The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we ...report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation). GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expression-specific contacts in organizing the genome in mammalian nuclei.
Signaling by the transcription factor nuclear factor kappa B (NF-κB) involves its release from inhibitor kappa B (IκB) in the cytosol, followed by translocation into the nucleus. NF-κB regulation of ...IκBα transcription represents a delayed negative feedback loop that drives oscillations in NF-κB translocation. Single-cell time-lapse imaging and computational modeling of NF-κB (RelA) localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased IκBα transcription. Transcription of target genes depended on oscillation persistence, involving cycles of RelA phosphorylation and dephosphorylation. The functional consequences of NF-κB signaling may thus depend on number, period, and amplitude of oscillations.
Large parts of the Antarctic ice sheet lying on bedrock below sea level may be vulnerable to marine-ice-sheet instability (MISI), a self-sustaining retreat of the grounding line triggered by oceanic ...or atmospheric changes. There is growing evidence that MISI may be underway throughout the Amundsen Sea embayment (ASE), which contains ice equivalent to more than a metre of global sea-level rise. If triggered in other regions, the centennial to millennial contribution could be several metres. Physically plausible projections are challenging: numerical models with sufficient spatial resolution to simulate grounding-line processes have been too computationally expensive to generate large ensembles for uncertainty assessment, and lower-resolution model projections rely on parameterizations that are only loosely constrained by present day changes. Here we project that the Antarctic ice sheet will contribute up to 30 cm sea-level equivalent by 2100 and 72 cm by 2200 (95% quantiles) where the ASE dominates. Our process-based, statistical approach gives skewed and complex probability distributions (single mode, 10 cm, at 2100; two modes, 49 cm and 6 cm, at 2200). The dependence of sliding on basal friction is a key unknown: nonlinear relationships favour higher contributions. Results are conditional on assessments of MISI risk on the basis of projected triggers under the climate scenario A1B (ref. 9), although sensitivity to these is limited by theoretical and topographical constraints on the rate and extent of ice loss. We find that contributions are restricted by a combination of these constraints, calibration with success in simulating observed ASE losses, and low assessed risk in some basins. Our assessment suggests that upper-bound estimates from low-resolution models and physical arguments (up to a metre by 2100 and around one and a half by 2200) are implausible under current understanding of physical mechanisms and potential triggers.
SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein ...(S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.
It is widely accepted, based on data from the last few decades and on model simulations, that anthropogenic climate change will cause increased fire activity. However, less attention has been paid to ...the relationship between abrupt climate changes and heightened fire activity in the paleorecord. We use 35 charcoal and pollen records to assess how fire regimes in North America changed during the last glacial-interglacial transition (15 to 10 ka), a time of large and rapid climate changes. We also test the hypothesis that a comet impact initiated continental-scale wildfires at 12.9 ka; the data do not support this idea, nor are continent-wide fires indicated at any time during deglaciation. There are, however, clear links between large climate changes and fire activity. Biomass burning gradually increased from the glacial period to the beginning of the Younger Dryas. Although there are changes in biomass burning during the Younger Dryas, there is no systematic trend. There is a further increase in biomass burning after the Younger Dryas. Intervals of rapid climate change at 13.9, 13.2, and 11.7 ka are marked by large increases in fire activity. The timing of changes in fire is not coincident with changes in human population density or the timing of the extinction of the megafauna. Although these factors could have contributed to fire-regime changes at individual sites or at specific times, the charcoal data indicate an important role for climate, and particularly rapid climate change, in determining broad-scale levels of fire activity.
We present Atacama Large Millimeter/submillimeter Array and Multi-Unit Spectroscopic Explorer observations of the brightest cluster galaxy in Abell 2597, a nearby (z = 0.0821) cool core cluster of ...galaxies. The data map the kinematics of a three billion solar mass filamentary nebula that spans the innermost 30 kpc of the galaxy's core. Its warm ionized and cold molecular components are both cospatial and comoving, consistent with the hypothesis that the optical nebula traces the warm envelopes of many cold molecular clouds that drift in the velocity field of the hot X-ray atmosphere. The clouds are not in dynamical equilibrium, and instead show evidence for inflow toward the central supermassive black hole, outflow along the jets it launches, and uplift by the buoyant hot bubbles those jets inflate. The entire scenario is therefore consistent with a galaxy-spanning "fountain," wherein cold gas clouds drain into the black hole accretion reservoir, powering jets and bubbles that uplift a cooling plume of low-entropy multiphase gas, which may stimulate additional cooling and accretion as part of a self-regulating feedback loop. All velocities are below the escape speed from the galaxy, and so these clouds should rain back toward the galaxy center from which they came, keeping the fountain long lived. The data are consistent with major predictions of chaotic cold accretion, precipitation, and stimulated feedback models, and may trace processes fundamental to galaxy evolution at effectively all mass scales.
The Fermi γ-ray source 1FGL J1417.7-4407 (J1417) is a compact X-ray binary with a neutron star primary and a red giant companion in a ∼5.4 days orbit. This initial conclusion, based on optical and ...X-ray data, was confirmed when a 2.66 ms radio pulsar was found at the same location (and with the same orbital properties) as the optical/X-ray source. However, these initial studies found conflicting evidence about the accretion state and other properties of the binary. We present new optical, radio, and X-ray observations of J1417 that allow us to better understand this unusual system. We show that one of the main pieces of evidence previously put forward for an accretion disk-the complex morphology of the persistent H emission line-can be better explained by the presence of a strong, magnetically driven stellar wind from the secondary and its interaction with the pulsar wind. The radio spectral index derived from VLA/ATCA observations is broadly consistent with that expected from a millisecond pulsar, further disfavoring an accretion disk scenario. X-ray observations show evidence for a double-peaked orbital light curve, similar to that observed in some redback millisecond pulsar binaries and likely due to an intrabinary shock. Refined optical light-curve fitting gives a distance of 3.1 0.6 kpc, confirmed by a Gaia DR2 parallax measurement. At this distance the X-ray luminosity of J1417 is ( ) ×1033 erg s−1, which is more luminous than all known redback systems in the rotational-powered pulsar state, perhaps due to the wind from the giant companion. The unusual phenomenology of this system and its differing evolutionary path from redback millisecond pulsar binaries points to a new eclipsing pulsar "spider" subclass that is a possible progenitor of normal field millisecond pulsar binaries.
The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High-throughput screening commonly used for drug discovery has ...the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a framework for connecting high-throughput toxicity testing (HTT) and other results to potential impacts on human and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables integrated approaches to testing and assessment (IATA), which incorporate results of assays at various levels of biologic organization such as in silico; HTT; chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME); and an AOP describing the biologic basis of toxicity. Thus, it is envisaged that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any adverse outcome would allow for the development of IATA and permit more detailed AOP and ADME research, where higher precision is needed based on the decision context.
A historical analysis of California Current System (CCS) circulation, performed using the Regional Ocean Modeling System with four‐dimensional variational data assimilation, was used to study ...upwelling variability during the 1988–2010 period. We examined upwelling directly from the vertical velocity field, which elucidates important temporal and spatial variability not captured by traditional coastal upwelling indices. Through much of the CCS, upwelling within 50 km of the coast has increased, as reported elsewhere. However, from 50 to 200 km offshore, upwelling trends are negative and interannual variability is 180° out of phase with the nearshore signal. This cross‐shore pattern shows up as the primary mode of variability in central and northern CCS vertical velocity anomalies, accounting for ∼40% of the total variance. Corresponding time series of the dominant modes in the central and northern CCS are strongly correlated with large‐scale climate indices, suggesting that climate fluctuations may alternately favor different biological communities.
Key Points
Interannual upwelling variability is studied from modeled vertical velocity
Nearshore (<50 km) and offshore (50–200 km) upwelling variability are out of phase
Cross‐shelf upwelling structure is coupled to large‐scale climate variability
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