Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states

Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNFα (>100 min apart) give a high probability of NF-κB activation. However, fewer cells respond to shorter pulse intervals (<100 min) suggesting a heterogeneous refractory state. This refractory state is established in the signal transduction network downstream of TNFR and upstream of IKK, and depends on the level of the NF-κB system negative feedback protein A20. If a second pulse within the refractory phase is IL-1β instead of TNFα, all of the cells respond. This suggests a mechanism by which two cytokines can synergistically activate an inflammatory response. Gene expression analyses show strong correlation between the cellular dynamic response and NF-κB-dependent target gene activation. These data suggest that refractory states in the NF-κB system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation

The metamorphosis of the Type Ib SN 2019yvr: late-time interaction

We present observational evidence of late-time interaction between the ejecta of the hydrogen-poor Type Ib supernova (SN) 2019yvr and hydrogen-rich circumstellar material (CSM), similar to the Type Ib SN 2014C. A narrow H α emission line appears simultaneously with a break in the light-curve decline rate at around 80–100 d after explosion. From the interaction delay and the ejecta velocity, under the assumption that the CSM is detached from the progenitor, we estimate the CSM inner radius to be located at ∼6.5–9.1 × 1015 cm. The H α emission line persists throughout the nebular phase at least up to +420 d post-explosion, with a full width at half maximum of ∼2000 km s−1. Assuming a steady mass-loss, the estimated mass-loss rate from the luminosity of the H α line is ∼3–7 × 10−5 M yr−1. From hydrodynamical modelling and analysis of the nebular spectra, we find a progenitor He-core mass of 3–4 M, which would imply an initial mass of 13–15 M. Our result supports the case of a relatively low-mass progenitor possibly in a binary system as opposed to a higher mass single star undergoing a luminous blue variable phase

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Signalling ballet in space and time

Although we have amassed extensive catalogues of signalling network components, our understanding of the spatiotemporal control of emergent network structures has lagged behind. Dynamic behaviour is starting to be explored throughout the genome, but analysis of spatial behaviours is still confined to individual proteins. The challenge is to reveal how cells integrate temporal and spatial information to determine specific biological functions. Key findings are the discovery of molecular signalling machines such as Ras nanoclusters, spatial activity gradients and flexible network circuitries that involve transcriptional feedback. They reveal design principles of spatiotemporal organization that are crucial for network function and cell fate decisions.SFI Grant No. 06/CE/B1129 & NIH grant numbers GM059570, GM066717. Deposited by bulk impor