Variant Histone H2A.Z Is Globally Localized to the Promoters of Inactive Yeast Genes and Regulates Nucleosome Positioning

H2A.Z is an evolutionary conserved histone variant involved in transcriptional regulation, antisilencing, silencing, and genome stability. The mechanism(s) by which H2A.Z regulates these various biological functions remains poorly defined, in part due to the lack of knowledge regarding its physical location along chromosomes and the bearing it has in regulating chromatin structure. Here we mapped H2A.Z across the yeast genome at an approximately 300-bp resolution, using chromatin immunoprecipitation combined with tiling microarrays. We have identified 4,862 small regions—typically one or two nucleosomes wide—decorated with H2A.Z. Those “Z loci” are predominantly found within specific nucleosomes in the promoter of inactive genes all across the genome. Furthermore, we have shown that H2A.Z can regulate nucleosome positioning at the GAL1 promoter. Within HZAD domains, the regions where H2A.Z shows an antisilencing function, H2A.Z is localized in a wider pattern, suggesting that the variant histone regulates a silencing and transcriptional activation via different mechanisms. Our data suggest that the incorporation of H2A.Z into specific promoter-bound nucleosomes configures chromatin structure to poise genes for transcriptional activation. The relevance of these findings to higher eukaryotes is discussed

Association of latent factors of neuroinflammation with Alzheimer's disease pathology and longitudinal cognitive decline

INTRODUCTION: We investigated the association of inflammatory mechanisms with markers of Alzheimer's disease (AD) pathology and rates of cognitive decline in the AD spectrum.METHODS: We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in cerebrospinal fluid.RESULTS: We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline.DISCUSSION: Latent factors provided access to directly unobservable components of the neuroinflammatory response and their association with AD pathology and cognitive decline.</p

KiDS-1000 Cosmology:Multi-probe weak gravitational lensing and spectroscopic galaxy clustering constraints

We present a joint cosmological analysis of weak gravitational lensing observations from the Kilo-Degree Survey (KiDS-1000), with redshift-space galaxy clustering observations from the Baryon Oscillation Spectroscopic Survey (BOSS), and galaxy-galaxy lensing observations from the overlap between KiDS-1000, BOSS and the spectroscopic 2-degree Field Lensing Survey (2dFLenS). This combination of large-scale structure probes breaks the degeneracies between cosmological parameters for individual observables, resulting in a constraint on the structure growth parameter $S_8=\sigma_8 \sqrt{\Omega_{\rm m}/0.3} = 0.766^{+0.020}_{-0.014}$, that has the same overall precision as that reported by the full-sky cosmic microwave background observations from Planck. The recovered $S_8$ amplitude is low, however, by $8.3 \pm 2.6$ % relative to Planck. This result builds from a series of KiDS-1000 analyses where we validate our methodology with variable depth mock galaxy surveys, our lensing calibration with image simulations and null-tests, and our optical-to-near-infrared redshift calibration with multi-band mock catalogues and a spectroscopic-photometric clustering analysis. The systematic uncertainties identified by these analyses are folded through as nuisance parameters in our cosmological analysis. Inspecting the offset between the marginalised posterior distributions, we find that the $S_8$-difference with Planck is driven by a tension in the matter fluctuation amplitude parameter, $\sigma_8$. We quantify the level of agreement between the CMB and our large-scale structure constraints using a series of different metrics, finding differences with a significance ranging between $\sim\! 3\,\sigma$, when considering the offset in $S_{8}$, and $\sim\! 2\,\sigma$, when considering the full multi-dimensional parameter space.Comment: 25 pages, 11 figures, 5 tables, A&A accepted, including a new appendix on Intrinsic Alignments. The KiDS-1000 data products are available for download at http://kids.strw.leidenuniv.nl/DR4/lensing.php. This data release includes open source software, the shear-photo-z catalogue, the cosmic shear and 3x2pt data vectors and covariances, and posteriors in the form of Multinest chain

Cognitive Trajectories in Preclinical and Prodromal Alzheimer's Disease Related to Amyloid Status and Brain Atrophy:A Bayesian Approach

