Hybrid meson decay from the lattice

We discuss the allowed decays of a hybrid meson in the heavy quark limit. We deduce that an important decay will be into a heavy quark non-hybrid state and a light quark meson, in other words, the de-excitation of an excited gluonic string by emission of a light quark-antiquark pair. We discuss the study of hadronic decays from the lattice in the heavy quark limit and apply this approach to explore the transitions from a spin-exotic hybrid to $\chi_b \eta$ and $\chi_b S$ where $S$ is a scalar meson. We obtain a signal for the transition emitting a scalar meson and we discuss the phenomenological implications.Comment: 18 pages, LATEX, 3 ps figure

Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics

Background and Purpose Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies. Experimental Approach We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca2+i) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression. Key Results Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca2+i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G670E). Conclusions and Implications The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses

The importance of comprehensive parameter sampling and multiple observations for robust constraint of aerosol radiative forcing

© 2018 Author(s). Observational constraint of simulated aerosol and cloud properties is an essential part of building trustworthy climate models for calculating aerosol radiative forcing. Models are usually tuned to achieve good agreement with observations, but tuning produces just one of many potential variants of a model, so the model uncertainty cannot be determined. Here we estimate the uncertainty in aerosol effective radiative forcing (ERF) in a tuned climate model by constraining 4 million variants of the HadGEM3-UKCA aerosol-climate model to match nine common observations (top-of-atmosphere shortwave flux, aerosol optical depth, PM2.5, cloud condensation nuclei at 0.2% supersaturation (CCN0.2), and concentrations of sulfate, black carbon and organic carbon, as well as decadal trends in aerosol optical depth and surface shortwave radiation.) The model uncertainty is calculated by using a perturbed parameter ensemble that samples 27 uncertainties in both the aerosol model and the physical climate model, and we use synthetic observations generated from the model itself to determine the potential of each observational type to constrain this uncertainty. Focusing over Europe in July, we show that the aerosol ERF uncertainty can be reduced by about 30% by constraining it to the nine observations, demonstrating that producing climate models with an observationally plausible base state can contribute to narrowing the uncertainty in aerosol ERF. However, the uncertainty in the aerosol ERF after observational constraint is large compared to the typical spread of a multi-model ensemble. Our results therefore raise questions about whether the underlying multi-model uncertainty would be larger if similar approaches as adopted here were applied more widely. The approach presented in this study could be used to identify the most effective observations for model constraint. It is hoped that aerosol ERF uncertainty can be further reduced by introducing process-related constraints; however, any such results will be robust only if the enormous number of potential model variants is explored

Identifying climate model structural inconsistencies allows for tight constraint of aerosol radiative forcing

Aerosol radiative forcing uncertainty affects estimates of climate sensitivity and limits model skill in terms of making climate projections. Efforts to improve the representations of physical processes in climate models, including extensive comparisons with observations, have not significantly constrained the range of possible aerosol forcing values. A far stronger constraint, in particular for the lower (most-negative) bound, can be achieved using global mean energy balance arguments based on observed changes in historical temperature. Here, we show that structural deficiencies in a climate model, revealed as inconsistencies among observationally constrained cloud properties in the model, limit the effectiveness of observational constraint of the uncertain physical processes. We sample the uncertainty in 37 model parameters related to aerosols, clouds, and radiation in a perturbed parameter ensemble of the UK Earth System Model and evaluate 1 million model variants (different parameter settings from Gaussian process emulators) against satellite-derived observations over several cloudy regions. Our analysis of a very large set of model variants exposes model internal inconsistencies that would not be apparent in a small set of model simulations, of an order that may be evaluated during model-tuning efforts. Incorporating observations associated with these inconsistencies weakens any forcing constraint because they require a wider range of parameter values to accommodate conflicting information. We show that, by neglecting variables associated with these inconsistencies, it is possible to reduce the parametric uncertainty in global mean aerosol forcing by more than 50 %, constraining it to a range (around −1.3 to −0.1 W m−2) in close agreement with energy balance constraints. Our estimated aerosol forcing range is the maximum feasible constraint using our structurally imperfect model and the chosen observations. Structural model developments targeted at the identified inconsistencies would enable a larger set of observations to be used for constraint, which would then very likely narrow the uncertainty further and possibly alter the central estimate. Such an approach provides a rigorous pathway to improved model realism and reduced uncertainty that has so far not been achieved through the normal model development approach

