Notch Simultaneously Orchestrates Multiple Helper T Cell Programs Independently of Cytokine Signals

SummaryTwo models are proposed to explain Notch function during helper T (Th) cell differentiation. One argues that Notch instructs one Th cell fate over the other, whereas the other posits that Notch function is dictated by cytokines. Here we provide a detailed mechanistic study investigating the role of Notch in orchestrating Th cell differentiation. Notch neither instructed Th cell differentiation nor did cytokines direct Notch activity, but instead, Notch simultaneously regulated the Th1, Th2, and Th17 cell genetic programs independently of cytokine signals. In addition to regulating these programs in both polarized and nonpolarized Th cells, we identified Ifng as a direct Notch target. Notch bound the Ifng CNS-22 enhancer, where it synergized with Tbet at the promoter. Thus, Notch acts as an unbiased amplifier of Th cell differentiation. Our data provide a paradigm for Notch in hematopoiesis, with Notch simultaneously orchestrating multiple lineage programs, rather than restricting alternate outcomes

Cosmological Constraints from the Clustering of the Sloan Digital Sky Survey DR7 Luminous Red Galaxies

We present the power spectrum of the reconstructed halo density field derived from a sample of Luminous Red Galaxies (LRGs) from the Sloan Digital Sky Survey Seventh Data Release (DR7). The halo power spectrum has a direct connection to the underlying dark matter power for k <= 0.2 h/Mpc, well into the quasi-linear regime. This enables us to use a factor of ~8 more modes in the cosmological analysis than an analysis with kmax = 0.1 h/Mpc, as was adopted in the SDSS team analysis of the DR4 LRG sample (Tegmark et al. 2006). The observed halo power spectrum for 0.02 < k < 0.2 h/Mpc is well-fit by our model: chi^2 = 39.6 for 40 degrees of freedom for the best fit LCDM model. We find \Omega_m h^2 * (n_s/0.96)^0.13 = 0.141^{+0.009}_{-0.012} for a power law primordial power spectrum with spectral index n_s and \Omega_b h^2 = 0.02265 fixed, consistent with CMB measurements. The halo power spectrum also constrains the ratio of the comoving sound horizon at the baryon-drag epoch to an effective distance to z=0.35: r_s/D_V(0.35) = 0.1097^{+0.0039}_{-0.0042}. Combining the halo power spectrum measurement with the WMAP 5 year results, for the flat LCDM model we find \Omega_m = 0.289 +/- 0.019 and H_0 = 69.4 +/- 1.6 km/s/Mpc. Allowing for massive neutrinos in LCDM, we find \sum m_{\nu} < 0.62 eV at the 95% confidence level. If we instead consider the effective number of relativistic species Neff as a free parameter, we find Neff = 4.8^{+1.8}_{-1.7}. Combining also with the Kowalski et al. (2008) supernova sample, we find \Omega_{tot} = 1.011 +/- 0.009 and w = -0.99 +/- 0.11 for an open cosmology with constant dark energy equation of state w.Comment: 26 pages, 19 figures, submitted to MNRAS. The power spectrum and a module to calculate the likelihoods is publicly available at http://lambda.gsfc.nasa.gov/toolbox/lrgdr/ . v2 fixes abstract formatting issu

Testing cosmological structure formation using redshift-space distortions

Observations of redshift-space distortions in spectroscopic galaxy surveys offer an attractive method for observing the build-up of cosmological structure. In this paper we develop and test a new statistic based on anisotropies in the measured galaxy power spectrum, which is independent of galaxy bias and matches the matter power spectrum shape on large scales. The amplitude provides a constraint on the derivative of the linear growth rate through f.sigma_8. This demonstrates that spectroscopic galaxy surveys offer many of the same advantages as weak lensing surveys, in that they both use galaxies as test particles to probe all matter in the Universe. They are complementary as redshift-space distortions probe non-relativistic velocities and therefore the temporal metric perturbations, while weak lensing tests the sum of the temporal and spatial metric perturbations. The degree to which our estimator can be pushed into the non-linear regime is considered and we show that a simple Gaussian damping model, similar to that previously used to model the behaviour of the power spectrum on very small scales, can also model the quasi-linear behaviour of our estimator. This enhances the information that can be extracted from surveys for LCDM models.Comment: 12 pages, 7 figures, version accepted for publication in MNRA

