Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turn-inducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weigh

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

The role of leadership in salespeople’s price negotiation behavior

Salespeople assume a key role in defending firms’ price levels in price negotiations with customers. The degree to which salespeople defend prices should critically depend upon their leaders’ influence. However, the influence of leadership on salespeople’s price defense behavior is barely understood, conceptually or empirically. Therefore, building on social learning theory, the authors propose that salespeople might adopt their leaders’ price defense behavior given a transformational leadership style. Furthermore, drawing on the contingency leadership perspective, the authors argue that this adoption fundamentally depends on three variables deduced from the motivation–ability–opportunity (MAO) framework, that is, salespeople’s learning motivation, negotiation efficacy, and perceived customer lenience. Results of a multi-level model using data from 92 salespeople and 264 salesperson–customer interactions confirm these predictions. The first to explore contingencies of salespeople’s adoption of their transformational leaders’ price negotiation behaviors, this study extends marketing theory and provides actionable guidance to practitioners

Global Analysis of Extracytoplasmic Stress Signaling in Escherichia coli

The Bae, Cpx, Psp, Rcs, and σE pathways constitute the Escherichia coli signaling systems that detect and respond to alterations of the bacterial envelope. Contributions of these systems to stress response have previously been examined individually; however, the possible interconnections between these pathways are unknown. Here we investigate the dynamics between the five stress response pathways by determining the specificities of each system with respect to signal-inducing conditions, and monitoring global transcriptional changes in response to transient overexpression of each of the effectors. Our studies show that different extracytoplasmic stress conditions elicit a combined response of these pathways. Involvement of the five pathways in the various tested stress conditions is explained by our unexpected finding that transcriptional responses induced by the individual systems show little overlap. The extracytoplasmic stress signaling pathways in E. coli thus regulate mainly complementary functions whose discrete contributions are integrated to mount the full adaptive response

Erratum: "Searches for Gravitational Waves from Known Pulsars at Two Harmonics in 2015–2017 LIGO Data" (2019, ApJ, 879, 10)

This is a correction for 2019 ApJ 879 1

Search for gravitational waves from Scorpius X-1 in the second Advanced LIGO observing run with an improved hidden Markov model

We present results from a semicoherent search for continuous gravitational waves from the low-mass x-ray binary Scorpius X-1, using a hidden Markov model (HMM) to track spin wandering. This search improves on previous HMM-based searches of LIGO data by using an improved frequency domain matched filter, the J-statistic, and by analyzing data from Advanced LIGO’s second observing run. In the frequency range searched, from 60 to 650 Hz, we find no evidence of gravitational radiation. At 194.6 Hz, the most sensitive search frequency, we report an upper limit on gravitational wave strain (at 95% confidence) of h95%0=3.47×10−25 when marginalizing over source inclination angle. This is the most sensitive search for Scorpius X-1, to date, that is specifically designed to be robust in the presence of spin wandering

Search for gravitational waves from Scorpius X-1 in the second Advanced LIGO observing run with an improved hidden Markov model

We present results from a semicoherent search for continuous gravitational waves from the low-mass x-ray binary Scorpius X-1, using a hidden Markov model (HMM) to track spin wandering. This search improves on previous HMM-based searches of LIGO data by using an improved frequency domain matched filter, the J-statistic, and by analyzing data from Advanced LIGO's second observing run. In the frequency range searched, from 60 to 650 Hz, we find no evidence of gravitational radiation. At 194.6 Hz, the most sensitive search frequency, we report an upper limit on gravitational wave strain (at 95% confidence) of h095%=3.47×10-25 when marginalizing over source inclination angle. This is the most sensitive search for Scorpius X-1, to date, that is specifically designed to be robust in the presence of spin wandering. © 2019 American Physical Society

All-sky search for continuous gravitational waves from isolated neutron stars in the early O3 LIGO data

We report on an all-sky search for continuous gravitational waves in the frequency band 20-2000 Hz and with a frequency time derivative in the range of [-1.0,+0.1]×10-8 Hz/s. Such a signal could be produced by a nearby, spinning and slightly nonaxisymmetric isolated neutron star in our Galaxy. This search uses the LIGO data from the first six months of Advanced LIGO's and Advanced Virgo's third observational run, O3. No periodic gravitational wave signals are observed, and 95% confidence-level (C.L.) frequentist upper limits are placed on their strengths. The lowest upper limits on worst-case (linearly polarized) strain amplitude h0 are ∼1.7×10-25 near 200 Hz. For a circularly polarized source (most favorable orientation), the lowest upper limits are ∼6.3×10-26. These strict frequentist upper limits refer to all sky locations and the entire range of frequency derivative values. For a population-averaged ensemble of sky locations and stellar orientations, the lowest 95% C.L. upper limits on the strain amplitude are ∼1.4×10-25. These upper limits improve upon our previously published all-sky results, with the greatest improvement (factor of ∼2) seen at higher frequencies, in part because quantum squeezing has dramatically improved the detector noise level relative to the second observational run, O2. These limits are the most constraining to date over most of the parameter space searched

Gravitational Waves and Gamma-Rays from a Binary Neutron Star Merger: GW170817 and GRB 170817A

On 2017 August 17, the gravitational-wave event GW170817 was observed by the Advanced LIGO and Virgo detectors, and the gamma-ray burst (GRB) GRB 170817A was observed independently by the Fermi Gamma-ray Burst Monitor, and the Anti-Coincidence Shield for the Spectrometer for the International Gamma-Ray Astrophysics Laboratory. The probability of the near-simultaneous temporal and spatial observation of GRB 170817A and GW170817 occurring by chance is $5.0\times {10}^{-8}$. We therefore confirm binary neutron star mergers as a progenitor of short GRBs. The association of GW170817 and GRB 170817A provides new insight into fundamental physics and the origin of short GRBs. We use the observed time delay of $(+1.74\pm 0.05)\,{\rm{s}}$ between GRB 170817A and GW170817 to: (i) constrain the difference between the speed of gravity and the speed of light to be between $-3\times {10}^{-15}$ and $+7\times {10}^{-16}$ times the speed of light, (ii) place new bounds on the violation of Lorentz invariance, (iii) present a new test of the equivalence principle by constraining the Shapiro delay between gravitational and electromagnetic radiation. We also use the time delay to constrain the size and bulk Lorentz factor of the region emitting the gamma-rays. GRB 170817A is the closest short GRB with a known distance, but is between 2 and 6 orders of magnitude less energetic than other bursts with measured redshift. A new generation of gamma-ray detectors, and subthreshold searches in existing detectors, will be essential to detect similar short bursts at greater distances. Finally, we predict a joint detection rate for the Fermi Gamma-ray Burst Monitor and the Advanced LIGO and Virgo detectors of 0.1-1.4 per year during the 2018-2019 observing run and 0.3-1.7 per year at design sensitivity

GWTC-2.1: Deep extended catalog of compact binary coalescences observed by LIGO and Virgo during the first half of the third observing run

The second Gravitational-Wave Transient Catalog, GWTC-2, reported on 39 compact binary coalescences observed by the Advanced LIGO and Advanced Virgo detectors between 1 April 2019 15 ∶ 00 UTC and 1 October 2019 15 ∶ 00 UTC. Here, we present GWTC-2.1, which reports on a deeper list of candidate events observed over the same period. We analyze the final version of the strain data over this period with improved calibration and better subtraction of excess noise, which has been publicly released. We employ three matched-filter search pipelines for candidate identification, and estimate the probability of astrophysical origin for each candidate event. While GWTC-2 used a false alarm rate threshold of 2 per year, we include in GWTC-2.1, 1201 candidates that pass a false alarm rate threshold of 2 per day. We calculate the source properties of a subset of 44 high-significance candidates that have a probability of astrophysical origin greater than 0.5. Of these candidates, 36 have been reported in GWTC-2. We also calculate updated source properties for all binary black hole events previously reported in GWTC-1. If the eight additional high-significance candidates presented here are astrophysical, the mass range of events that are unambiguously identified as binary black holes (both objects ≥ 3 M⊙ ) is increased compared to GWTC-2, with total masses from ∼ 14 M ⊙ for GW190924_021846 to ∼ 182 M⊙ for GW190426_190642. Source properties calculated using our default prior suggest that the primary components of two new candidate events (GW190403_051519 and GW190426_190642) fall in the mass gap predicted by pair-instability supernova theory. We also expand the population of binaries with significantly asymmetric mass ratios reported in GWTC-2 by an additional two events (the mass ratio is less than 0.65 and 0.44 at 90% probability for GW190403_051519 and GW190917_114630 respectively), and find that two of the eight new events have effective inspiral spins χeff > 0 (at 90% credibility), while no binary is consistent with χeff < 0 at the same significance. We provide updated estimates for rates of binary black hole and binary neutron star coalescence in the local Universe