The value of remote marine aerosol measurements for constraining radiative forcing uncertainty

Aerosol measurements over the Southern Ocean are used to constrain aerosol-cloud interaction radiative forcing (RFaci) uncertainty in a global climate model. Forcing uncertainty is quantified using 1 million climate model variants that sample the uncertainty in nearly 30 model parameters. Measurements of cloud condensation nuclei and other aerosol properties from an Antarctic circumnavigation expedition strongly constrain natural aerosol emissions: default sea spray emissions need to be increased by around a factor of 3 to be consistent with measurements. Forcing uncertainty is reduced by around 7% using this set of several hundred measurements, which is comparable to the 8% reduction achieved using a diverse and extensive set of over 9000 predominantly Northern Hemisphere measurements. When Southern Ocean and Northern Hemisphere measurements are combined, uncertainty in RFaci is reduced by 21 %, and the strongest 20% of forcing values are ruled out as implausible. In this combined constraint, observationally plausible RFaci is around 0.17Wm-2 weaker (less negative) with 95% credible values ranging from-2:51 to-1:17Wm-2 (standard deviation of-2:18 to-1:46Wm-2). The Southern Ocean and Northern Hemisphere measurement datasets are complementary because they constrain different processes. These results highlight the value of remote marine aerosol measurements. © 2020 Laser Institute of America. All rights reserved

Effectiveness of Genomic Prediction of Maize Hybrid Performance in Different Breeding Populations and Environments

Genomic prediction is expected to considerably increase genetic gains by increasing selection intensity and accelerating the breeding cycle. In this study, marker effects estimated in 255 diverse maize (Zea mays L.) hybrids were used to predict grain yield, anthesis date, and anthesis-silking interval within the diversity panel and testcross progenies of 30 F(2)-derived lines from each of five populations. Although up to 25% of the genetic variance could be explained by cross validation within the diversity panel, the prediction of testcross performance of F(2)-derived lines using marker effects estimated in the diversity panel was on average zero. Hybrids in the diversity panel could be grouped into eight breeding populations differing in mean performance. When performance was predicted separately for each breeding population on the basis of marker effects estimated in the other populations, predictive ability was low (i.e., 0.12 for grain yield). These results suggest that prediction resulted mostly from differences in mean performance of the breeding populations and less from the relationship between the training and validation sets or linkage disequilibrium with causal variants underlying the predicted traits. Potential uses for genomic prediction in maize hybrid breeding are discussed emphasizing the need of (1) a clear definition of the breeding scenario in which genomic prediction should be applied (i.e., prediction among or within populations), (2) a detailed analysis of the population structure before performing cross validation, and (3) larger training sets with strong genetic relationship to the validation set

CAD-RADS™ 2.0 - 2022 Coronary Artery Disease – Reporting and Data System an expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT), the American College of Cardiology (ACC), the American College of Radiology (ACR) and the North America society of cardiovascular imaging (NASCI)

Coronary Artery Disease Reporting and Data System (CAD-RADS) was created to standardize reporting system for patients undergoing coronary CT angiography (CCTA) and to guide possible next steps in patient management. The goal of this updated 2022 CAD-RADS 2.0 is to improve the initial reporting system for CCTA by considering new technical developments in Cardiac CT, including data from recent clinical trials and new clinical guidelines. The updated CAD-RADS classification will follow an established framework of stenosis, plaque burden, and modifiers, which will include assessment of lesion-specific ischemia using CT fractional-flow-reserve (CT-FFR) or myocardial CT perfusion (CTP), when performed. Similar to the method used in the original CAD-RADS version, the determinant for stenosis severity classification will be the most severe coronary artery luminal stenosis on a per-patient basis, ranging from CAD-RADS 0 (zero) for absence of any plaque or stenosis to CAD-RADS 5 indicating the presence of at least one totally occluded coronary artery. Given the increasing data supporting the prognostic relevance of coronary plaque burden, this document will provide various methods to estimate and report total plaque burden. The addition of P1 to P4 descriptors are used to denote increasing categories of plaque burden. The main goal of CAD-RADS, which should always be interpreted together with the impression found in the report, remains to facilitate communication of test results with referring physicians along with suggestions for subsequent patient management. In addition, CAD-RADS will continue to provide a framework of standardization that may benefit education, research, peer-review, artificial intelligence development, clinical trial design, population health and quality assurance with the ultimate goal of improving patient care

Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA

Exploring Difference or Just Watching the Experts at Work? Interrogating Patient and Public Involvement (PPI) in a Cancer Research Setting Using the Work of Jurgen Habermas

Patient and public involvement (PPI) has emerged as a key consideration for organisations delivering health research and has spawned a burgeoning literature in the health and social sciences. The literature makes clear that PPI in health research encompasses a heterogeneous set of practices with levels of participation and involvement ranging from relatively minimal contributions to research processes to actively driving the research agenda. In this paper, we draw on the work of Jurgen Habermas to explore the ways in which PPI was accomplished in a cancer research setting in England. Drawing on ethnographic data with PPI participants and professional researchers, we describe the ways in which the life-world experiences of PPI participants were shaped by the health research system. We argue that PPI in this setting is less about exploring differences with regard to a plurality of expertise and more about simply watching or supporting the professional researchers at work

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Funding Information: We thank Dr. David James, Dr. Frederick Lang, Dr. Cameron Brennan, and Dr. Harley Kornblum for GBM-PDX neurospheres. We thank Dr. Karen Arden for continuous support and critical evaluation of the results. We thank Dr. Robert Davis, Dr. German Gomez, Dr. Tiffany Taylor, Dr. Rachel Reed, Dr. Melissa Mcalonis, and Dr. Sora Lee for technical support. In memory of Rosa Lupo. This work was supported by the Defeat GBM Research Collaborative, a subsidiary of the National Brain Tumor Society (F.B.F. and P.S.M.), R01-NS080939 (F.B.F.), the James S. McDonnell Foundation (F.B.F.), the National Cancer Institute (2T32CA009523-29A1) (A.H.T), and 1RO1NS097649-01 (C.C.C.). C.Z. was partially supported by an American-Italian Cancer Foundation post-doctoral research fellowship. F.L. received a Gao Feng Gao Yuan Scholarship Award. T.C.G., A.K.S., P.S.M., W.K.C., and F.B.F. receive salary and additional support from the Ludwig Institute for Cancer Research. Publisher Copyright: © 2017 Zanca et al.In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.publishersversionPeer reviewe

Fluorescence changes reveal kinetic steps of muscarinic receptor–mediated modulation of phosphoinositides and Kv7.2/7.3 K+ channels

G protein–coupled receptors initiate signaling cascades. M1 muscarinic receptor (M1R) activation couples through Gαq to stimulate phospholipase C (PLC), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2). Depletion of PIP2 closes PIP2-requiring Kv7.2/7.3 potassium channels (M current), thereby increasing neuronal excitability. This modulation of M current is relatively slow (6.4 s to reach within 1/e of the steady-state value). To identify the rate-limiting steps, we investigated the kinetics of each step using pairwise optical interactions likely to represent fluorescence resonance energy transfer for M1R activation, M1R/Gβ interaction, Gαq/Gβ separation, Gαq/PLC interaction, and PIP2 hydrolysis. Electrophysiology was used to monitor channel closure. Time constants for M1R activation (<100 ms) and M1R/Gβ interaction (200 ms) are both fast, suggesting that neither of them is rate limiting during muscarinic suppression of M current. Gαq/Gβ separation and Gαq/PLC interaction have intermediate 1/e times (2.9 and 1.7 s, respectively), and PIP2 hydrolysis (6.7 s) occurs on the timescale of M current suppression. Overexpression of PLC accelerates the rate of M current suppression threefold (to 2.0 s) to become nearly contemporaneous with Gαq/PLC interaction. Evidently, channel release of PIP2 and closure are rapid, and the availability of active PLC limits the rate of M current suppression