Challenges of Profile Likelihood Evaluation in Multi-Dimensional SUSY Scans

Statistical inference of the fundamental parameters of supersymmetric theories is a challenging and active endeavor. Several sophisticated algorithms have been employed to this end. While Markov-Chain Monte Carlo (MCMC) and nested sampling techniques are geared towards Bayesian inference, they have also been used to estimate frequentist confidence intervals based on the profile likelihood ratio. We investigate the performance and appropriate configuration of MultiNest, a nested sampling based algorithm, when used for profile likelihood-based analyses both on toy models and on the parameter space of the Constrained MSSM. We find that while the standard configuration is appropriate for an accurate reconstruction of the Bayesian posterior, the profile likelihood is poorly approximated. We identify a more appropriate MultiNest configuration for profile likelihood analyses, which gives an excellent exploration of the profile likelihood (albeit at a larger computational cost), including the identification of the global maximum likelihood value. We conclude that with the appropriate configuration MultiNest is a suitable tool for profile likelihood studies, indicating previous claims to the contrary are not well founded.Comment: 21 pages, 9 figures, 1 table; minor changes following referee report. Matches version accepted by JHE

AAV Exploits Subcellular Stress Associated with Inflammation, Endoplasmic Reticulum Expansion, and Misfolded Proteins in Models of Cystic Fibrosis

Barriers to infection act at multiple levels to prevent viruses, bacteria, and parasites from commandeering host cells for their own purposes. An intriguing hypothesis is that if a cell experiences stress, such as that elicited by inflammation, endoplasmic reticulum (ER) expansion, or misfolded proteins, then subcellular barriers will be less effective at preventing viral infection. Here we have used models of cystic fibrosis (CF) to test whether subcellular stress increases susceptibility to adeno-associated virus (AAV) infection. In human airway epithelium cultured at an air/liquid interface, physiological conditions of subcellular stress and ER expansion were mimicked using supernatant from mucopurulent material derived from CF lungs. Using this inflammatory stimulus to recapitulate stress found in diseased airways, we demonstrated that AAV infection was significantly enhanced. Since over 90% of CF cases are associated with a misfolded variant of Cystic Fibrosis Transmembrane Conductance Regulator (ΔF508-CFTR), we then explored whether the presence of misfolded proteins could independently increase susceptibility to AAV infection. In these models, AAV was an order of magnitude more efficient at transducing cells expressing ΔF508-CFTR than in cells expressing wild-type CFTR. Rescue of misfolded ΔF508-CFTR under low temperature conditions restored viral transduction efficiency to that demonstrated in controls, suggesting effects related to protein misfolding were responsible for increasing susceptibility to infection. By testing other CFTR mutants, G551D, D572N, and 1410X, we have shown this phenomenon is common to other misfolded proteins and not related to loss of CFTR activity. The presence of misfolded proteins did not affect cell surface attachment of virus or influence expression levels from promoter transgene cassettes in plasmid transfection studies, indicating exploitation occurs at the level of virion trafficking or processing. Thus, we surmised that factors enlisted to process misfolded proteins such as ΔF508-CFTR in the secretory pathway also act to restrict viral infection. In line with this hypothesis, we found that AAV trafficked to the microtubule organizing center and localized near Golgi/ER transport proteins. Moreover, AAV infection efficiency could be modulated with siRNA-mediated knockdown of proteins involved in processing ΔF508-CFTR or sorting retrograde cargo from the Golgi and ER (calnexin, KDEL-R, β-COP, and PSMB3). In summary, our data support a model where AAV exploits a compromised secretory system and, importantly, underscore the gravity with which a stressed subcellular environment, under internal or external insults, can impact infection efficiency

Searches for continuous gravitational waves from nine young supernova remnants

We describe directed searches for continuous gravitational waves in data from the sixth LIGO science data run. The targets were nine young supernova remnants not associated with pulsars; eight of the remnants are associated with non-pulsing suspected neutron stars. One target's parameters are uncertain enough to warrant two searches, for a total of ten. Each search covered a broad band of frequencies and first and second frequency derivatives for a fixed sky direction. The searches coherently integrated data from the two LIGO interferometers over time spans from 5.3-25.3 days using the matched-filtering F-statistic. We found no credible gravitational-wave signals. We set 95% confidence upper limits as strong (low) as $4\times10^{-25}$ on intrinsic strain, $2\times10^{-7}$ on fiducial ellipticity, and $4\times10^{-5}$ on r-mode amplitude. These beat the indirect limits from energy conservation and are within the range of theoretical predictions for neutron-star ellipticities and r-mode amplitudes.Comment: Science summary available at http://www.ligo.org/science/Publication-S6DirectedSNR/index.ph

