The origins of the high-energy cosmic neutrino flux remain largely unknown. Recently, one high-energy neutrino was associated with a tidal disruption event (TDE). Here we present AT2019fdr, an ...exceptionally luminous TDE candidate, coincident with another high-energy neutrino. Our observations, including a bright dust echo and soft late-time x-ray emission, further support a TDE origin of this flare. The probability of finding two such bright events by chance is just 0.034%. We evaluate several models for neutrino production and show that AT2019fdr is capable of producing the observed high-energy neutrino, reinforcing the case for TDEs as neutrino sources.
Abstract
The focusing of high-energy X-rays is most commonly achieved by commercially available compound refractive lenses (CRL), which are added together in larger structures. There is a need for ...high-energy X-ray beamlines to enable focusing in only one dimension down to a few micrometers to study layered materials and thin films. High-energy X-rays above 50 keV require often 100 lenses or more, therefore it is more efficient to etch the complete arrays of lenses into a monolithic substrate like a silicon wafer. Custom lens arrays were fabricated for the high-energy x-ray beamlines 11-ID-B, and 11-ID-C at the Argonne National Laboratory. The fabrication required tuning parameters of the Bosch process to optimize the etching of deep vertical sidewalls at a reasonable speed without overheating. The beamline 11-ID-B is equipped with lens arrays of 85-110 lenses for 59 keV and 190-250 lenses for 87 keV photon energy, focusing the beam vertically below 5.0 µm at the sample positions between 1600 mm to 2100 mm. 11-ID-C has received arrays of 435 lenses that focus 106 keV X-rays to a vertical height of 2.0 µm at the sample position. In both cases, the flux density gain in the focal spot is larger than a factor of 20, relative to using slits to cut the beam size. The lens setup is permanently installed and can be moved in and out of the beam during the experiment without further alignment. The lenses have enabled
operando
diffraction studies on interfaces in batteries and the development of pair distribution function (PDF) analysis using grazing incidence geometry.
Considerable epidemiologic evidence links consuming lower glycemic index (GI) diets with good health, particularly upon aging. The GI is a kinetic parameter that reflects the ability of carbohydrate ...(CHO) contained in consumed foods to raise blood glucose in vivo. Newer nutritional, clinical, and experimental data link intake of lower dietary GI foods to favorable outcomes of chronic diseases, and compel further examination of the record. Based upon the new information there are two specific questions: 1) should the GI concept be promoted as a way to prolong health, and 2) should food labels contain GI information? Further, what are the remaining concerns about methodological issues and consistency of epidemiological data and clinical trials that need to be resolved in order to exploit the benefits of consuming lower GI diets? These issues are addressed in this review.
Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) ...and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma.
Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue.
Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively.
Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.
Abstract
The proliferation of dams since 1950 promoted sediment deposition in reservoirs, which is thought to be starving the coast of sediment and decreasing the resilience of communities to storms ...and sea-level rise. Diminished river loads measured upstream from the coast, however, should not be assumed to propagate seaward. Here, we show that century-long records of sediment mass accumulation rates (g cm
−2
yr
−1
) and sediment accumulation rates (cm yr
−1
) more than doubled after 1950 in coastal depocenters around North America. Sediment sources downstream of dams compensate for the river-sediment lost to impoundments. Sediment is accumulating in coastal depocenters at a rate that matches or exceeds relative sea-level rise, apart from rapidly subsiding Texas and Louisiana where water depths are increasing and intertidal areas are disappearing. Assuming no feedbacks, accelerating global sea-level rise will eventually surpass current sediment accumulation rates, underscoring the need for including coastal-sediment management in habitat-restoration projects.
