Reconciling intrinsic properties of activating TNF receptors by native ligands versus synthetic agonists

The extracellular domain of tumor necrosis factor receptors (TNFR) generally require assembly into a homotrimeric quaternary structure as a prerequisite for initiation of signaling via the cytoplasmic domains. TNF receptor homotrimers are natively activated by similarly homo-trimerized TNF ligands, but can also be activated by synthetic agonists including engineered antibodies and Fc-ligand fusion proteins. A large body of literature from pre-clinical models supports the hypothesis that synthetic agonists targeting a diverse range of TNF receptors (including 4-1BB, CD40, OX40, GITR, DR5, TNFRSF25, HVEM, LTβR, CD27, and CD30) could amplify immune responses to provide clinical benefit in patients with infectious diseases or cancer. Unfortunately, however, the pre-clinical attributes of synthetic TNF receptor agonists have not translated well in human clinical studies, and have instead raised fundamental questions regarding the intrinsic biology of TNF receptors. Clinical observations of bell-shaped dose response curves have led some to hypothesize that TNF receptor overstimulation is possible and can lead to anergy and/or activation induced cell death of target cells. Safety issues including liver toxicity and cytokine release syndrome have also been observed in humans, raising questions as to whether those toxicities are driven by overstimulation of the targeted TNF receptor, a non-TNF receptor related attribute of the synthetic agonist, or both. Together, these clinical findings have limited the development of many TNF receptor agonists, and may have prevented generation of clinical data which reflects the full potential of TNF receptor agonism. A number of recent studies have provided structural insights into how different TNF receptor agonists bind and cluster TNF receptors, and these insights aid in deconvoluting the intrinsic biology of TNF receptors with the mechanistic underpinnings of synthetic TNF receptor agonist therapeutics

The Origin of Line Emission in Massive z~2.3 Galaxies: Evidence for Cosmic Downsizing of AGN Host Galaxies

Using the Gemini Near-InfraRed Spectrograph (GNIRS), we have assembled a complete sample of 20 K-selected galaxies at 2.0<z<2.7 with high quality near-infrared spectra. As described in a previous paper, 9 of these 20 galaxies have strongly suppressed star formation and no detected emission lines. The present paper concerns the 11 galaxies with detected Halpha emission, and studies the origin of the line emission using the GNIRS spectra and follow-up observations with SINFONI on the VLT. Based on their [NII]/Halpha ratios, the spatial extent of the line emission and several other diagnostics, we infer that four of the eleven emission-line galaxies host narrow line active galactic nuclei (AGNs). The AGN host galaxies have stellar populations ranging from evolved to star-forming. Combining our sample with a UV-selected galaxy sample at the same redshift that spans a broader range in stellar mass, we find that black-hole accretion is more effective at the high-mass end of the galaxy distribution (~2.9x10^11 Msun) at z~2.3. Furthermore, by comparing our results with SDSS data, we show that the AGN activity in massive galaxies has decreased significantly between z~2.3 and z~0. AGNs with similar normalized accretion rates as those detected in our K-selected galaxies reside in less massive galaxies (~4.0x10^10 Msun) at low redshift. This is direct evidence for downsizing of AGN host galaxies. Finally, we speculate that the typical stellar mass-scale of the actively accreting AGN host galaxies, both at low and at high redshift, might be similar to the mass-scale at which star-forming galaxies seem to transform into red, passive systems.Comment: Accepted for publication in the Astrophysical Journa

The Space Density and Colors of Massive Galaxies at 2<z<3: the Predominance of Distant Red Galaxies

Using the deep multi-wavelength MUSYC, GOODS, and FIRES surveys we construct a stellar mass-limited sample of galaxies at 2<z<3. The sample comprises 294 galaxies with M>10^11 Solar masses distributed over four independent fields with a total area of almost 400 sq arcmin. The mean number density of massive galaxies in this redshift range is (2.2+-0.6) x 10^-4 Mpc^-3. We present median values and 25th and 75th percentiles for the distributions of observed R mags, observed J-K colors, and rest-frame UV continuum slopes, M/L(V) ratios, and U-V colors. The galaxies show a large range in all these properties. The ``median galaxy'' is faint in the observer's optical (R=25.9), red in the observed near-IR (J-K=2.48), has a rest-frame UV spectrum which is relatively flat (beta=-0.4), and rest-frame optical colors resembling those of nearby spiral galaxies (U-V=0.62). We determine which galaxies would be selected as Lyman break galaxies (LBGs) or Distant Red Galaxies (DRGs, having J-K>2.3) in this mass-limited sample. By number DRGs make up 69% of the sample and LBGs 20%, with a small amount of overlap. By mass DRGs make up 77% and LBGs 17%. Neither technique provides a representative sample of massive galaxies at 2<z<3 as they only sample the extremes of the population. As we show here, multi-wavelength surveys with high quality photometry are essential for an unbiased census of massive galaxies in the early Universe. The main uncertainty in this analysis is our reliance on photometric redshifts; confirmation of the results presented here requires extensive near-infrared spectroscopy of optically-faint samples.Comment: Accepted for publication in ApJ Letter

Resolving diverse oxygen transport pathways across Sr-doped lanthanum ferrite and metal-perovskite heterostructures

