The Human Heterochromatin Landscape: Genomic Subtypes, Bound Proteins, And Contributions To Cell Identity

Large portions of mammalian genomes are packaged into structurally compact heterochromatin, which protects genome integrity and suppresses transcription of lineage-inappropriate genes. Characterization of heterochromatic regions has relied on genomic mapping of associated histone modifications, such as H3K9me3 and H3K27me3, and purification of proteins interacting with these modifications. Heterochromatic regions marked by H3K9me3 have been shown to impede gene activation during reprogramming to pluripotency, and I find that H3K9me3 domains can similarly impede conversion of fibroblasts to hepatocytes. However, both H3K9me3 and H3K27me3 can be found in transcriptionally active chromatin, limiting the accuracy of histone marks alone for identifying heterochromatin domains or bound proteins that impede reprogramming. I developed a biophysical method to purify heterochromatic regions, using sucrose gradients to isolate chromatin fragments that are resistant to sonication. Sequencing of the purified material (Gradient-seq) revealed the genomic landscape of structural heterochromatin in human fibroblasts, which is transcribed at low levels and contains largely distinct H3K9me3 and H3K27me3 domains, as well as unmarked regions. Gradient-seq also uncovered subtypes of H3K9me3 and H3K27me3 domains that are structurally euchromatic, a distinction corroborated by increased gene transcription, hypomethylation at CpG islands, decreased association with the nuclear lamina, and increased activation during hepatic reprogramming. Using quantitative proteomics, we found 172 proteins associated with heterochromatin after gradient sedimentation and H3K9me3-directed IP. The identified proteins include known transcriptional repressors and are enriched for proteins shown to impede reprogramming to pluripotency. We show that the RNA-binding protein RBMX, one of the proteins most enriched by gradient sedimentation and H3K9me3 IP, is a functional regulator of heterochromatin. RBMX and the related protein RBMXL1 are required for silencing of select heterochromatinized genes, and depletion of these proteins in fibroblasts renders H3K9me3-marked hepatocyte genes more competent for activation during reprogramming to the hepatic lineage. Thus, our biophysical method for heterochromatin isolation has allowed us to create a genome-wide map of chromatin compaction in human cells, to identify chromatin domain subtypes that impede conversion between differentiated lineages, and to discover novel heterochromatin proteins that contribute to this reprogramming barrier

Universal properties of Fermi gases in arbitrary dimensions

We consider spin-1/2 Fermi gases in arbitrary, integer or non-integer spatial dimensions, interacting via a Dirac delta potential. We first generalize the method of Tan's distributions and implement short-range boundary conditions to arbitrary dimension and we obtain a set of universal relations for the Fermi gas. Three-dimensional scattering under very general conditions of transversal confinement is described by an effectively reduced-dimensional scattering length, which we show depends on the three-dimensional scattering length in a universal way. Our formula for non-integer dimensions interpolates between the known results in integer dimensions 1, 2 and 3. Without any need to solve the associated multichannel scattering problem, we find that confinement-induced resonances occur in all dimensions different from D=2, while reduced-dimensional contacts, related to the tails of the momentum distributions, are connected to the three-dimensional contact by a correction factor of purely geometric origin.Comment: 6 pages, 0 figure

Resolving the M2-brane

We construct deformed, T^2 wrapped, rotating M2-branes on a resolved cone over Q^{1,1,1} and Q^{1,1,1}/Z_2, as well as on a product of two Eguchi-Hanson instantons. All worldvolume directions of these supersymmetric and regular solutions are fibred over the transverse space. These constitute gravity duals of D=3, N=2 gauge theories. In particular, the deformed M2-brane on a resolved cone over Q^{1,1,1} and the S^1 wrapped M2-brane on a resolved cone over Q^{1,1,1}/Z_2 provide explicit realizations of holographic renormalization group flows in M-theory for which both conformal and Lorentz symmetries are broken in the IR region and restored in the UV limit. These solutions can be dualized to supersymmetric type IIB pp-waves, which are rendered non-singular either by additional flux or a twisted time-like direction.Comment: Latex, 23 pages, references adde