Electrical synaptic transmission relies on neuronal gap junctions containing channels constructed by Connexins. While at chemical synapses neurotransmitter-gated ion channels are critically supported ...by scaffolding proteins, it is unknown if channels at electrical synapses require similar scaffold support. Here, we investigated the functional relationship between neuronal Connexins and Zonula Occludens 1 (ZO1), an intracellular scaffolding protein localized to electrical synapses. Using model electrical synapses in zebrafish Mauthner cells, we demonstrated that ZO1 is required for robust synaptic Connexin localization, but Connexins are dispensable for ZO1 localization. Disrupting this hierarchical ZO1/Connexin relationship abolishes electrical transmission and disrupts Mauthner cell-initiated escape responses. We found that ZO1 is asymmetrically localized exclusively postsynaptically at neuronal contacts where it functions to assemble intercellular channels. Thus, forming functional neuronal gap junctions requires a postsynaptic scaffolding protein. The critical function of a scaffolding molecule reveals an unanticipated complexity of molecular and functional organization at electrical synapses.
Abstract Context Although specialty palliative care in hospital and outpatient settings is associated with lower acute care use, its impact in U.S. nursing homes (NHs) is unknown. Objectives To ...understand how NH use of palliative care consults is associated with end-of-life hospitalizations. Methods Seven consult providers in four states and 24 counties shared data on the number of consult visits and residents served (per NH) in study years 2000–2010. All NHs in the 24 counties were studied ( n = 286). An NH-level longitudinal file included consult data, aggregated Medicare resident assessment and claims data, and NH characteristics. Consult introduction was “yes” when 1% of residents received consults. Volume was the number of consult visits per 100 residents, annually. Panel multivariate regression with NH fixed effects examined whether rates of hospital deaths and hospitalizations in the last 30 days of life differentially changed for NHs introducing consults, or increasing consult volume. Results One hundred seventy (59%) of the 286 NHs introduced consults by 2010. NHs with consults, compared to others, had residents with higher acuity and functional impairment, and lower nurse but higher nursing assistant staffing. Controlling for covariate differences and compared to NHs without consults, NHs introducing consults had a 1% (95% CI −0.021, 0.002) greater reduction in hospital death rates and a 1.6% (95% CI −0.031, −0.002) greater reduction in hospitalizations in the last 30 days of life. No statistically significant associations between volume and study outcomes were observed. Conclusion The introduction of specialty palliative care consults in NHs is associated with overall reductions in end-of-life hospitalizations.
Bipolaris oryzae causes brown spot in rice (Oryza sativa) inflicting substantial grain yield losses worldwide. Knowledge of the population structure, genetic diversity and sexual recombination of the ...fungal pathogen can help to implement effective disease management strategies. In this study, B. oryzae isolates sampled from Iran, the Philippines and Japan were analysed with 12 simple‐sequence repeat (SSR) markers, newly developed from the genome sequence of the fungus. Among the 288 B. oryzae isolates genotyped, 278 unique haplotypes were identified. High genotype numbers (richness) with even distribution (evenness) were found within the collection sites. Both mating types, MAT1‐1 and MAT1‐2, were present in each collection area, and the sexual state was induced under controlled conditions with production of viable ascospores. However, the tests of linkage disequilibrium rejected of the hypothesis of random mating. Discriminant analysis of principal components (DAPC) revealed that the B. oryzae collection formed three clusters, each consisting of isolates from different collection sites. Analysis of molecular variance (amova) showed that genetic variation among clusters was 18.7%, with the rest of the variation distributed within clusters (RST = 0.187, P < 0.001). Statistically significant pairwise genetic differentiation was found between the clusters. These results show that Asian B. oryzae isolates are genetically diverse, and, overall, distributed in three groups. These findings will be helpful in managing the disease and guide the use of representative isolates needed for selection of resistant rice varieties.
Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can ...suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025.
We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo.
MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein-positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%-10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples.
These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.
Basing her arguments on Aristotle and Aquinas and the Catholic tradition, one of Britain's greatest twentieth‐century philosophers, Elizabeth Anscombe, sought to revive opposition to usury. Her ...claims are based on misunderstandings, but they raise the important issue, explored by Friedrich Hayek and discussed by David Hume, of the different obligations owed to people in dire circumstances and to small groups such as families – and to people in the extended market order. Usury, ‘demanding interest on the mere strength of a loan’, is legitimate but only in the extended market order – not usually in the case of family, friends and the poor or desperate.
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