Rare earth elements or yttrium can weaken the strong basal textures of magnesium sheets and are of interest for the improvement of sheet formability. The weakening of magnesium sheet textures with ...increasing content of Ce, Nd and Y is connected to the solid solubility of the respective element. A relationship is drawn between the weak textures and the appearance of deformation bands with compression and double twins during rolling and a grain growth restriction during annealing of the sheets.
The RENO experiment has observed the disappearance of reactor electron antineutrinos, consistent with neutrino oscillations, with a significance of 4.9 standard deviations. Antineutrinos from six 2.8 ... GW(th) reactors at the Yonggwang Nuclear Power Plant in Korea, are detected by two identical detectors located at 294 and 1383 m, respectively, from the reactor array center. In the 229 d data-taking period between 11 August 2011 and 26 March 2012, the far (near) detector observed 17102 (154088) electron antineutrino candidate events with a background fraction of 5.5% (2.7%). The ratio of observed to expected numbers of antineutrinos in the far detector is 0.920±0.009(stat)±0.014(syst). From this deficit, we determine sin(2)2θ(13)=0.113±0.013(stat)±0.019(syst) based on a rate-only analysis.
Little is known about the biological roles of glycosylated RNAs (glycoRNAs), a recently discovered class of glycosylated molecules, because of a lack of visualization methods. We report sialic acid ...aptamer and RNA in situ hybridization-mediated proximity ligation assay (ARPLA) to visualize glycoRNAs in single cells with high sensitivity and selectivity. The signal output of ARPLA occurs only when dual recognition of a glycan and an RNA triggers in situ ligation, followed by rolling circle amplification of a complementary DNA, which generates a fluorescent signal by binding fluorophore-labeled oligonucleotides. Using ARPLA, we detect spatial distributions of glycoRNAs on the cell surface and their colocalization with lipid rafts as well as the intracellular trafficking of glycoRNAs through SNARE protein-mediated secretory exocytosis. Studies in breast cell lines suggest that surface glycoRNA is inversely associated with tumor malignancy and metastasis. Investigation of the relationship between glycoRNAs and monocyte-endothelial cell interactions suggests that glycoRNAs may mediate cell-cell interactions during the immune response.
This study aimed to prospectively examine whether low normal glucose levels and hypoglycaemia are associated with increased mortality due to external causes, especially unintentional accidents.
A ...total of 345,318 normoglycaemic Korean adults who had undergone health examinations during 2002–2003 were followed-up to 2013. To avoid potential biases related to glucose-lowering medication use, those with known diabetes or hyperglycaemia were excluded.
During 3.6 million person-years of follow-up, 1293 participants died because of unintentional accidents. Hazard ratios (HRs) for these accidental deaths were 1.26 (95% CI: 1.11–1.42), 1.60 (1.21–2.11) and 3.07 (1.37–6.85) for fasting serum glucose (FSG) levels of 70–79, 55–69 and <55mg/dL (3.9–4.4, 3.05–3.83 and <3.05mmol/L), respectively, compared with 80–99mg/dL (4.44–5.5mmol/L). FSG levels<80mg/dL were associated with an approximately 30% higher mortality due to accidents: specifically, 40% were non-fall-related injury; 50% were automobile-related; and 80% were motorcycle-related. The associations were weak (approximately 10% higher mortality, with P>0.05 for each cause) for deaths due to traffic accidents (pedestrians, pedal cyclists), falls, intentional self-harm and physical assault. The population attributable risks for FSG levels <80mg/dL were 10% (95% CI: 2–18%) for non-fall-related injury, 11% (6–17%) for car accidents and 17% (6–27%) for motorcycle accidents.
FSG levels of 70–79mg/dL (3.9–4.4mmol/L) as well as <70mg/dL are risk factors for accidental death. Appropriate management of the impact of FSG levels <80mg/dL might reduce unintended deaths due to non-fall-related injury, and automobile and motorcycle accidents, by ≥10%.
Four assays registered with the US Food and Drug Administration (FDA) detect programmed cell death ligand 1 (PD-L1) to enrich for patient response to anti-programmed cell death 1 and anti-PD-L1 ...therapies. The tests use 4 separate PD-L1 antibodies on 2 separate staining platforms and have their own scoring systems, which raises questions about their similarity and the potential interchangeability of the tests.
To compare the performance of 4 PD-L1 platforms, including 2 FDA-cleared assays, 1 test for investigational use only, and 1 laboratory-developed test.
Four serial histologic sections from 90 archival non-small cell lung cancers from January 1, 2008, to December 31, 2010, were distributed to 3 sites that performed the following immunohistochemical assays: 28-8 antibody on the Dako Link 48 platform, 22c3 antibody on the Dako Link 48 platform, SP142 antibody on the Ventana Benchmark platform, and E1L3N antibody on the Leica Bond platform. The slides were scanned and scored by 13 pathologists who estimated the percentage of malignant and immune cells expressing PD-L1. Statistical analyses were performed from December 1, 2015, to August 30, 2016, to compare antibodies and pathologists' scoring of tumor and immune cells.
