is to provide ...up-to-date recommendations to optimise performance during sporting activities undertaken in hot ambient conditions. The most important intervention one can adopt to reduce physiological strain and optimise performance is to heat acclimatise. Heat acclimatisation should comprise repeated exercise-heat exposures over 1-2 weeks. In addition, athletes should initiate competition and training in a euhydrated state and minimise dehydration during exercise. Following the development of commercial cooling systems (eg, cooling-vest), athletes can implement cooling strategies to facilitate heat loss or increase heat storage capacity before training or competing in the heat. Moreover, event organisers should plan for large shaded areas, along with cooling and rehydration facilities, and schedule events in accordance with minimising the health risks of athletes, especially in mass participation events and during the first hot days of the year. Following the recent examples of the 2008 Olympics and the 2014 FIFA World Cup, sport governing bodies should consider allowing additional (or longer) recovery periods between and during events, for hydration and body cooling opportunities, when competitions are held in the heat.
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