Perovskite structured transition metal oxides are important technological materials for catalysis and solid oxide fuel cell applications. Their functionality often depends on oxygen diffusivity and mobility through complex oxide heterostructures, which can be significantly impacted by structural and chemical modifications, such as doping. Further, when utilized within electrochemical cells, interfacial reactions with other components (e.g. Ni- and Cr-based alloy electrodes and interconnects) can influence the perovskite's reactivity and ion transport, leading to complex dependencies that are difficult to control in real-world environments. Here we use isotopic tracers and atom probe tomography to directly visualize oxygen diffusion and transport pathways across perovskite and metal-perovskite heterostructures, i.e. (Ni-Cr coated) Sr-doped lanthanum ferrite (LSFO). Annealing in 18O2(g) results in elemental and isotopic redistributions through oxygen exchange (OE) in the LSFO while Ni-Cr undergoes oxidation via multiple mechanisms and transport pathways. Complementary density functional theory (DFT) calculations at experimental conditions provide rationale for OE reaction mechanisms and reveal a complex interplay of different thermodynamic and kinetic drivers. Our results shed light on the fundamental coupling of defects and oxygen transport in an important class of catalytic materials.Comment: 39 pages, 10 figure

Stereochemical and Skeletal Diversity Arising from Amino Propargylic Alcohols

An efficient synthetic pathway to the possible stereoisomers of skeletally diverse heterocyclic small molecules is presented. The change in shape brought about by different intramolecular cyclizations of diastereoisomeric amino propargylic alcohols is quantified using principal moment-of-inertia (PMI) shape analysis.Chemistry and Chemical Biolog

Massive Stars In The W33 Giant Molecular Complex

Rich in H II regions, giant molecular clouds are natural laboratories to study massive stars and sequential star formation. The Galactic star-forming complex W33 is located at = ∼ ◦ l 12.8 and at a distance of 2.4 kpc and has a size of ≈10 pc and a total mass of ≈(0.8−8.0) × 105 M⊙. The integrated radio and IR luminosity of W33—when combined with the direct detection of methanol masers, the protostellar object W33A, and the protocluster embedded within the radio source W33 main—mark the region as a site of vigorous ongoing star formation. In order to assess the long-term star formation history, we performed an infrared spectroscopic search for massive stars, detecting for the first time 14 early-type stars, including one WN6 star and four O4–7 stars. The distribution of spectral types suggests that this population formed during the past ∼2–4 Myr, while the absence of red supergiants precludes extensive star formation at ages 6–30 Myr. This activity appears distributed throughout the region and does not appear to have yielded the dense stellar clusters that characterize other star-forming complexes such as Carina and G305. Instead, we anticipate that W33 will eventually evolve into a loose stellar aggregate, with Cyg OB2 serving as a useful, albeit richer and more massive, comparator. Given recent distance estimates, and despite a remarkably similar stellar population, the rich cluster Cl 1813–178 located on the northwest edge of W33 does not appear to be physically associated with W33

A network-specific approach to percolation in networks with bidirectional links

Methods for determining the percolation threshold usually study the behavior of network ensembles and are often restricted to a particular type of probabilistic node/link removal strategy. We propose a network-specific method to determine the connectivity of nodes below the percolation threshold and offer an estimate to the percolation threshold in networks with bidirectional links. Our analysis does not require the assumption that a network belongs to a specific ensemble and can at the same time easily handle arbitrary removal strategies (previously an open problem for undirected networks). In validating our analysis, we find that it predicts the effects of many known complex structures (e.g., degree correlations) and may be used to study both probabilistic and deterministic attacks.Comment: 6 pages, 8 figure

Galaxy Zoo: CANDELS barred discs and bar fractions

The formation of bars in disc galaxies is a tracer of the dynamical maturity of the population. Previous studies have found that the incidence of bars in discs decreases from the local Universe to z ~ 1, and by z > 1 simulations predict that bar features in dynamically mature discs should be extremely rare. Here, we report the discovery of strong barred structures in massive disc galaxies at z ~ 1.5 in deep rest-frame optical images from the Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey. From within a sample of 876 disc galaxies identified by visual classification in Galaxy Zoo, we identify 123 barred galaxies. Selecting a subsample within the same region of the evolving galaxy luminosity function (brighter than L*), we find that the bar fraction across the redshift range 0.5 ≤ z ≤ 2 (fbar = 10.7+6.3 -3.5 per cent after correcting for incompleteness) does not significantly evolve.We discuss the implications of this discovery in the context of existing simulations and our current understanding of the way disc galaxies have evolved over the last 11 billion yearsPeer reviewedFinal Accepted Versio

The relative abundance of compact and normal massive early-type galaxies and its evolution from redshift z~2 to the present

We report on the evolution of the number density and size of early-type galaxies from z~2 to z~0. We select a sample of 563 massive (M>10^{10} Msun), passively evolving (SSFR<10^{-2} Gyr^{-1}) and morphologically spheroidal galaxies at 0<z<2.5, using the panchromatic photometry and spectroscopic redshifts available in the GOODS fields. We combine ACS and WFC3 HST images to study the morphology of our galaxies in their optical rest-frame in the whole 0<z<2.5 range. We find that throughout the explored redshift range the passive galaxies selected with our criteria have weak morphological K-correction, with size being slightly smaller in the optical than in the UV rest-frame (by ~20 and ~10 at z>1.2 and z<1.2, respectively). We measure a significant evolution of the mass-size relation of early-type galaxies, with the fractional increment that is almost independent on the stellar mass. Early-type galaxies (ETGs) formed at z>1 appear to be preferentially small, and the evolution of the mass-size relation at z<1 is driven by both the continuous size growth of the compact galaxies and the appearance of new ETGs with large sizes. We also find that the number density of all passive early-type galaxies increases rapidly, by a factor of 5, from z~2 to z~1, and then more mildly by another factor of 1.5 from z~1 to z~0. We interpret these results as the evidence that the bulk of the ETGs are formed at 1<z<3 through a mechanism that leaves very compact remnants. At z<1 the compact ETGs grow gradually in size, becoming normal size galaxies, and at the same time new ETGs with normal-large sizes are formed.Comment: accepted for publication in Ap