Suppression of β-Catenin by Antisense Oligomers Augments Tumor Response to Isolated Limb Perfusion in a Rodent Model of Adenomatous Polyposis Coli–Mutant Colon Cancer

BACKGROUNDIsolated hepatic perfusion has been used in patients with colorectal cancer (CRC) metastatic to the liver. We sought to determine whether perfusion with antisense oligodeoxynucleotides results in the downregulation of beta-catenin and whether this improves tumor response to isolated limb perfusion (ILP) in a heterotopic model of human CRC.METHODSAdenomatous polyposis coli-mutant human CRC xenografts were implanted into athymic rats. Animals were randomized to the following groups: (1) no treatment, (2) control ILP, (3) melphalan ILP, (4) ILP with antisense specific for beta-catenin, (5) ILP with nonspecific antisense, and (6) melphalan plus beta-catenin-specific antisense ILP. Tumor response and Western blot analysis of protein expression were evaluated.RESULTSThe maximal decrease (mean +/- SE) in tumor volume was 0% +/- 10% for no treatment, 19% +/- 14% for control ILP, 58% +/- 3% for melphalan ILP, 58% +/- 9% for beta-catenin-specific ILP, 13% +/- 19% for nonspecific antisense ILP, and 73% +/- 6% for melphalan plus beta-catenin-specific ILP (P < .05 for melphalan ILP, beta-catenin-specific ILP, and melphalan plus antisense ILP). Tumor regrowth was delayed for 6 days after control ILP, 24 days after melphalan ILP, 20 days after beta-catenin-specific ILP, 10 days after nonspecific antisense ILP, and 60 days after melphalan plus beta-catenin-specific ILP (P < .05 for melphalan plus beta-catenin-specific ILP compared with all others). Western blotting revealed prolonged suppression of beta-catenin expression after beta-catenin-specific ILP.CONCLUSIONSShort-term beta-catenin antisense treatment improves tumor response rates after ILP in a rodent model of human CRC

Planck 2013 results. XII. Diffuse component separation

© 2014 ESO. Planck has produced detailed all-sky observations over nine frequency bands between 30 and 857 GHz. These observations allow robust reconstruction of the primordial cosmic microwave background (CMB) temperature fluctuations over nearly the full sky, as well as new constraints on Galactic foregrounds, including thermal dust and line emission from molecular carbon monoxide (CO). This paper describes the component separation framework adopted by Planck for many cosmological analyses, including CMB power spectrum determination and likelihood construction on large angular scales, studies of primordial non-Gaussianity and statistical isotropy, the integrated Sachs-Wolfe effect, gravitational lensing, and searches for topological defects. We test four foreground-cleaned CMB maps derived using qualitatively different component separation algorithms. The quality of our reconstructions is evaluated through detailed simulations and internal comparisons, and shown through various tests to be internally consistent and robust for CMB power spectrum and cosmological parameter estimation up to â.," = 2000. The parameter constraints on ΛCDM cosmologies derived from these maps are consistent with those presented in the cross-spectrum based Planck likelihood analysis. We choose two of the CMB maps for specific scientific goals. We also present maps and frequency spectra of the Galactic low-frequency, CO, and thermal dust emission. The component maps are found to provide a faithful representation of the sky, as evaluated by simulations, with the largest bias seen in the CO component at 3%. For the low-frequency component, the spectral index varies widely over the sky, ranging from about β =-4 to-2. Considering both morphology and prior knowledge of the low frequencycomponents, the index map allows us to associate a steep spectral index (β&lt;-3.2) with strong anomalous microwave emission, corresponding to a spinning dust spectrum peaking below 20 GHz, a flat index of β&gt;-2.3 with strong free-free emission, and intermediate values with synchrotron emission