Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions

The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5 beta and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule- stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules

Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells

Taxanes remain first line chemotherapy in management of metastatic breast cancer and have a key role in epithelial ovarian cancer, with increasingly common use of weekly paclitaxel dosing regimens. However, their clinical utility is limited by the development of chemoresistance. To address this, we modelled in vitro paclitaxel resistance in MCF-7 cells. We show that at clinically relevant drug doses, emerging paclitaxel resistance is associated with profound changes in cell death responses and a switch from apoptosis to autophagy as the principal mechanism of drug-induced cytotoxicity. This was characterised by a complete absence of caspase-mediated apoptotic cell death (using the pan-caspase-inhibitor Z-VAD) in paclitaxel-resistant MCF-7TaxR cells, compared with parent MCF-7 or MDA-MB-231 cell lines on paclitaxel challenge, downregulation of caspase-7, caspase-9 and BCl2-interacting mediator of cell death (BIM) expression. Silencing with small interfering RNA to BIM in MCF-7 parental cells was sufficient to confer paclitaxel resistance, inferring the significance in downregulation of this protein in contributing to the resistant phenotype of the MCF-7TaxR cell line. Conversely, there was an increased autophagic response in the MCF-7TaxR cell line with reduced phospho-mTOR and relative resistance to the mTOR inhibitors rapamycin and RAD001. In conclusion, we show for the first time that paclitaxel resistance is associated with profound changes in cell death response with deletion of multiple apoptotic factors balanced by upregulation of the autophagic pathway and collateral sensitivity to platinum

Planck intermediate results. XLI. A map of lensing-induced B-modes

The secondary cosmic microwave background (CMB) $B$-modes stem from the post-decoupling distortion of the polarization $E$-modes due to the gravitational lensing effect of large-scale structures. These lensing-induced $B$-modes constitute both a valuable probe of the dark matter distribution and an important contaminant for the extraction of the primary CMB $B$-modes from inflation. Planck provides accurate nearly all-sky measurements of both the polarization $E$-modes and the integrated mass distribution via the reconstruction of the CMB lensing potential. By combining these two data products, we have produced an all-sky template map of the lensing-induced $B$-modes using a real-space algorithm that minimizes the impact of sky masks. The cross-correlation of this template with an observed (primordial and secondary) $B$-mode map can be used to measure the lensing $B$-mode power spectrum at multipoles up to $2000$. In particular, when cross-correlating with the $B$-mode contribution directly derived from the Planck polarization maps, we obtain lensing-induced $B$-mode power spectrum measurement at a significance level of $12\,\sigma$, which agrees with the theoretical expectation derived from the Planck best-fit $\Lambda$CDM model. This unique nearly all-sky secondary $B$-mode template, which includes the lensing-induced information from intermediate to small ($10\lesssim \ell\lesssim 1000$) angular scales, is delivered as part of the Planck 2015 public data release. It will be particularly useful for experiments searching for primordial $B$-modes, such as BICEP2/Keck Array or LiteBIRD, since it will enable an estimate to be made of the lensing-induced contribution to the measured total CMB $B$-modes.Comment: 20 pages, 12 figures; Accepted for publication in A&A; The B-mode map is part of the PR2-2015 Cosmology Products; available as Lensing Products in the Planck Legacy Archive http://pla.esac.esa.int/pla/#cosmology; and described in the 'Explanatory Supplement' https://wiki.cosmos.esa.int/planckpla2015/index.php/Specially_processed_maps#2015_Lensing-induced_B-mode_ma

Planck intermediate results: LI. Features in the cosmic microwave background temperature power spectrum and shifts in cosmological parameters