The 6dF Galaxy Survey: z \approx 0 measurement of the growth rate and sigma_8

We present a detailed analysis of redshift-space distortions in the two-point correlation function of the 6dF Galaxy Survey (6dFGS). The K-band selected sub-sample which we employ in this study contains 81971 galaxies distributed over 17000deg^2 with an effective redshift z = 0.067. By modelling the 2D galaxy correlation function, xi(r_p,pi), we measure the parameter combination f(z)sigma_8(z) = 0.423 +/- 0.055. Alternatively, by assuming standard gravity we can break the degeneracy between sigma_8 and the galaxy bias parameter, b. Combining our data with the Hubble constant prior from Riess et al (2011), we measure sigma_8 = 0.76 +/- 0.11 and Omega_m = 0.250 +/- 0.022, consistent with constraints from other galaxy surveys and the Cosmic Microwave Background data from WMAP7. Combining our measurement of fsigma_8 with WMAP7 allows us to test the relationship between matter and gravity on cosmic scales by constraining the growth index of density fluctuations, gamma. Using only 6dFGS and WMAP7 data we find gamma = 0.547 +/- 0.088, consistent with the prediction of General Relativity. We note that because of the low effective redshift of 6dFGS our measurement of the growth rate is independent of the fiducial cosmological model (Alcock-Paczynski effect). We also show that our conclusions are not sensitive to the model adopted for non-linear redshift-space distortions. Using a Fisher matrix analysis we report predictions for constraints on fsigma_8 for the WALLABY survey and the proposed TAIPAN survey. The WALLABY survey will be able to measure fsigma_8 with a precision of 4-10%, depending on the modelling of non-linear structure formation. This is comparable to the predicted precision for the best redshift bins of the Baryon Oscillation Spectroscopic Survey (BOSS), demonstrating that low-redshift surveys have a significant role to play in future tests of dark energy and modified gravity.Comment: 17 pages, 13 figures, 1 tabl

Protocol for the development of a core outcome set for stillbirth care research (iCHOOSE Study)

IntroductionStillbirth is associated with significant physical, psychosocial and economic consequences for parents, families, wider society and the healthcare system. There is emerging momentum to design and evaluate interventions for care after stillbirth and in subsequent pregnancies. However, there is insufficient evidence to inform clinical practice compounded by inconsistent outcome reporting in research studies. To address this paucity of evidence, we plan to develop a core outcome set for stillbirth care research, through an international consensus process with key stakeholders including parents, healthcare professionals and researchers.Methods and analysisThe development of this core outcome set will be divided into five distinct phases: (1) Identifying potential outcomes from a mixed-methods systematic review and analysis of interviews with parents who have experienced stillbirth; (2) Creating a comprehensive outcome long-list and piloting of a Delphi questionnaire using think-aloud interviews; (3) Choosing the most important outcomes by conducting an international two-round Delphi survey including high-income, middle-income and low-income countries; (4) Deciding the core outcome set by consensus meetings with key stakeholders and (5) Dissemination and promotion of the core outcome set. A parent and public involvement panel and international steering committee has been convened to coproduce every stage of the development of this core outcome set.Ethics and disseminationEthical approval for the qualitative interviews has been approved by Berkshire Ethics Committee REC Reference 12/SC/0495. Ethical approval for the think-aloud interviews, Delphi survey and consensus meetings has been awarded from the University of Bristol Faculty of Health Sciences Research Ethics Committee (Reference number: 116535). The dissemination strategy is being developed with the parent and public involvement panel and steering committee. Results will be published in peer-reviewed specialty journals, shared at national and international conferences and promoted through parent organisations and charities.PROSPERO registration numberCRD42018087748.</jats:sec

Novel Foxo1-dependent transcriptional programs control Treg cell function

Regulatory T (T(reg)) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling T(reg) cell homeostasis and function, whereas the early T(reg)-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the T(reg)-cell-commitment stage to control T(reg) cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of T(reg )cell function. T(reg) cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with T(reg)-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of T(reg) cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt-Foxo1 signalling module controls a novel genetic program indispensable for T(reg) cell function