Lipid specificity of the immune effector perforin

Perforin is a pore forming protein used by cytotoxic T lymphocytes to remove cancerous or virus-infected cells during immune response. During the response, the lymphocyte membrane becomes refractory to perforin function by accumulating densely ordered lipid rafts and externalizing negatively charged lipid species. The dense membrane packing lowers the capacity of perforin to bind, and negatively charged lipids scavenge any residual protein before pore formation. Using atomic force microscopy on model membrane systems, we here provide insight into the molecular basis of perforin lipid specificity

Human PrimPol is a highly error-prone polymerase regulated by single-stranded DNA binding proteins

PrimPol is a recently identified polymerase involved in eukaryotic DNA damage tolerance, employed in both re-priming and translesion synthesis mechanisms to bypass nuclear and mitochondrial DNA lesions. In this report, we investigate how the enzymatic activities of human PrimPol are regulated. We show that, unlike other TLS polymerases, PrimPol is not stimulated by PCNA and does not interact with it in vivo. We identify that PrimPol interacts with both of the major single-strand binding proteins, RPA and mtSSB in vivo. Using NMR spectroscopy, we characterize the domains responsible for the PrimPol-RPA interaction, revealing that PrimPol binds directly to the N-terminal domain of RPA70. In contrast to the established role of SSBs in stimulating replicative polymerases, we find that SSBs significantly limit the primase and polymerase activities of PrimPol. To identify the requirement for this regulation, we employed two forward mutation assays to characterize PrimPol's replication fidelity. We find that PrimPol is a mutagenic polymerase, with a unique error specificity that is highly biased towards insertion-deletion errors. Given the error-prone disposition of PrimPol, we propose a mechanism whereby SSBs greatly restrict the contribution of this enzyme to DNA replication at stalled forks, thus reducing the mutagenic potential of PrimPol during genome replication

Weak lensing power spectra for precision cosmology: Multiple-deflection, reduced shear and lensing bias corrections

It is usually assumed that the ellipticity power spectrum measured in weak lensing observations can be expressed as an integral over the underlying matter power spectrum. This is true at second order in the gravitational potential. We extend the standard calculation, constructing all corrections to fourth order in the gravitational potential. There are four types of corrections: corrections to the lensing shear due to multiple-deflections; corrections due to the fact that shape distortions probe the reduced shear $\gamma/(1-\kappa)$ rather than the shear itself; corrections associated with the non-linear conversion of reduced shear to mean ellipticity; and corrections due to the fact that observational galaxy selection and shear measurement is based on galaxy brightnesses and sizes which have been (de)magnified by lensing. We show how the previously considered corrections to the shear power spectrum correspond to terms in our analysis, and highlight new terms that were not previously identified. All correction terms are given explicitly as integrals over the matter power spectrum, bispectrum, and trispectrum, and are numerically evaluated for the case of sources at z=1. We find agreement with previous works for the ${\mathcal O}(\Phi^3)$ terms. We find that for ambitious future surveys, the ${\mathcal O}(\Phi^4)$ terms affect the power spectrum at the ~ 1-5 $\sigma$ level; they will thus need to be accounted for, but are unlikely to represent a serious difficulty for weak lensing as a cosmological probe.Comment: 14 pages, 3 figures; matches A & A accepted versio

Self calibration of photometric redshift scatter in weak lensing surveys

Photo-z errors, especially catastrophic errors, are a major uncertainty for precision weak lensing cosmology. We find that the shear-(galaxy number) density and density-density cross correlation measurements between photo-z bins, available from the same lensing surveys, contain valuable information for self-calibration of the scattering probabilities between the true-z and photo-z bins. The self-calibration technique we propose does not rely on cosmological priors nor parameterization of the photo-z probability distribution function, and preserves all of the cosmological information available from shear-shear measurement. We estimate the calibration accuracy through the Fisher matrix formalism. We find that, for advanced lensing surveys such as the planned stage IV surveys, the rate of photo-z outliers can be determined with statistical uncertainties of 0.01-1% for $z<2$ galaxies. Among the several sources of calibration error that we identify and investigate, the {\it galaxy distribution bias} is likely the most dominant systematic error, whereby photo-z outliers have different redshift distributions and/or bias than non-outliers from the same bin. This bias affects all photo-z calibration techniques based on correlation measurements. Galaxy bias variations of $O(0.1)$ produce biases in photo-z outlier rates similar to the statistical errors of our method, so this galaxy distribution bias may bias the reconstructed scatters at several-$\sigma$ level, but is unlikely to completely invalidate the self-calibration technique.Comment: v2: 19 pages, 10 figures. Added one figure. Expanded discussions. Accepted to MNRA