XMM-Newton Detection of the Rare FR II BAL Quasar FIRST J101614.3+520916

We have detected FIRST J101614.3+520916 with the XMM-Newton X-ray Observatory. FIRST J101614.3+520916, one of the most extreme radio-loud, broad absorption line (BAL) quasars so far discovered, is also a Fanaroff-Riley type II (FR II) radio source. We find that, compared to its estimated intrinsic X-ray flux, the observed X-rays are likely suppressed, and that the observed hardness ratio indicates significant soft X-ray photons. This is inconsistent with the simplest model, a normal quasar spectrum absorbed by a large neutral HI column density, which would primarily absorb the softer photons. More complex models, involving partial covering, an ionized absorber, ionized mirror reflection, or jet contributions need to be invoked to explain this source. The suppressed but soft X-ray emission in this radio-loud BAL quasar is consistent with the behavior displayed by other BAL quasars, both radio-loud and radio-quiet.Comment: 5 pages, 2 figures. Accepted in AJ. (Typos corrected.

Daily changes in phytoplankton lipidomes reveal mechanisms of energy storage in the open ocean

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Communications 9 (2018): 5179, doi:10.1038/s41467-018-07346-z.Sunlight is the dominant control on phytoplankton biosynthetic activity, and darkness deprives them of their primary external energy source. Changes in the biochemical composition of phytoplankton communities over diel light cycles and attendant consequences for carbon and energy flux in environments remain poorly elucidated. Here we use lipidomic data from the North Pacific subtropical gyre to show that biosynthesis of energy-rich triacylglycerols (TAGs) by eukaryotic nanophytoplankton during the day and their subsequent consumption at night drives a large and previously uncharacterized daily carbon cycle. Diel oscillations in TAG concentration comprise 23 ± 11% of primary production by eukaryotic nanophytoplankton representing a global flux of about 2.4 Pg C yr−1. Metatranscriptomic analyses of genes required for TAG biosynthesis indicate that haptophytes and dinoflagellates are active members in TAG production. Estimates suggest that these organisms could contain as much as 40% more calories at sunset than at sunrise due to TAG production.This work was supported by a grant from the Simons Foundation, and is a contribution of the Simons Collaboration on Ocean Processes and Ecology (SCOPE award # 329108, B.A.S.V.M.). K.W.B. was further supported by the Postdoctoral Scholarship Program at Woods Hole Oceanographic Institution & U.S. Geological Survey

Frozen Disorder in a Driven System

We investigate the effects of quenched disorder on the universal properties of a randomly driven Ising lattice gas. The Hamiltonian fixed point of the pure system becomes unstable in the presence of a quenched local bias, giving rise to a new fixed point which controls a novel universality class. We determine the associated scaling forms of correlation and response functions, quoting critical exponents to two-loop order in an expansion around the upper critical dimension d$_c=5$.Comment: 5 pages RevTex. Uses multicol.sty. Accepted for publication in PR

Recent results on multiplicative noise

Recent developments in the analysis of Langevin equations with multiplicative noise (MN) are reported. In particular, we: (i) present numerical simulations in three dimensions showing that the MN equation exhibits, like the Kardar-Parisi-Zhang (KPZ) equation both a weak coupling fixed point and a strong coupling phase, supporting the proposed relation between MN and KPZ; (ii) present dimensional, and mean field analysis of the MN equation to compute critical exponents; (iii) show that the phenomenon of the noise induced ordering transition associated with the MN equation appears only in the Stratonovich representation and not in the Ito one, and (iv) report the presence of a new first-order like phase transition at zero spatial coupling, supporting the fact that this is the minimum model for noise induced ordering transitions.Comment: Some improvements respect to the first versio

Evidential Deep Learning: Enhancing Predictive Uncertainty Estimation for Earth System Science Applications

