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Since the last IAEA-FEC in 2021, significant progress on the development of long pulse steady state scenario and its related key physics and technologies have been achieved, including the reproducible 403 s long-pulse steady-state H-mode plasma with pure radio frequency (RF) power heating. A thousand-second time scale (∼1056 s) fully non-inductive plasma with high injected energy up to 1.73 GJ has also been achieved. The EAST operational regime of high β _P has been significantly extended ( H _98y2 > 1.3, β _P ∼ 4.0, β _N ∼ 2.4 and n _e / n _GW ∼ 1.0) using RF and neutral beam injection (NBI). The full edge localized mode suppression using the n = 4 resonant magnetic perturbations has been achieved in ITER-like standard type-I ELMy H-mode plasmas with q _95 ≈ 3.1 on EAST, extrapolating favorably to the ITER baseline scenario. The sustained large ELM control and stable partial detachment have been achieved with Ne seeding. The underlying physics of plasma-beta effect for error field penetration, where toroidal effect dominates, is disclosed by comparing the results in cylindrical theory and MARS-Q simulation in EAST. Breakdown and plasma initiation at low toroidal electric fields (

Abstract Many species show spatial variation in body size, often associated with climatic patterns. Studying species with contrasting geographical patterns related to climate might help elucidate the role of different drivers. We analysed changes in the body mass of two sympatric medium-sized carnivores—pine marten (Martes martes) and stone marten (Martes foina)—across Europe over 59 years. The body mass of pine marten increased with decreasing latitude, whereas stone marten body mass varied in a more complex pattern across its geographic range. Over time, the average body mass of pine martens increased by 255 g (24%), while stone marten by 86 g (6%). The greatest increase of body mass along both martens’ geographic range was observed in central and southern Europe, where both species occur in sympatry. The body mass increase slowed down over time, especially in allopatric regions. The average pine/stone marten body mass ratio increased from 0.87 in 1960 to 0.99 in 2019, potentially strengthening the competition between them. Thus, a differential response in body size to several drivers over time might have led to an adaptive advantage for pine martens. This highlights the importance of considering different responses among interacting species when studying animal adaptation to climate change.

Abstract The Mastcam‐Z radiometric calibration targets mounted on the NASA's Perseverance rover proved to be effective in the calibration of Mastcam‐Z images to reflectance (I/F) over the first 350 sols on Mars. Mastcam‐Z imaged the calibration targets regularly to perform reflectance calibration on multispectral image sets of targets on the Martian surface. For each calibration target image, mean radiance values were extracted for 41 distinct regions of the targets, including patches of color and grayscale materials. Eight strong permanent magnets, placed under the primary target, attracted magnetic dust and repelled it from central surfaces, allowing the extraction of radiance values from eight regions relatively clean from dust. These radiances were combined with reflectances obtained from laboratory measurements, a one‐term linear fit model was applied, and the slopes of the fits were retrieved as estimates of the solar irradiance and used to convert Mastcam‐Z images from radiance to reflectance. Derived irradiance time series are smoothly varying in line with expectations based on the changing Mars‐Sun distance, being only perturbed by a few significant dust events. The deposition of dust on the calibration targets was largely concentrated on the magnets, ensuring a minimal influence of dust on the calibration process. The fraction of sunlight directly hitting the calibration targets was negatively correlated with the atmospheric optical depth, as expected. Further investigation will aim at explaining the origin of a small offset observed in the fit model employed for calibration, and the causes of a yellowing effect affecting one of the calibration targets materials.

Abstract This study aimed to develop a highly sensitive SARS-CoV-2 nucleocapsid antigen assay using the single molecule array (Simoa) technology and compare it with real time RT-PCR as used in routine clinical practice with the ambition to achieve a comparative technical and clinical sensitivity. Samples were available from 148 SARS-CoV-2 real time RT-PCR positive and 73 SARS-CoV-2 real time RT-PCR negative oropharyngeal swabs. For determination of technical sensitivity SARS-CoV-2 virus culture material was used. The samples were treated with lysis buffer and analyzed using both an in-house and a pre-commercial SARS-CoV-2 nucleocapsid antigen assay on Simoa. Both nucleocapsid antigen assays have a technical sensitivity corresponding to around 100 SARS-CoV-2 RNA molecules/mL. Using a cut-off at 0.1 pg/mL the pre-commercial SARS-CoV-2 nucleocapsid antigen assay had a sensitivity of 96% (95% CI 91.4–98.5%) and specificity of 100% (95% CI 95.1–100%). In comparison the in-house nucleocapsid antigen assay had sensitivity of 95% (95% CI 89.3–98.1%) and a specificity of 100% (95% CI 95.1–100%) using a cut-off at 0.01 pg/mL. The two SARS-CoV-2 nucleocapsid antigen assays correlated with r = 0.91 (P

The prognosis of castration-resistant prostate cancers remains dismal, but accurate preclinical models can lead to effective therapies. Here the Melbourne Urological Research Alliance establish prostate cancer patient-derived xenografts, use the tumors for organoids and single-cell RNA-seq, and show the efficacy of PARP inhibitor combination treatments.

Nitrate contamination of subsurface aquifers is an ongoing environmental challenge due to nitrogen (N) leaching from intensive N fertilization and management on agricultural fields. The distribution and fate of nitrate in aquifers are primarily governed by geological, hydrological and geochemical conditions of the subsurface. Therefore, we propose a novel approach to modeling both geology and redox architectures simultaneously in high-resolution 3D (25m×25m×2m) using multiple-point geostatistical (MPS) simulation. Data consist of (1) mainly resistivities of the subsurface mapped with towed transient electromagnetic measurements (tTEM), (2) lithologies from borehole observations, (3) redox conditions from colors reported in borehole observations, and (4) chemistry analyses from water samples. Based on the collected data and supplementary surface geology maps and digital elevation models, the simulation domain was subdivided into geological elements with similar geological traits and depositional histories. The conceptual understandings of the geological and redox architectures of the study system were introduced to the simulation as training images for each geological element. On the basis of these training images and conditioning data, independent realizations were jointly simulated of geology and redox inside each geological element and stitched together into a larger model. The joint simulation of geological and redox architectures, which is one of the strengths of MPS compared to other geostatistical methods, ensures that the two architectures in general show coherent patterns. Despite the inherent subjectivity of interpretations of the training images and geological element boundaries, they enable an easy and intuitive incorporation of qualitative knowledge of geology and geochemistry in quantitative simulations of the subsurface architectures. Altogether, we conclude that our approach effectively simulates the consistent geological and redox architectures of the subsurface that can be used for hydrological modeling with nitrogen (N) transport, which may lead to a better understanding of N fate in the subsurface and to future more targeted regulation of agriculture.

Abstract The cortical cytoskeleton, consisting of the cytoplasmic actin isoforms β and/or γ‐actin, has been implicated in insulin‐stimulated GLUT4 translocation and glucose uptake in muscle and adipose cell culture. Furthermore, transgenic inhibition of multiple actin‐regulating proteins in muscle inhibits insulin‐stimulated muscle glucose uptake. The current study tested if γ‐actin was required for insulin‐stimulated glucose uptake in mouse skeletal muscle. Based on our previously reported age‐dependent phenotype in muscle‐specific β‐actin gene deletion (−/−) mice, we included cohorts of growing 8–14 weeks old and mature 18–32 weeks old muscle‐specific γ‐actin−/− mice or wild‐type littermates. In growing mice, insulin significantly increased the glucose uptake in slow‐twitch oxidative soleus and fast‐twitch glycolytic EDL muscles from wild‐type mice, but not γ‐actin−/−. In relative values, the maximal insulin‐stimulated glucose uptake was reduced by ~50% in soleus and by ~70% in EDL muscles from growing γ‐actin−/− mice compared to growing wild‐type mice. In contrast, the insulin‐stimulated glucose uptake responses in mature adult γ‐actin−/− soleus and EDL muscles were indistinguishable from the responses in wild‐type muscles. Mature adult insulin‐stimulated phosphorylations on Akt, p70S6K, and ULK1 were not significantly affected by genotype. Hence, insulin‐stimulated muscle glucose uptake shows an age‐dependent impairment in young growing but not in fully grown γ‐actin−/− mice, bearing phenotypic resemblance to β‐actin−/− mice. Overall, γ‐actin does not appear required for insulin‐stimulated muscle glucose uptake in adulthood. Furthermore, our data emphasize the need to consider the rapid growth of young mice as a potential confounder in transgenic mouse phenotyping studies.

