Replication timing maintains the global epigenetic state in human cells

ACKNOWLEDGMENTS We thank R. Didier and B. Alexander of the FSU Flow Cytometry and Confocal Microscopy Facilities for their help with flow cytometry and fluorescence-activated cell sorting for this project. Thanks to A. Brown of the FSU Biological Science Core Labs and to Y. Yang and C. Vied of the FSU Translational Labs. Thanks to S. R. Westermann of SCIGRAPHIX for generating the model figure. Thanks to B. van Steensel, J. Phillips-Cremins, and P. Fraser for critical reading of the manuscript. Funding: This work was supported by NIH grant GM083337 to D.M.G., GM035463 to V.G.C., and GM085354 to D.M.G., S.D., and V.G.C. D.L. is supported by the Hong Kong Research Grant Council (ECS 26104216). T.B. is supported by the William C. and Joyce C. O’Neil Charitable Trust, Memorial Sloan Kettering Single Cell Sequencing InitiativePeer reviewedPostprin

Risk factors and early markers for echovirus type 11 associated haemorrhage-hepatitis syndrome in neonates, a retrospective cohort study

BackgroundEchovirus type 11(E-11) can cause fatal haemorrhage-hepatitis syndrome in neonates. This study aims to investigate clinical risk factors and early markers of E-11 associated neonatal haemorrhage-hepatitis syndrome.MethodsThis is a multicentre retrospective cohort study of 105 neonates with E-11 infection in China. Patients with haemorrhage-hepatitis syndrome (the severe group) were compared with those with mild disease. Clinical risk factors and early markers of haemorrhage-hepatitis syndrome were analysed. In addition, cytokine analysis were performed in selective patients to explore the immune responses.ResultsIn addition to prematurity, low birth weight, premature rupture of fetal membrane, total parenteral nutrition (PN) (OR, 28.7; 95% CI, 2.8–295.1) and partial PN (OR, 12.9; 95% CI, 2.2–77.5) prior to the onset of disease were identified as risk factors of developing haemorrhage-hepatitis syndrome. Progressive decrease in haemoglobin levels (per 10 g/L; OR, 1.5; 95% CI, 1.1–2.0) and platelet (PLT) < 140 × 10⁹/L at early stage of illness (OR, 17.7; 95% CI, 1.4–221.5) were associated with the development of haemorrhage-hepatitis syndrome. Immunological workup revealed significantly increased interferon-inducible protein-10(IP-10) (P < 0.0005) but decreased IFN-α (P < 0.05) in peripheral blood in severe patients compared with the mild cases.ConclusionsPN may potentiate the development of E-11 associated haemorrhage-hepatitis syndrome. Early onset of thrombocytopenia and decreased haemoglobin could be helpful in early identification of neonates with the disease. The low level of IFN-α and elevated expression of IP-10 may promote the progression of haemorrhage-hepatitis syndrome

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Roles of Polycomb Complexes in the Reconstruction of 3D Genome Architecture during Preimplantation Embryonic Development

The appropriate deployment of developmental programs depends on complex genetic information encoded by genomic DNA sequences and their positioning and contacts in the three-dimensional (3D) space within the nucleus. Current studies using novel techniques including, but not limited to, Hi-C, ChIA-PET, and Hi-ChIP reveal that regulatory elements (Res), such as enhancers and promoters, may participate in the precise regulation of expression of tissue-specific genes important for both embryogenesis and organogenesis by recruiting Polycomb Group (PcG) complexes. PcG complexes usually poise the transcription of developmental genes by forming Polycomb bodies to compact poised enhancers and promoters marked by H3K27me3 in the 3D space. Additionally, recent studies have also uncovered their roles in transcriptional activation. To better understand the full complexities in the mechanisms of how PcG complexes regulate transcription and long-range 3D contacts of enhancers and promoters during developmental programs, we outline novel insights regarding PcG-associated dramatic changes in the 3D chromatin conformation in developmental programs of early embryos and naïve-ground-state transitions of pluripotent embryonic stem cells (ESCs), and highlight the distinct roles of unique and common subunits of canonical and non-canonical PcG complexes in shaping genome architectures and transcriptional programs

A Coupled Model of the 1D River Network and 3D Estuary Based on Hydrodynamics and Suspended Sediment Simulation

River networks and estuaries are very common in coastal areas. Runoff from the upper stream interacts with tidal current from open sea in these two systems, leading to a complex hydrodynamics process. Therefore, it is necessary to consider the two systems as a whole to study the flow and suspended sediment transport. Firstly, a 1D model is established in the Pearl River network and a 3D model is applied in its estuary. As sufficient mass exchanges between the river network and its estuary, a strict mathematical relationship of water level at the interfaces can be adopted to couple the 1D model with the 3D model. By doing so, the coupled model does not need to have common nested grids. The river network exchanges the suspended sediment with its estuary by adding the continuity conditions at the interfaces. The coupled model is, respectively, calibrated in the dry season and the wet season. The results demonstrate that the coupled model works excellently in simulating water level and discharge. Although there are more errors in simulating suspended sediment concentration due to some reasons, the coupled model is still good enough to evaluate the suspended sediment transport in river network and estuary systems