Cosmic Shear E/B-mode Estimation with Binned Correlation Function Data

In this work I study the problem of E/B-mode separation with binned cosmic shear two-point correlation function data. Motivated by previous work on E/B-mode separation with shear two-point correlation functions and the practical considerations of data analysis, I consider E/B-mode estimators which are linear combinations of the binned shear correlation function data points. I demonstrate that these estimators mix E- and B-modes generally. I then show how to define estimators which minimize this E/B-mode mixing and give practical recipes for their construction and use. Using these optimal estimators, I demonstrate that the vector space composed of the binned shear correlation function data points can be decomposed into approximately ambiguous, E- and B-mode subspaces. With simple Fisher information estimates, I show that a non-trivial amount of information on typical cosmological parameters is contained in the ambiguous mode subspace computed in this formalism. Next, I give two examples which apply these practical estimators and recipes to generic problems in cosmic shear data analysis: data compression and spatially locating B-mode contamination. In particular, by using wavelet-like estimators with the shear correlation functions directly, one can pinpoint B-mode contamination to specific angular scales and extract information on its shape. Finally, I discuss how these estimators can be used as part of blinded or closed-box cosmic shear data analyses in order to assess and find B-mode contamination at high-precision while avoiding observer biases.Comment: 15 pages, 5 figures, 3 appendices, MNRAS submitted, comments welcome

Precision cluster mass determination from weak lensing

Weak gravitational lensing has been used extensively in the past decade to constrain the masses of galaxy clusters, and is the most promising observational technique for providing the mass calibration necessary for precision cosmology with clusters. There are several challenges in estimating cluster masses, particularly (a) the sensitivity to astrophysical effects and observational systematics that modify the signal relative to the theoretical expectations, and (b) biases that can arise due to assumptions in the mass estimation method, such as the assumed radial profile of the cluster. All of these challenges are more problematic in the inner regions of the cluster, suggesting that their influence would ideally be suppressed for the purpose of mass estimation. However, at any given radius the differential surface density measured by lensing is sensitive to all mass within that radius, and the corrupted signal from the inner parts is spread out to all scales. We develop a new statistic that is ideal for estimation of cluster masses because it completely eliminates mass contributions below a chosen scale (which we suggest should be about 20 per cent of the virial radius), and thus reduces sensitivity to systematic and astrophysical effects. We use simulated and analytical profiles to quantify systematic biases on the estimated masses for several standard methods of mass estimation, finding that these can lead to significant mass biases that range from ten to over fifty per cent. The mass uncertainties when using our new statistic are reduced by up to a factor of ten relative to the standard methods, while only moderately increasing the statistical errors. This new method of mass estimation will enable a higher level of precision in future science work with weak lensing mass estimates for galaxy clusters.Comment: 27 pages, 7 figures, submitted to MNRAS; v2 has expanded explanation for clarity, no change in results or conclusion

Intrinsic electrochemical activity of single walled carbon nanotube–Nafion assemblies

The intrinsic electrochemical properties and activity of single walled carbon nanotube (SWNT) network electrodes modified by a drop-cast Nafion film have been determined using the one electron oxidation of ferrocene trimethyl ammonium (FcTMA+) as a model redox probe in the Nafion film. Facilitated by the very low transport coefficient of FcTMA+ in Nafion (apparent diffusion coefficient of 1.8 × 10−10 cm2 s−1), SWNTs in the 2-D network behave as individual elements, at short (practical) times, each with their own characteristic diffusion, independent of neighbouring sites, and the response is diagnostic of the proportion of SWNTs active in the composite. Data are analysed using candidate models for cases where: (i) electron transfer events only occur at discrete sites along the sidewall (with a defect density typical of chemical vapour deposition SWNTs); (ii) all of the SWNTs in a network are active. The first case predicts currents that are much smaller than seen experimentally, indicating that significant portions of SWNTs are active in the SWNT–Nafion composite. However, the predictions for a fully active SWNT result in higher currents than seen experimentally, indicating that a fraction of SWNTs are not connected and/or that not all SWNTs are wetted completely by the Nafion film to provide full access of the redox mediator to the SWNT surface

Trans-endocytosis of CD80 and CD86:a molecular basis for the cell-extrinsic function of CTLA-4

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system

Constraining primordial non-Gaussianity with future galaxy surveys

We study the constraining power on primordial non-Gaussianity of future surveys of the large-scale structure of the Universe for both near-term surveys (such as the Dark Energy Survey - DES) as well as longer term projects such as Euclid and WFIRST. Specifically we perform a Fisher matrix analysis forecast for such surveys, using DES-like and Euclid-like configurations as examples, and take account of any expected photometric and spectroscopic data. We focus on two-point statistics and we consider three observables: the 3D galaxy power spectrum in redshift space, the angular galaxy power spectrum, and the projected weak-lensing shear power spectrum. We study the effects of adding a few extra parameters to the basic LCDM set. We include the two standard parameters to model the current value for the dark energy equation of state and its time derivative, w_0, w_a, and we account for the possibility of primordial non-Gaussianity of the local, equilateral and orthogonal types, of parameter fNL and, optionally, of spectral index n_fNL. We present forecasted constraints on these parameters using the different observational probes. We show that accounting for models that include primordial non-Gaussianity does not degrade the constraint on the standard LCDM set nor on the dark-energy equation of state. By combining the weak lensing data and the information on projected galaxy clustering, consistently including all two-point functions and their covariance, we find forecasted marginalised errors sigma (fNL) ~ 3, sigma (n_fNL) ~ 0.12 from a Euclid-like survey for the local shape of primordial non-Gaussianity, while the orthogonal and equilateral constraints are weakened for the galaxy clustering case, due to the weaker scale-dependence of the bias. In the lensing case, the constraints remain instead similar in all configurations.Comment: 20 pages, 10 Figures. Minor modifications; accepted by MNRA