A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.

Silicone elastomers have been heavily investigated as candidates for the flexible insulator material in dielectric elastomer transducers and are as such almost ideal candidates because of their inherent softness and compliance. However, silicone elastomers suffer from low dielectric permittivity. This shortcoming has been attempted optimized through different approaches during recent years. Material optimization with the sole purpose of increasing the dielectric permittivity may lead to the introduction of problematic phenomena such as premature electrical breakdown due to high leakage currents of the thin elastomer film. Within this work, electrical breakdown phenomena of various types of permittivity-enhanced silicone elastomers are investigated. Results showed that different types of polymer backbone chemistries lead to differences in electrical breakdown patterns, which were revealed through SEM imaging. This may pave the way towards a better understanding of electrical breakdown mechanisms of dielectric elastomers and potentially lead to materials with increased electrical breakdown strengths.

Abstract Both function and dysfunction of serine protease inhibitors (serpins) involve massive conformational change in their tertiary structure but the dynamics facilitating these events remain poorly understood. We have studied the dynamic preludes to conformational change in the serpin plasminogen activator inhibitor 1 (PAI-1). We report the first multi-microsecond atomistic molecular dynamics simulations of PAI-1 and compare the data with experimental hydrogen/deuterium-exchange data (HDXMS). The simulations reveal notable conformational flexibility of helices D, E and F and major fluctuations are observed in the W86-loop which occasionally leads to progressive detachment of β-strand 2 A from β-strand 3 A. An interesting correlation between Cα-RMSD values from simulations and experimental HDXMS data is observed. Helices D, E and F are known to be important for the overall stability of active PAI-1 as ligand binding in this region can accelerate or decelerate the conformational inactivation. Plasticity in this region may thus be mechanistically linked to the conformational change, possibly through facilitation of further unfolding of the hydrophobic core, as previously reported. This study provides a promising example of how computer simulations can help tether out mechanisms of serpin function and dysfunction at a spatial and temporal resolution that is far beyond the reach of any experiment.

Background: Pesticide self-poisoning as a method of suicide is a major global health problem. Objectives: To estimate the cost and per patient cost of treating pesticide self-poisoning at different hospital levels in a Sri Lankan district, and to examine the distribution of cost components. Another objective was to investigate changes in total cost of treatment of pesticide poisoning for all causes at different administrative levels in Sri Lanka in 2005 and 2015. Methods: The economic framework was a costing analysis, adopting a government perspective. Cost data were collected prospectively over a 4-month period in 2016 for patients admitted for pesticide self-poisoning to six hospitals in the Anuradhapura District. Assumption-based scenario analyses were run to determine changes in total pesticide poisoning treatment costs. Results: We included 67 self-poisoned patients in the study. The total cost of treatment was US$ 5,714 at an average treatment cost of US$ 85.3 (9.7–286.6) per patient (across all hospital levels). Hospital costs constituted 67% of the total cost for treating self-poisoning cases and patient-specific costs accounted for 29%. Direct cost of patient hospital transfer constituted the smallest share of costs (4%) but accounted for almost half of the total costs at primary level. The estimated total cost of treating all causes of pesticide poisoning in Sri Lanka was US$ 2.5 million or 0.19% of the total government health expenditure (GHE) in 2015. Conclusion: Our findings indicate that the average per patient cost of pesticide self-poisoning treatment has increased while the total cost of pesticide poisoning treatment as a percentage of the total GHE in Sri Lanka has declined over the past decade. A continuous focus on banning the most hazardous pesticides available would likely further drive down the cost of pesticide self-poisoning and pesticide poisoning to the government.