Identifying climate model structural inconsistencies allows for tight constraint of aerosol radiative forcing

Aerosol radiative forcing uncertainty affects estimates of climate sensitivity and limits model skill in terms of making climate projections. Efforts to improve the representations of physical processes in climate models, including extensive comparisons with observations, have not significantly constrained the range of possible aerosol forcing values. A far stronger constraint, in particular for the lower (most-negative) bound, can be achieved using global mean energy balance arguments based on observed changes in historical temperature. Here, we show that structural deficiencies in a climate model, revealed as inconsistencies among observationally constrained cloud properties in the model, limit the effectiveness of observational constraint of the uncertain physical processes. We sample the uncertainty in 37 model parameters related to aerosols, clouds, and radiation in a perturbed parameter ensemble of the UK Earth System Model and evaluate 1 million model variants (different parameter settings from Gaussian process emulators) against satellite-derived observations over several cloudy regions. Our analysis of a very large set of model variants exposes model internal inconsistencies that would not be apparent in a small set of model simulations, of an order that may be evaluated during model-tuning efforts. Incorporating observations associated with these inconsistencies weakens any forcing constraint because they require a wider range of parameter values to accommodate conflicting information. We show that, by neglecting variables associated with these inconsistencies, it is possible to reduce the parametric uncertainty in global mean aerosol forcing by more than 50 %, constraining it to a range (around −1.3 to −0.1 W m−2) in close agreement with energy balance constraints. Our estimated aerosol forcing range is the maximum feasible constraint using our structurally imperfect model and the chosen observations. Structural model developments targeted at the identified inconsistencies would enable a larger set of observations to be used for constraint, which would then very likely narrow the uncertainty further and possibly alter the central estimate. Such an approach provides a rigorous pathway to improved model realism and reduced uncertainty that has so far not been achieved through the normal model development approach

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Measurement of prompt D0^{0} and D‾\overline{D}0^{0} meson azimuthal anisotropy and search for strong electric fields in PbPb collisions at root SNN\sqrt{S_{NN}} = 5.02 TeV

The strong Coulomb field created in ultrarelativistic heavy ion collisions is expected to produce a rapiditydependent difference (Av2) in the second Fourier coefficient of the azimuthal distribution (elliptic flow, v2) between D0 (uc) and D0 (uc) mesons. Motivated by the search for evidence of this field, the CMS detector at the LHC is used to perform the first measurement of Av2. The rapidity-averaged value is found to be (Av2) = 0.001 ? 0.001 (stat)? 0.003 (syst) in PbPb collisions at ?sNN = 5.02 TeV. In addition, the influence of the collision geometry is explored by measuring the D0 and D0mesons v2 and triangular flow coefficient (v3) as functions of rapidity, transverse momentum (pT), and event centrality (a measure of the overlap of the two Pb nuclei). A clear centrality dependence of prompt D0 meson v2 values is observed, while the v3 is largely independent of centrality. These trends are consistent with expectations of flow driven by the initial-state geometry. ? 2021 The Author. Published by Elsevier B.V. This is an open access article under the CC BY licens

Observation of electroweak production of Wγ with two jets in proton-proton collisions at √s = 13 TeV

A first observation is presented for the electroweak production of a W boson, a photon, and two jets in proton-proton collisions. The W boson decays are selected by requiring one identified electron or muon and an imbalance in transverse momentum. The two jets are required to have a high dijet mass and a large separation in pseudorapidity. The measurement is based on data collected with the CMS detector at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb$^{-1}$. The observed (expected) significance for this process is 4.9 (4.6) standard deviations. After combining with previously reported CMS results at 8 TeV, the observed (expected) significance is 5.3 (4.8) standard deviations. The cross section for the electroweak W$_{γjj}$ production in a restricted fiducial region is measured as 20.4 +/- 4.5 fb and the total cross section for W$_{γ}$ production in association with 2 jets in the same fiducial region is 108 +/- 16 fb. All results are in good agreement with recent theoretical predictions. Constraints are placed on anomalous quartic gauge couplings in terms of dimension-8 effective field theory operators