Background: Cognitive decline is a key outcome of clinical studies in Alzheimer’s disease (AD). Objective: To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. Methods: We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. Results: We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. Conclusions: We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid

Cognitive Trajectories in Preclinical and Prodromal Alzheimer's Disease Related to Amyloid Status and Brain Atrophy: A Bayesian Approach

Background: Cognitive decline is a key outcome of clinical studies in Alzheimer's disease (AD). Objective: To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. Methods: We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. Results: We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. Conclusions: We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid

KiDS-450: cosmological constraints from weak lensing peak statistics – I. Inference from analytical prediction of high signal-to-noise ratio convergence peaks

This paper is the first of a series of papers constraining cosmological parameters with weak lensing peak statistics using ∼ 450 deg2 of imaging data from the Kilo Degree Survey (KiDS-450). We measure high signal-to-noise ratio (SNR: ν) weak lensing convergence peaks in the range of 3 < ν < 5, and employ theoretical models to derive expected values. These models are validated using a suite of simulations. We take into account two major systematic effects, the boost factor and the effect of baryons on the mass–concentration relation of dark matter haloes. In addition, we investigate the impacts of other potential astrophysical systematics including the projection effects of large-scale structures, intrinsic galaxy alignments, as well as residual measurement uncertainties in the shear and redshift calibration. Assuming a flat Λ cold dark matter model, we find constraints for S8=σ8(Ωm/0.3)0.5=0.746+0.046−0.107S8=σ8(Ωm/0.3)0.5=0.746−0.107+0.046 according to the degeneracy direction of the cosmic shear analysis and Σ8=σ8(Ωm/0.3)0.38=0.696+0.048−0.050Σ8=σ8(Ωm/0.3)0.38=0.696−0.050+0.048 based on the derived degeneracy direction of our high-SNR peak statistics. The difference between the power index of S8 and in Σ8 indicates that combining cosmic shear with peak statistics has the potential to break the degeneracy in σ8 and Ωm. Our results are consistent with the cosmic shear tomographic correlation analysis of the same data set and ∼2σ lower than the Planck 2016 results

mRNA Secondary Structures Fold Sequentially But Exchange Rapidly In Vivo

Self-cleavage assays of RNA folding reveal that mRNA structures fold sequentially in vitro and in vivo, but exchange between adjacent structures is much faster in vivo than it is in vitro

The third data release of the Kilo-Degree Survey and associated data products

The Kilo-Degree Survey (KiDS) is an ongoing optical wide-field imaging survey with the OmegaCAM camera at the VLT Survey Telescope. It aims to image 1500 square degrees in four filters (ugri). The core science driver is mapping the large-scale matter distribution in the Universe, using weak lensing shear and photometric redshift measurements. Further science cases include galaxy evolution, Milky Way structure, detection of high-redshift clusters, and finding rare sources such as strong lenses and quasars. Here we present the third public data release (DR3) and several associated data products, adding further area, homogenized photometric calibration, photometric redshifts and weak lensing shear measurements to the first two releases. A dedicated pipeline embedded in the Astro-WISE information system is used for the production of the main release. Modifications with respect to earlier releases are described in detail. Photometric redshifts have been derived using both Bayesian template fitting, and machine-learning techniques. For the weak lensing measurements, optimized procedures based on the THELI data reduction and lensfit shear measurement packages are used. In DR3 stacked ugri images, weight maps, masks, and source lists for 292 new survey tiles (~300 sq.deg) are made available. The multi-band catalogue, including homogenized photometry and photometric redshifts, covers the combined DR1, DR2 and DR3 footprint of 440 survey tiles (447 sq.deg). Limiting magnitudes are typically 24.3, 25.1, 24.9, 23.8 (5 sigma in a 2 arcsec aperture) in ugri, respectively, and the typical r-band PSF size is less than 0.7 arcsec. The photometric homogenization scheme ensures accurate colors and an absolute calibration stable to ~2% for gri and ~3% in u. Separately released are a weak lensing shear catalogue and photometric redshifts based on two different machine-learning techniques.Comment: small modifications; 27 pages, 12 figures, accepted for publication in Astronomy & Astrophysic