Molecular hydrogen ions in weakly bound states close to the first dissociation threshold are attractive quantum sensors for measuring the proton-to-electron mass ratio and hyperfine-induced ...ortho-para mixing. The experimental accuracy of previous spectroscopic studies relying on fast ion beams could be improved by using state-of-the-art ion trap setups. With the electric dipole moment vanishing in H\(_2^+\) and preventing fast spontaneous emission, radiative lifetimes of the order of weeks are found. We include the effect of black-body radiation that can lead to photodissociation and rovibronic state redistribution to obtain effective lifetimes for trapped ion experiments. Rate coefficients for bound-bound and bound-continuum processes were calculated using adiabatic nuclear wave functions and nonadiabatic energies, including relativistic and radiative corrections. Effective lifetimes for the weakly bound states were obtained by solving a rate equation model and lifetimes in the range of 4 to 523~ms and \(>\)215~ms were found at room temperature and liquid nitrogen temperature, respectively. Black-body induced photodissociation was identified as the lifetime-limiting effect, which guarantees the purity of state-selectively generated molecular ion ensembles. The role of hyperfine-induced \(g/u\)-mixing, which allows pure rovibrational transitions, was found to be negligible.
Marine species are declining at an unprecedented rate, catalyzing many nations to adopt conservation and management targets within their jurisdictions. However, marine species and the biophysical ...processes that sustain them are naive to international borders. An understanding of the prevalence of cross‐border species distributions is important for informing high‐level conservation strategies, such as bilateral or regional agreements. Here, we examined 28,252 distribution maps to determine the number and locations of transboundary marine plants and animals. More than 90% of species have ranges spanning at least two jurisdictions, with 58% covering more than 10 jurisdictions. All jurisdictions have at least one transboundary species, with the highest concentrations of transboundary species in the USA, Australia, Indonesia, and the Areas Beyond National Jurisdiction. Distributions of mapped biodiversity indicate that overcoming the challenges of multinational governance is critical for a much wider suite of species than migratory megavertebrates and commercially exploited fish stocks—the groups that have received the vast majority of multinational management attention. To effectively protect marine biodiversity, international governance mechanisms (particularly those related to the Convention on Biological Diversity, the Convention on Migratory Species, and Regional Seas Organizations) must be expanded to promote multinational conservation planning, and complimented by a holistic governance framework for biodiversity beyond national jurisdiction.
An understanding of how species are distributed across political borders in the ocean is important for informing high‐level conservation strategies. We used 28,252 marine species range maps to determine the number and locations of transboundary plant and animal species. More than 90% of mapped marine species have ranges spanning at least two jurisdictions, with 58% covering more than 10 jurisdictions. All jurisdictions have at least one transboundary species, with the highest concentrations of transboundary species in the United States, Australia, Indonesia, and the Areas Beyond National Jurisdiction.
A qualitative, longitudinal study of two groups of experienced professionals beginning work in a research organization provided insights into how newcomers with work experience adjust to and become ...assimilated into new jobs and work settings. Multiple methods were used to collect data on the newcomers' work experiences before and after assuming their new jobs. Repeated interviews with them during their first six months in their new jobs revealed that their past experience affected their assimilation in three primary ways: through the personal identities they had developed and carried with them, through the know-how they had acquired in past jobs and how well it fit with their new jobs, and through the personal tactics they had learned for managing their work and managing change. In general, newcomers with diverse experience adjusted better than those with narrow experience because (1) they found it easier to enact dimensions of their personal identities that allowed them to function effectively in the new situation, (2) they more easily found a fit between know-how gleaned from that experience and their new jobs, and (3) they could draw on a wider variety of personal tactics that they had previously used to help them adjust.
Observations of Pluto's surface made by the New Horizons spacecraft indicates present-day nitrogen ice glaciation in and around the basin known as Sputnik Planum. Motivated by these observations, we ...have developed an evolutionary glacial flow model of solid nitrogen ice taking into account its published thermophysical and rheologies properties. This model assumes that glacial ice layers flow laminarly and have low aspect ratios which permits a vertically integrated mathematical formulation. We assess the conditions for the validity of laminar nitrogen ice motion by revisiting the problem of the onset of solid-state buoyant convection of nitrogen ice for a variety of bottom thermal boundary conditions. Subject to uncertainties in nitrogen ice rheology, nitrogen ice layers are estimated to flow laminarly for thicknesses less than 400-1000 meters. The resulting mass-flux formulation for when the nitrogen ice flows as a laminar dry glacier is characterized by an Arrhenius-Glen functional form. The flow model developed is used here to qualitatively answer some questions motivated by observed glacial flow features found on Sputnik Planum. We find that the wavy transverse dark features found along the northern shoreline of Sputnik Planum may be a transitory imprint of shallow topography just beneath the ice surface suggesting the possibility that a major shoreward flow event happened relatively recently within the last few hundred years. Model results also support the interpretation that the prominent darkened features resembling flow lobes observed along the eastern shoreline of the Sputnik Planum basin may be a result of wet nitrogen glacial ice flowing into the basin from the pitted highlands of eastern Tombaugh Regio.
The topography of rifts on icy bodies can be used to probe their internal properties. Uplifted and curved rift flanks occur when the elastic thickness (te) of the crust is low, indicative of high ...heat flow out of the body. Stereo topography of Pluto shows no evidence of rift-flank uplift associated with large extensional graben to the west of Sputnik Planitia. Modeling the amount of topographic deflection expected from varying elastic thicknesses yields a conservative lower bound on te of 8 km at the time of deformation; the maximum implied heat flux since graben formation is 66–85 mWm−2. This upper bound is consistent with the predicted paleo-heat fluxes from radioactive decay (~6 mWm−2), but likely only marginally consistent with nearby apparently viscously-relaxed impact craters. Additionally, we also analyze the shear stresses on these faults and find that Pluto's faults only need to support low stresses in the range of 100–300 kPa to explain their dimensions.
•Extensional graben on Pluto's surface show little to no signals of flexure.•This sets a lower limit of 8 km for the elastic layer of Pluto's icy crust.•An upper bound of 85 mWm−2 on the surface heat flux is also set.•This upper bound limits explanations for surface features via high heat flux processes.
This study examined vascular actions of angiotensin 1-7 (ANG 1-7) in human atrial and adipose arterioles.
The endothelium-derived hyperpolarizing factor of flow-mediated dilation (FMD) switches from ...antiproliferative nitric oxide (NO) to proatherosclerotic hydrogen peroxide in arterioles from humans with coronary artery disease (CAD). Given the known vasoprotective properties of ANG 1-7, we tested the hypothesis that overnight ANG 1-7 treatment restores the NO component of FMD in arterioles from patients with CAD. Endothelial telomerase activity is essential for preserving the NO component of vasodilation in the human microcirculation; thus, we also tested whether telomerase activity was necessary for ANG 1-7-mediated vasoprotection by treating separate arterioles with ANG 1-7±the telomerase inhibitor 2-(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-ylaminobenzoic acid. ANG 1-7 dilated arterioles from patients without CAD, whereas dilation was significantly reduced in arterioles from patients with CAD. In atrial arterioles from patients with CAD incubated with ANG 1-7 overnight, the NO synthase inhibitor NG-nitro-l-arginine methyl ester abolished FMD, whereas the hydrogen peroxide scavenger polyethylene glycol catalase had no effect. Conversely, in vessels incubated with ANG 1-7+2-(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-ylaminobenzoic acid, NG-nitro-l-arginine methyl ester had no effect on FMD, but polyethylene glycol catalase abolished dilation. In cultured human coronary artery endothelial cells, ANG 1-7 significantly increased telomerase activity. These results indicate that ANG 1-7 dilates human microvessels, and dilation is abrogated in the presence of CAD. Furthermore, ANG 1-7 treatment is sufficient to restore the NO component of FMD in arterioles from patients with CAD in a telomerase-dependent manner.
ANG 1-7 exerts vasoprotection in the human microvasculature via modulation of telomerase activity.
Photocurable nanocomposites have tremendous potential in tissue engineering, advanced manufacturing, and structural, multifunctional materials. This project investigates the effect of silica (SiO2) ...nanoparticle loading content on the thermal, mechanical, physical, and morphological characteristics of the nanocomposite. An increased concentration of SiO2 nanoparticles causes a decrease in the gel fraction of the nanocomposite, which, at low nanoparticle loading, degrades the thermal and mechanical properties. However, further addition (>3.8 wt %) causes an increase in the glass-transition temperature, Young’s modulus, and ultimate compressive strength. The addition of the nanoparticles had no significant effect on the hydrophilicity according to water uptake experiments. Small-angle X-ray scattering experiments, in conjunction with scanning electron microscopy and transmission electron microscopy, indicated a multimodal particle size distribution and the presence of large-scale aggregates.
Traditionally thought of primarily as the predominant regulator of myocardial perfusion, it is becoming more accepted that the human coronary microvasculature also exerts a more direct influence on ...the surrounding myocardium. Coronary microvascular dysfunction (CMD) not only precedes large artery atherosclerosis, but is associated with other cardiovascular diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy. It is also highly predictive of cardiovascular events in patients with or without atherosclerotic cardiovascular disease. This review focuses on this recent paradigm shift and delves into the clinical consequences of CMD. Concepts of how resistance arterioles contribute to disease will be discussed, highlighting how the microvasculature may serve as a potential target for novel therapies and interventions. Finally, both invasive and non‐invasive methods with which to assess the coronary microvasculature both for diagnostic and risk stratification purposes will be reviewed.
Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised ...controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.
These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8–10, and prostate-specific antigen PSA concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0–2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544.
Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63–73) and median PSA 34 ng/ml (14·7–47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60–84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable NE–NE) than in the control groups (not reached, 97–NE; hazard ratio HR 0·53, 95% CI 0·44–0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70–1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached IQR NE–NE in the combination-therapy groups vs not reached 103–NE in the control groups; HR 0·60, 95% CI 0·48–0·73, p<0·0001), prostate cancer-specific survival (not reached NE–NE vs not reached NE–NE; 0·49, 0·37–0·65, p<0·0001), biochemical failure-free-survival (not reached NE–NE vs 86 months 83–NE; 0·39, 0·33–0·47, p<0·0001), and progression-free-survival (not reached NE–NE vs not reached 103–NE; 0·44, 0·36–0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death).
Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population.
Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
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