Reliability modeling for dependent competing failure processes with phase-type distribution considering changing degradation rate

In this paper, a system reliability model subject to Dependent Competing Failure Processes (DCFP) with phase-type (PH) distribution considering changing degradation rate is proposed. When the sum of continuous degradation and sudden degradation exceeds the soft failure threshold, soft failure occurs. The interarrival time between two successive shocks and total number of shocks before hard failure occurring follow the continuous PH distribution and discrete PH distribution, respectively. The hard failure reliability is calculated using the PH distribution survival function. Due to the shock on soft failure process, the degradation rate of soft failure will increase. When the number of shocks reaches a specific value, degradation rate changes. The hard failure is calculated by the extreme shock model, cumulative shock model, and run shock model, respectively. The closed-form reliability function is derived combining with the hard and soft failure reliability model. Finally, a Micro-Electro-Mechanical System (MEMS) demonstrates the effectiveness of the proposed model

Paper-based Photocatalysts Immobilization without Coffee Ring Effect for Photocatalytic Water Purification

Photocatalytic water purification is important for the degradation of organic pollutants, attracting intensive interests. Photocatalysts are preferred to be immobilized on a substrate in order to reduce the laborious separation and recycling steps. To get uniform irradiation, the photocatalysts are preferred to be even/uniform on the substrate without aggregation. Generally, the “coffee ring effect” occurs on the substrate during solvent evaporation, unfortunately resulting in the aggregation of the photocatalysts. This aggregation inevitably blocks the exposure of active sites, reactant exchange, and light absorption. Here, we reported a paper-based photocatalyst immobilization method to solve the “coffee ring” problem. We also used a “drop reactor” to achieve good photocatalytic efficiency with the advantages of large surface area, short diffusion lengths, simple operation, and uniform light absorption. Compared with the coffee ring type, the paper-based method showed higher water purification efficiency, indicating its potential application value in the future

Condensin II Counteracts Cohesin and RNA Polymerase II in the Establishment of 3D Chromatin Organization

Summary: Interaction domains in Drosophila chromosomes form by segregation of active and inactive chromatin in the absence of CTCF loops, but the role of transcription versus other architectural proteins in chromatin organization is unclear. Here, we find that positioning of RNAPII via transcription elongation is essential in the formation of gene loops, which in turn interact to form compartmental domains. Inhibition of transcription elongation or depletion of cohesin decreases gene looping and formation of active compartmental domains. In contrast, depletion of condensin II, which also localizes to active chromatin, causes increased gene looping, formation of compartmental domains, and stronger intra-chromosomal compartmental interactions. Condensin II has a similar role in maintaining inter-chromosomal interactions responsible for pairing between homologous chromosomes, whereas inhibition of transcription elongation or cohesin depletion has little effect on homolog pairing. The results suggest distinct roles for cohesin and condensin II in the establishment of 3D nuclear organization in Drosophila. : Using Hi-C analyses, Rowley et al. show that Drosophila genes form loops between the TSS and TTS, which in turn interact to form compartmental domains. Cohesin and condensin act in opposite ways on the formation of gene loops and domains. Keywords: CTCF, transcription, compartment, TAD, pairing, transvection, loop, Hi-C, HiChI

Ecdysone-induced 3D chromatin reorganization involves active enhancers bound by Pipsqueak and Polycomb

Evidence suggests that Polycomb (Pc) is present at chromatin loop anchors in Drosophila. Pc is recruited to DNA through interactions with the GAGA binding factors GAF and Pipsqueak (Psq). Using HiChIP in Drosophila cells, we find that the psq gene, which has diverse roles in development and tumorigenesis, encodes distinct isoforms with unanticipated roles in genome 3D architecture. The BR-C, ttk, and bab domain (BTB)-containing Psq isoform (PsqL) colocalizes genome-wide with known architectural proteins. Conversely, Psq lacking the BTB domain (PsqS) is consistently found at Pc loop anchors and at active enhancers, including those that respond to the hormone ecdysone. After stimulation by this hormone, chromatin 3D organization is altered to connect promoters and ecdysone-responsive enhancers bound by PsqS. Our findings link Psq variants lacking the BTB domain to Pc-bound active enhancers, thus shedding light into their molecular function in chromatin changes underlying the response to hormone stimulus.I.G.-P. was supported by a predoctoral FPI fellowship from the Spanish Ministry of Economy and Competitiveness (MINECO) (BES-2010-030958). M.J.R. was supported by NIH Pathway to Independence Award NIGMS K99GM127671. This work was funded by the Fundación Botín Grant, the Generalitat Valenciana (PROMETEO/2017/146), the Fundación Cientifica Asociación Española Contra el Cáncer (AECC) (CICPF16001DOMÍ), the Spanish Ministry of Economy and Competitiveness (MINECO) (BFU2015-64239-R), and cofinanced by the European Regional Development Fund (ERDF) and the Spanish State Research Agency through the “Severo Ochoa” Program for Centers of Excellence in R&D (SEV-2013-0317) to M.D. This work was also supported by Pathway to Independence Award K99/R00 GM127671 (to M.J.R.) and U.S. Public Health Service Award R01 GM035463 (to V.G.C.) from the NIH.Peer reviewe