Robust quantification of predictive uncertainty is critical for understanding factors that drive weather and climate outcomes. Ensembles provide predictive uncertainty estimates and can be decomposed physically, but both physics and machine learning ensembles are computationally expensive. Parametric deep learning can estimate uncertainty with one model by predicting the parameters of a probability distribution but do not account for epistemic uncertainty.. Evidential deep learning, a technique that extends parametric deep learning to higher-order distributions, can account for both aleatoric and epistemic uncertainty with one model. This study compares the uncertainty derived from evidential neural networks to those obtained from ensembles. Through applications of classification of winter precipitation type and regression of surface layer fluxes, we show evidential deep learning models attaining predictive accuracy rivaling standard methods, while robustly quantifying both sources of uncertainty. We evaluate the uncertainty in terms of how well the predictions are calibrated and how well the uncertainty correlates with prediction error. Analyses of uncertainty in the context of the inputs reveal sensitivities to underlying meteorological processes, facilitating interpretation of the models. The conceptual simplicity, interpretability, and computational efficiency of evidential neural networks make them highly extensible, offering a promising approach for reliable and practical uncertainty quantification in Earth system science modeling. In order to encourage broader adoption of evidential deep learning in Earth System Science, we have developed a new Python package, MILES-GUESS (https://github.com/ai2es/miles-guess), that enables users to train and evaluate both evidential and ensemble deep learning

Evaluation of rate law approximations in bottom-up kinetic models of metabolism.

BackgroundThe mechanistic description of enzyme kinetics in a dynamic model of metabolism requires specifying the numerical values of a large number of kinetic parameters. The parameterization challenge is often addressed through the use of simplifying approximations to form reaction rate laws with reduced numbers of parameters. Whether such simplified models can reproduce dynamic characteristics of the full system is an important question.ResultsIn this work, we compared the local transient response properties of dynamic models constructed using rate laws with varying levels of approximation. These approximate rate laws were: 1) a Michaelis-Menten rate law with measured enzyme parameters, 2) a Michaelis-Menten rate law with approximated parameters, using the convenience kinetics convention, 3) a thermodynamic rate law resulting from a metabolite saturation assumption, and 4) a pure chemical reaction mass action rate law that removes the role of the enzyme from the reaction kinetics. We utilized in vivo data for the human red blood cell to compare the effect of rate law choices against the backdrop of physiological flux and concentration differences. We found that the Michaelis-Menten rate law with measured enzyme parameters yields an excellent approximation of the full system dynamics, while other assumptions cause greater discrepancies in system dynamic behavior. However, iteratively replacing mechanistic rate laws with approximations resulted in a model that retains a high correlation with the true model behavior. Investigating this consistency, we determined that the order of magnitude differences among fluxes and concentrations in the network were greatly influential on the network dynamics. We further identified reaction features such as thermodynamic reversibility, high substrate concentration, and lack of allosteric regulation, which make certain reactions more suitable for rate law approximations.ConclusionsOverall, our work generally supports the use of approximate rate laws when building large scale kinetic models, due to the key role that physiologically meaningful flux and concentration ranges play in determining network dynamics. However, we also showed that detailed mechanistic models show a clear benefit in prediction accuracy when data is available. The work here should help to provide guidance to future kinetic modeling efforts on the choice of rate law and parameterization approaches

Epizootic Emergence of Usutu Virus in Wild and Captive Birds in Germany

This study aimed to identify the causative agent of mass mortality in wild and captive birds in southwest Germany and to gather insights into the phylogenetic relationship and spatial distribution of the pathogen. Since June 2011, 223 dead birds were collected and tested for the presence of viral pathogens. Usutu virus (USUV) RNA was detected by real-time RT-PCR in 86 birds representing 6 species. The virus was isolated in cell culture from the heart of 18 Blackbirds (Turdus merula). USUV-specific antigen was demonstrated by immunohistochemistry in brain, heart, liver, and lung of infected Blackbirds. The complete polyprotein coding sequence was obtained by deep sequencing of liver and spleen samples of a dead Blackbird from Mannheim (BH65/11-02-03). Phylogenetic analysis of the German USUV strain BH65/11-02-03 revealed a close relationship with strain Vienna that caused mass mortality among birds in Austria in 2001. Wild birds from lowland river valleys in southwest Germany were mainly affected by USUV, but also birds kept in aviaries. Our data suggest that after the initial detection of USUV in German mosquitoes in 2010, the virus spread in 2011 and caused epizootics among wild and captive birds in southwest Germany. The data also indicate an increased risk of USUV infections in humans in Germany