FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR

Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence

One-Loop Calculation of the Oblique S Parameter in Higgsless Electroweak Models

We present a one-loop calculation of the oblique S parameter within Higgsless models of electroweak symmetry breaking and analyze the phenomenological implications of the available electroweak precision data. We use the most general effective Lagrangian with at most two derivatives, implementing the chiral symmetry breaking SU(2)_L x SU(2)_R -> SU(2)_{L+R} with Goldstones, gauge bosons and one multiplet of vector and axial-vector massive resonance states. Using the dispersive representation of Peskin and Takeuchi and imposing the short-distance constraints dictated by the operator product expansion, we obtain S at the NLO in terms of a few resonance parameters. In asymptotically-free gauge theories, the final result only depends on the vector-resonance mass and requires M_V > 1.8 TeV (3.8 TeV) to satisfy the experimental limits at the 3 \sigma (1\sigma) level; the axial state is always heavier, we obtain M_A > 2.5 TeV (6.6 TeV) at 3\sigma (1\sigma). In strongly-coupled models, such as walking or conformal technicolour, where the second Weinberg sum rule does not apply, the vector and axial couplings are not determined by the short-distance constraints; but one can still derive a lower bound on S, provided the hierarchy M_V < M_A remains valid. Even in this less constrained situation, we find that in order to satisfy the experimental limits at 3\sigma one needs M_{V,A} > 1.8 TeV.Comment: 34 pages, 9 figures. Version published in JHEP. Some references and sentences have been added to facilitate the discussio

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses

Corrections to the SU(3)×SU(3){\bf SU(3)\times SU(3)} Gell-Mann-Oakes-Renner relation and chiral couplings L8rL^r_8 and H2rH^r_2

Next to leading order corrections to the $SU(3) \times SU(3)$ Gell-Mann-Oakes-Renner relation (GMOR) are obtained using weighted QCD Finite Energy Sum Rules (FESR) involving the pseudoscalar current correlator. Two types of integration kernels in the FESR are used to suppress the contribution of the kaon radial excitations to the hadronic spectral function, one with local and the other with global constraints. The result for the pseudoscalar current correlator at zero momentum is $\psi_5(0) = (2.8 \pm 0.3) \times 10^{-3} GeV^{4}$, leading to the chiral corrections to GMOR: $\delta_K = (55 \pm 5)$. The resulting uncertainties are mostly due to variations in the upper limit of integration in the FESR, within the stability regions, and to a much lesser extent due to the uncertainties in the strong coupling and the strange quark mass. Higher order quark mass corrections, vacuum condensates, and the hadronic resonance sector play a negligible role in this determination. These results confirm an independent determination from chiral perturbation theory giving also very large corrections, i.e. roughly an order of magnitude larger than the corresponding corrections in chiral $SU(2) \times SU(2)$. Combining these results with our previous determination of the corrections to GMOR in chiral $SU(2) \times SU(2)$, $\delta_\pi$, we are able to determine two low energy constants of chiral perturbation theory, i.e. $L^r_8 = (1.0 \pm 0.3) \times 10^{-3}$, and $H^r_2 = - (4.7 \pm 0.6) \times 10^{-3}$, both at the scale of the $\rho$-meson mass.Comment: Revised version with minor correction

Quasar accretion disk sizes from continuum reverberation mapping in the DES standard-star fields

Measurements of the physical properties of accretion disks in active galactic nuclei are important for better understanding the growth and evolution of supermassive black holes. We present the accretion disk sizes of 22 quasars from continuum reverberation mapping with data from the Dark Energy Survey (DES) standard star fields and the supernova C fields. We construct continuum lightcurves with the \textit{griz} photometry that span five seasons of DES observations. These data sample the time variability of the quasars with a cadence as short as one day, which corresponds to a rest frame cadence that is a factor of a few higher than most previous work. We derive time lags between bands with both JAVELIN and the interpolated cross-correlation function method, and fit for accretion disk sizes using the JAVELIN Thin Disk model. These new measurements include disks around black holes with masses as small as $\sim10^7$ $M_{\odot}$, which have equivalent sizes at 2500\AA \, as small as $\sim 0.1$ light days in the rest frame. We find that most objects have accretion disk sizes consistent with the prediction of the standard thin disk model when we take disk variability into account. We have also simulated the expected yield of accretion disk measurements under various observational scenarios for the Large Synoptic Survey Telescope Deep Drilling Fields. We find that the number of disk measurements would increase significantly if the default cadence is changed from three days to two days or one day.Comment: 33 pages, 24 figure

Astrometric calibration and performance of the Dark Energy Camera

We characterize the ability of the Dark Energy Camera (DECam) to perform relative astrometry across its 500~Mpix, 3 deg^2 science field of view, and across 4 years of operation. This is done using internal comparisons of ~4x10^7 measurements of high-S/N stellar images obtained in repeat visits to fields of moderate stellar density, with the telescope dithered to move the sources around the array. An empirical astrometric model includes terms for: optical distortions; stray electric fields in the CCD detectors; chromatic terms in the instrumental and atmospheric optics; shifts in CCD relative positions of up to ~10 um when the DECam temperature cycles; and low-order distortions to each exposure from changes in atmospheric refraction and telescope alignment. Errors in this astrometric model are dominated by stochastic variations with typical amplitudes of 10-30 mas (in a 30 s exposure) and 5-10 arcmin coherence length, plausibly attributed to Kolmogorov-spectrum atmospheric turbulence. The size of these atmospheric distortions is not closely related to the seeing. Given an astrometric reference catalog at density ~0.7 arcmin^{-2}, e.g. from Gaia, the typical atmospheric distortions can be interpolated to 7 mas RMS accuracy (for 30 s exposures) with 1 arcmin coherence length for residual errors. Remaining detectable error contributors are 2-4 mas RMS from unmodelled stray electric fields in the devices, and another 2-4 mas RMS from focal plane shifts between camera thermal cycles. Thus the astrometric solution for a single DECam exposure is accurate to 3-6 mas (0.02 pixels, or 300 nm) on the focal plane, plus the stochastic atmospheric distortion.Comment: Submitted to PAS

A hypothetico-deductive approach to assessing the social function of chemical signalling in a non-territorial solitary carnivore

The function of chemical signalling in non-territorial solitary carnivores is still relatively unclear. Studies on territorial solitary and social carnivores have highlighted odour capability and utility, however the social function of chemical signalling in wild carnivore populations operating dominance hierarchy social systems has received little attention. We monitored scent marking and investigatory behaviour of wild brown bears Ursus arctos, to test multiple hypotheses relating to the social function of chemical signalling. Camera traps were stationed facing bear ‘marking trees’ to document behaviour by different age sex classes in different seasons. We found evidence to support the hypothesis that adult males utilise chemical signalling to communicate dominance to other males throughout the non-denning period. Adult females did not appear to utilise marking trees to advertise oestrous state during the breeding season. The function of marking by subadult bears is somewhat unclear, but may be related to the behaviour of adult males. Subadults investigated trees more often than they scent marked during the breeding season, which could be a result of an increased risk from adult males. Females with young showed an increase in marking and investigation of trees outside of the breeding season. We propose the hypothesis that females engage their dependent young with marking trees from a young age, at a relatively ‘safe’ time of year. Memory, experience, and learning at a young age, may all contribute towards odour capabilities in adult bears

Forward Global Photometric Calibration of the Dark Energy Survey

Many scientific goals for the Dark Energy Survey (DES) require calibration of optical/NIR broadband $b = grizY$ photometry that is stable in time and uniform over the celestial sky to one percent or better. It is also necessary to limit to similar accuracy systematic uncertainty in the calibrated broadband magnitudes due to uncertainty in the spectrum of the source. Here we present a "Forward Global Calibration Method (FGCM)" for photometric calibration of the DES, and we present results of its application to the first three years of the survey (Y3A1). The FGCM combines data taken with auxiliary instrumentation at the observatory with data from the broad-band survey imaging itself and models of the instrument and atmosphere to estimate the spatial- and time-dependence of the passbands of individual DES survey exposures. "Standard" passbands are chosen that are typical of the passbands encountered during the survey. The passband of any individual observation is combined with an estimate of the source spectral shape to yield a magnitude $m_b^{\mathrm{std}}$ in the standard system. This "chromatic correction" to the standard system is necessary to achieve sub-percent calibrations. The FGCM achieves reproducible and stable photometric calibration of standard magnitudes $m_b^{\mathrm{std}}$ of stellar sources over the multi-year Y3A1 data sample with residual random calibration errors of $\sigma=5-6\,\mathrm{mmag}$ per exposure. The accuracy of the calibration is uniform across the $5000\,\mathrm{deg}^2$ DES footprint to within $\sigma=7\,\mathrm{mmag}$. The systematic uncertainties of magnitudes in the standard system due to the spectra of sources are less than $5\,\mathrm{mmag}$ for main sequence stars with $0.5<g-i<3.0$.Comment: 25 pages, submitted to A

Deepening democracy within Ireland's social partnership

Ireland's social partnership process, now under attack from a number of quarters, has repeatedly been charged with being 'undemocratic' in that it undermines the sovereign position of elected political representatives, with key policy formulation and decision-making taking place in fora outside the institutions of representative democracy. These critiques echo those against new forms of networked governance more globally. A key question therefore is how (and if) democracy may be deepened within social partnership or its potential successor(s). This article addresses this question by employing a post-liberal democratic framework to examine social partnership in practice, and by drawing lessons from another partnership process, Malawi's PRSP. Drawing from Malawi's experience, it is argued that democracy can be deepened within social partnership when governance deliberations and negotiations are conducted under conditions of vibrant public debate and genuine perspective-based representation, and when the communicative and discursive norms are widened to allow for such representation

COSMOGRAIL XVI: Time delays for the quadruply imaged quasar DES J0408-5354 with high-cadence photometric monitoring

We present time-delay measurements for the new quadruply imaged quasar DES J0408-5354, the first quadruply imaged quasar found in the Dark Energy Survey (DES). Our result is made possible by implementing a new observational strategy using almost daily observations with the MPIA 2.2m telescope at La Silla observatory and deep exposures reaching a signal-to-noise ratio of about 1000 per quasar image. This data quality allows us to catch small photometric variations (a few mmag rms) of the quasar, acting on temporal scales much shorter than microlensing, hence making the time delay measurement very robust against microlensing. In only 7 months we measure very accurately one of the time delays in DES J0408-5354: Dt(AB) = -112.1 +- 2.1 days (1.8%) using only the MPIA 2.2m data. In combination with data taken with the 1.2m Euler Swiss telescope, we also measure two delays involving the D component of the system Dt(AD) = -155.5 +- 12.8 days (8.2%) and Dt(BD) = -42.4 +- 17.6 days (41%), where all the error bars include systematics. Turning these time delays into cosmological constraints will require deep HST imaging or ground-based Adaptive Optics (AO), and information on the velocity field of the lensing galaxy.Comment: 9 pages, 5 figures, accepted for publication in Astronomy & Astrophysic