Percentages of malignant and immune cells expressing PD-L1.
Among the 90 samples, the SP142 assay was an outlier, with a significantly lower mean score of PD-L1 expression in both tumor and immune cells (tumor cells: 22c3, 2.96; 28-8, 3.26; SP142, 1.99; E1L3N, 3.20; overall mean, 2.85; and immune cells: 22c3, 2.15; 28-8, 2.28; SP142, 1.62; E1L3N, 2.28; overall mean, 2.08). Pairwise comparisons showed that the scores from the 28-8 and E1L3N tests were not significantly different but that the 22c3 test showed a slight (mean difference, 0.24-0.30) but statistically significant reduction in labeling of PD-L1 expression in tumor cells. Evaluation of intraclass correlation coefficients (ICCs) between antibodies to quantify interassay variability for PD-L1 expression in tumor cells showed high concordance between antibodies for tumor cell scoring (0.813; 95% CI, 0.815-0.839) and lower levels of concordance for immune cell scoring (0.277; 95% CI, 0.222-0.334). When examining variability between pathologists for any single assay, the concordance between pathologists' scoring for PD-L1 expression in tumor cells ranged from ICCs of 0.832 (95% CI, 0.820-0.844) to 0.882 (95% CI, 0.873-0.891) for each assay, while the ICCs from immune cells for each assay ranged from 0.172 (95% CI, 0.156-0.189) to 0.229 (95% CI, 0.211-0.248).
The assay using the SP142 antibody is an outlier that detected significantly less PD-L1 expression in tumor cells and immune cells. The assay for antibody 22c3 showed slight yet statistically significantly lower staining than either 28-8 or E1L3N, but this significance was detected only when using the mean of 13 pathologists' scores. The pathologists showed excellent concordance when scoring tumor cells stained with any antibody but poor concordance for scoring immune cells stained with any antibody. Thus, for tumor cell assessment of PD-L1, 3 of the 4 tests are concordant and reproducible as read by pathologists.
The blowout (or bubble) regime of laser wakefield acceleration is promising for generating monochromatic high-energy electron beams out of low-density plasmas. It is shown analytically and by ...particle-in-cell simulations that self-injection of the background plasma electrons into the quasistatic plasma bubble can be caused by slow temporal expansion of the bubble. Sufficient criteria for the electron trapping and bubble's expansion rate are derived using a semianalytic nonstationary Hamiltonian theory. It is further shown that the combination of bubble's expansion and contraction results in monoenergetic electron beams.
Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need ...in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production.
To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant.
The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction;
<0.05) and prolonged renal graft survival (28.0 days versus 5.2 days;
<0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell-mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access.
Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.
Aberrant splicing is frequently found in cancer, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signalling, a key pathway that regulates ...cell proliferation and organ size, is under control of a splicing switch. We show that TEAD4, the transcription factor that mediates Hippo-YAP signalling, undergoes alternative splicing facilitated by the tumour suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks an N-terminal DNA-binding domain, but maintains YAP interaction domain. TEAD4-S is located in both the nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumour growth in xenograft mouse models. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether, these data reveal a splicing switch that serves to fine tune the Hippo-YAP pathway.
ABSTRACT
In the standard ΛCDM (Lambda cold dark matter) paradigm, dwarf galaxies are expected to be dark matter-rich, as baryonic feedback is thought to quickly drive gas out of their shallow ...potential wells and quench star formation at early epochs. Recent observations of local dwarfs with extremely low dark matter content appear to contradict this picture, potentially bringing the validity of the standard model into question. We use NewHorizon, a high-resolution cosmological simulation, to demonstrate that sustained stripping of dark matter, in tidal interactions between a massive galaxy and a dwarf satellite, naturally produces dwarfs that are dark matter-deficient, even though their initial dark matter fractions are normal. The process of dark matter stripping is responsible for the large scatter in the halo-to-stellar mass relation in the dwarf regime. The degree of stripping is driven by the closeness of the orbit of the dwarf around its massive companion and, in extreme cases, produces dwarfs with halo-to-stellar mass ratios as low as unity, consistent with the findings of recent observational studies. ∼30 per cent of dwarfs show some deviation from normal dark matter fractions due to dark matter stripping, with 10 per cent showing high levels of dark matter deficiency (Mhalo/M⋆ < 10). Given their close orbits, a significant fraction of dark matter-deficient dwarfs merge with their massive companions (e.g. ∼70 per cent merge over time-scales of ∼3.5 Gyr), with the dark matter-deficient population being constantly replenished by new interactions between dwarfs and massive companions. The creation of these galaxies is therefore a natural by-product of galaxy evolution and their existence is not in tension with the standard paradigm.
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