The six parameters of the standard ΛCDM model have best-fit values derived from the Planck temperature power spectrum that are shifted somewhat from the best-fit values derived from WMAP data. These shifts are driven by features in the Planck temperature power spectrum at angular scales that had never before been measured to cosmic-variance level precision. We have investigated these shifts to determine whether they are within the range of expectation and to understand their origin in the data. Taking our parameter set to be the optical depth of the reionized intergalactic medium, the baryon density ω b , the matter density ω m , the angular size of the sound horizon the spectral index of the primordial power spectrum, n s , and A s e -2τ (where A s is the amplitude of the primordial power spectrum), we have examined the change in best-fit values between a WMAP-like large angular-scale data set (with multipole moment 800, or splitting at a different multipole, yields similar results. We examined the 800 power spectrum data and find that the features there that drive these shifts are a set of oscillations across a broad range of angular scales. Although they partly appear similar to the effects of enhanced gravitational lensing, the shifts in ΛCDM parameters that arise in response to these features correspond to model spectrum changes that are predominantly due to non-lensing effects; the only exception is, which, at fixed A s e -2τ , affects the > 800 temperature power spectrum solely through the associated change in A s and the impact of that on the lensing potential power spectrum. We also ask, "what is it about the power spectrum at < 800 that leads to somewhat different best-fit parameters than come from the full range?" We find that if we discard the data at < 30, where there is a roughly 2σ downward fluctuation in power relative to the model that best fits the full range, the < 800 best-fit parameters shift significantly towards the < 2500 best-fit parameters. In contrast, including < 30, this previously noted "low-deficit" drives n s up and impacts parameters correlated with n s , such as ω m and H 0 . As expected, the < 30 data have a much greater impact on the < 800 best fit than on the < 2500 best fit. So although the shifts are not very significant, we find that they can be understood through the combined effects of an oscillatory-like set of high-residuals and the deficit in low-power, excursions consistent with sample variance that happen to map onto changes in cosmological parameters. Finally, we examine agreement between PlanckTT data and two other CMB data sets, namely the Planck lensing reconstruction and the TT power spectrum measured by the South Pole Telescope, again finding a lack of convincing evidence of any significant deviations in parameters, suggesting that current CMB data sets give an internally consistent picture of the ΛCDM model

Planck intermediate results: XLVI. Reduction of large-scale systematic effects in HFI polarization maps and estimation of the reionization optical depth

© 2016 ESO. This paper describes the identification, modelling, and removal of previously unexplained systematic effects in the polarization data of the Planck High Frequency Instrument (HFI) on large angular scales, including new mapmaking and calibration procedures, new and more complete end-to-end simulations, and a set of robust internal consistency checks on the resulting maps. These maps, at 100, 143, 217, and 353 GHz, are early versions of those that will be released in final form later in 2016. The improvements allow us to determine the cosmic reionization optical depth τ using, for the first time, the low-multipole EE data from HFI, reducing significantly the central value and uncertainty, and hence the upper limit. Two different likelihood procedures are used to constrain τ from two estimators of the CMB E-and B-mode angular power spectra at 100 and 143 GHz, after debiasing the spectra from a small remaining systematic contamination. These all give fully consistent results. A further consistency test is performed using cross-correlations derived from the Low Frequency Instrument maps of the Planck 2015 data release and the new HFI data. For this purpose, end-to-end analyses of systematic effects from the two instruments are used to demonstrate the near independence of their dominant systematic error residuals. The tightest result comes from the HFI-based τ posterior distribution using the maximum likelihood power spectrum estimator from EE data only, giving a value 0.055 ± 0.009. In a companion paper these results are discussed in the context of the best-fit PlanckΛCDM cosmological model and recent models of reionization

Response of Benthic Foraminifera to organic matter quantity and quality and bioavailable concentrations of metals in Aveiro Lagoon (Portugal)

This work analyses the distribution of living benthic foraminiferal assemblages of surface sediments in different intertidal areas of Ria de Aveiro (Portugal), a polihaline and anthropized coastal lagoon. The relationships among foraminiferal assemblages in association with environmental parameters (temperature, salinity, Eh and pH), grain size, the quantity and quality of organic matter (enrichment in carbohydrates, proteins and lipids), pollution caused by metals, and mineralogical data are studied in an attempt to identify indicators of adaptability to environmental stress. In particular, concentrations of selected metals in the surficial sediment are investigated to assess environmental pollution levels that are further synthetically parameterised by the Pollution Load Index (PLI). The PLI variations allowed the identification of five main polluted areas. Concentrations of metals were also analysed in three extracted phases to evaluate their possible mobility, bioavailability and toxicity in the surficial sediment. Polluted sediment in the form of both organic matter and metals can be found in the most confined zones. Whereas enrichment in organic matter and related biopolymers causes an increase in foraminifera density, pollution by metals leads to a decline in foraminiferal abundance and diversity in those zones. The first situation may be justified by the existence of opportunistic species (with high reproduction rate) that can live in low oxic conditions. The second is explained by the sensitivity of some species to pressure caused by metals. The quality of the organic matter found in these places and the option of a different food source should also explain the tolerance of several species to pollution caused by metals, despite their low reproductive rate in the most polluted areas. In this study, species that are sensitive and tolerant to organic matter and metal enrichment are identified, as is the differential sensitivity/tolerance of some species to metals enrichment.CNPq [401803/2010-4]; [PEst-OE/CTE/UI4035/2014]info:eu-repo/semantics/publishedVersio

Planck 2015 results: XXVI. The Second Planck Catalogue of Compact Sources

The Second Planck Catalogue of Compact Sources is a list of discrete objects detected in single-frequency maps from the full duration of the Planck mission and supersedes previous versions. It consists of compact sources, both Galactic and extragalactic, detected over the entire sky. Compact sources detected in the lower frequency channels are assigned to the PCCS2, while at higher frequencies they are assigned to one of two subcatalogues, the PCCS2 or PCCS2E, depending on their location on the sky. The first of these (PCCS2) covers most of the sky and allows the user to produce subsamples at higher reliabilities than the target 80% integral reliability of the catalogue. The second (PCCS2E) contains sources detected in sky regions where the diffuse emission makes it difficult to quantify the reliability of the detections. Both the PCCS2 and PCCS2E include polarization measurements, in the form of polarized flux densities, or upper limits, and orientation angles for all seven polarization-sensitive Planck channels. The improved data-processing of the full-mission maps and their reduced noise levels allow us to increase the number of objects in the catalogue, improving its completeness for the target 80% reliability as compared with the previous versions, the PCCS and the Early Release Compact Source Catalogue (ERCSC).The Planck Collaboration acknowledges the support of: ESA; CNES and CNRS/INSU-IN2P3-INP (France); ASI, CNR, and INAF (Italy); NASA and DoE (USA); STFC and UKSA (UK); CSIC, MINECO, JA, and, RES (Spain); Tekes, AoF, and CSC (Finland); DLR and MPG (Germany); CSA (Canada); DTU Space (Denmark); SER/SSO (Switzerland); RCN (Norway); SFI (Ireland); FCT/MCTES (Portugal); ERC and PRACE (EU). A description of the Planck Collaboration and a list of its members, indicating which technical or scientific activities they have been involved in, can be found at http://www.cosmos.esa.int/web/planck/planck-collaboration. We are grateful to the H-ATLAS Executive Committee and primarily to the PIs, S. Eales and L. Dunne, for permission to use the unpublished H-ATLAS catalogue for the validation of the present catalogue. This research has made use of the “Aladin sky atlas” (Bonnarel et al. 2000), developed at CDS, Strasbourg Observatory, France. Part of this work was performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/), provided by Dell Inc. using Strategic Research Infrastructure Funding from the HEFCE and funding from the STFC. This research has made use of the NASA/IPAC Extragalactic Database (NED) which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration

Planck 2015 results: XVII. Constraints on primordial non-Gaussianity

The Planck full mission cosmic microwave background (CMB) temperature and E-mode polarization maps are analysed to obtain constraints on primordial non-Gaussianity (NG). Using three classes of optimal bispectrum estimators-separable template-fitting (KSW), binned, and modal-we obtain consistent values for the primordial local, equilateral, and orthogonal bispectrum amplitudes, quoting as our final result from temperature alone localNL = 2.5 ± 5.7, equilNL=-16 ± 70, fNLlocal=2.5±5.7, fNLequil=-16±70, and orthoNL =-34 ± 32fNLortho=-34±33 (68% CL, statistical). Combining temperature and polarization data we obtain fNLlocal=0.8±5.0, fNLequil=-4±43, and fNLortho=-26±21localNL = 0.8 ± 5.0, equilNL=-4 ± 43, and orthoNL =-26 ± 21 (68% CL, statistical). The results are based on comprehensive cross-validation of these estimators on Gaussian and non-Gaussian simulations, are stable across component separation techniques, pass an extensive suite of tests, and are consistent with estimators based on measuring the Minkowski functionals of the CMB. The effect of time-domain de-glitching systematics on the bispectrum is negligible. In spite of these test outcomes we conservatively label the results including polarization data as preliminary, owing to a known mismatch of the noise model in simulations and the data. Beyond estimates of individual shape amplitudes, we present model-independent, three-dimensional reconstructions of the Planck CMB bispectrum and derive constraints on early universe scenarios that generate primordial NG, including general single-field models of inflation, axion inflation, initial state modifications, models producing parity-violating tensor bispectra, and directionally dependent vector models. We present a wide survey of scale-dependent feature and resonance models, accounting for the "look elsewhere" effect in estimating the statistical significance of features. We also look for isocurvature NG, and find no signal, but we obtain constraints that improve significantly with the inclusion of polarization. The primordial trispectrum amplitude in the local model is constrained to be glocalNL = (-0.9 ± 7.7) X 104(68% CL statistical), and we perform an analysis of trispectrum shapes beyond the local case. The global picture that emerges is one of consistency with the premises of the ΛCDM cosmology, namely that the structure we observe today was sourced by adiabatic, passive, Gaussian, and primordial seed perturbations

Planck 2015 results: XIII. Cosmological parameters

We present results based on full-mission Planck observations of temperature and polarization anisotropies of the CMB. These data are consistent with the six-parameter inflationary LCDM cosmology. From the Planck temperature and lensing data, for this cosmology we find a Hubble constant, H0= (67.8 +/- 0.9) km/s/Mpc, a matter density parameter Omega_m = 0.308 +/- 0.012 and a scalar spectral index with n_s = 0.968 +/- 0.006. (We quote 68% errors on measured parameters and 95% limits on other parameters.) Combined with Planck temperature and lensing data, Planck LFI polarization measurements lead to a reionization optical depth of tau = 0.066 +/- 0.016. Combining Planck with other astrophysical data we find N_ eff = 3.15 +/- 0.23 for the effective number of relativistic degrees of freedom and the sum of neutrino masses is constrained to < 0.23 eV. Spatial curvature is found to be |Omega_K| < 0.005. For LCDM we find a limit on the tensor-to-scalar ratio of r <0.11 consistent with the B-mode constraints from an analysis of BICEP2, Keck Array, and Planck (BKP) data. Adding the BKP data leads to a tighter constraint of r < 0.09. We find no evidence for isocurvature perturbations or cosmic defects. The equation of state of dark energy is constrained to w = -1.006 +/- 0.045. Standard big bang nucleosynthesis predictions for the Planck LCDM cosmology are in excellent agreement with observations. We investigate annihilating dark matter and deviations from standard recombination, finding no evidence for new physics. The Planck results for base LCDM are in agreement with BAO data and with the JLA SNe sample. However the amplitude of the fluctuations is found to be higher than inferred from rich cluster counts and weak gravitational lensing. Apart from these tensions, the base LCDM cosmology provides an excellent description of the Planck CMB observations and many other astrophysical data sets

Small molecule compounds targeting the p53 pathway: are we finally making progress?

Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful