Young star clusters in circumnuclear starburst rings

We analyse the cluster luminosity functions (CLFs) of the youngest star clusters in three galaxies exhibiting prominent circumnuclear starburst rings. We focus specifically on NGC 1512 and NGC 6951, for which we have access to H$\alpha$ data that allow us to unambiguously identify the youngest sample clusters. To place our results on a firm statistical footing, we first explore in detail a number of important technical issues affecting the process from converting the observational data into the spectral-energy distributions of the objects in our final catalogues. The CLFs of the young clusters in both galaxies exhibit approximate power-law behaviour down to the 90 per cent observational completeness limits, thus showing that star cluster formation in the violent environments of starburst rings appears to proceed similarly as that elsewhere in the local Universe. We discuss this result in the context of the density of the interstellar medium in our starburst-ring galaxies.Comment: 14 pages, incl. 12 figures. Accepted for publication in MNRA

Modular Nucleic Acid Assembled p/MHC Microarrays for Multiplexed Sorting of Antigen-Specific T Cells

The human immune system consists of a large number of T cells capable of recognizing and responding to antigens derived from various sources. The development of peptide-major histocompatibility (p/MHC) tetrameric complexes has enabled the direct detection of these antigen-specific T cells. With the goal of increasing throughput and multiplexing of T cell detection, protein microarrays spotted with defined p/MHC complexes have been reported, but studies have been limited due to the inherent instability and reproducibility of arrays produced via conventional spotted methods. Herein, we report on a platform for the detection of antigen-specific T cells on glass substrates that offers significant advantages over existing surface-bound schemes. In this approach, called “Nucleic Acid Cell Sorting (NACS)”, single-stranded DNA oligomers conjugated site-specifically to p/MHC tetramers are employed to immobilize p/MHC tetramers via hybridization to a complementary-printed substrate. Fully assembled p/MHC arrays are used to detect and enumerate T cells captured from cellular suspensions, including primary human T cells collected from cancer patients. NACS arrays outperform conventional spotted arrays assessed in key criteria such as repeatability and homogeneity. The versatility of employing DNA sequences for cell sorting is exploited to enable the programmed, selective release of target populations of immobilized T cells with restriction endonucleases for downstream analysis. Because of the performance, facile and modular assembly of p/MHC tetramer arrays, NACS holds promise as a versatile platform for multiplexed T cell detection

A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells

Cellular immunity has an inherent high level of functional heterogeneity. Capturing the full spectrum of these functions requires analysis of large numbers of effector molecules from single cells. We report a microfluidic platform designed for highly multiplexed (more than ten proteins), reliable, sample-efficient (~1 × 10^4 cells) and quantitative measurements of secreted proteins from single cells. We validated the platform by assessment of multiple inflammatory cytokines from lipopolysaccharide (LPS)-stimulated human macrophages and comparison to standard immunotechnologies. We applied the platform toward the ex vivo quantification of T cell polyfunctional diversity via the simultaneous measurement of a dozen effector molecules secreted from tumor antigen–specific cytotoxic T lymphocytes (CTLs) that were actively responding to tumor and compared against a cohort of healthy donor controls. We observed profound, yet focused, functional heterogeneity in active tumor antigen–specific CTLs, with the major functional phenotypes quantitatively identified. The platform represents a new and informative tool for immune monitoring and clinical assessment

SDSS1133: An Unusually Persistent Transient in a Nearby Dwarf Galaxy

While performing a survey to detect recoiling supermassive black holes, we have identified an unusual source having a projected offset of 800 pc from a nearby dwarf galaxy. The object, SDSS J113323.97+550415.8, exhibits broad emission lines and strong variability. While originally classified as a supernova (SN) because of its nondetection in 2005, we detect it in recent and past observations over 63 yr and find over a magnitude of rebrightening in the last 2 years. Using high-resolution adaptive optics observations, we constrain the source emission region to be <12 pc and find a disturbed host-galaxy morphology indicative of recent merger activity. Observations taken over more than a decade show narrow [O III] lines, constant ultraviolet emission, broad Balmer lines, a constant putative black hole mass over a decade of observations despite changes in the continuum, and optical emission-line diagnostics consistent with an active galactic nucleus (AGN). However, the optical spectra exhibit blueshifted absorption, and eventually narrow Fe II and [Ca II] emission, each of which is rarely found in AGN spectra. While this peculiar source displays many of the observational properties expected of a potential black hole recoil candidate, some of the properties could also be explained by a luminous blue variable star (LBV) erupting for decades since 1950, followed by a Type IIn SN in 2001. Interpreted as an LBV followed by a SN analogous to SN 2009ip, the multi-decade LBV eruptions would be the longest ever observed, and the broad Halpha emission would be the most luminous ever observed at late times (>10 yr), larger than that of unusually luminous supernovae such as SN 1988Z, suggesting one of the most extreme episodes of pre-SN mass loss ever discovered.Comment: Accepted for publication in MNRA

Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.

BackgroundThe trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown.MethodWe investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation.ResultsIncreased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo.ConclusionsWe report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy

Intrinsic Absorption Lines in Seyfert 1 Galaxies. I. Ultraviolet Spectra from the Hubble Space Telescope

We present a study of the intrinsic absorption lines in the ultraviolet spectra of Seyfert 1 galaxies. We find that the fraction of Seyfert 1 galaxies that show absorption associated with their active nuclei is more than one-half (10/17), which is much higher than previous estimates (3 - 10%) . There is a one-to-one correspondence between Seyferts that show intrinsic UV absorption and X-ray ``warm absorbers''. The intrinsic UV absorption is generally characterized by high ionization: C IV and N V are seen in all 10 Seyferts with detected absorption (in addition to Ly-alpha), whereas Si IV is present in only four of these Seyferts, and Mg II absorption is only detected in NGC 4151. The absorption lines are blueshifted (or in a few cases at rest) with respect to the narrow emission lines, indicating that the absorbing gas is undergoing net radial outflow. At high resolution, the absorption often splits into distinct kinematic components that show a wide range in widths (20 - 400 km/s FWHM), indicating macroscopic motions (e.g., radial velocity subcomponents or turbulence) within a component. The strong absorption components have cores that are much deeper than the continuum flux levels, indicating that the regions responsible for these components lie completely outside of the broad emission-line regions. The covering factor of the absorbing gas in the line of sight, relative to the total underlying emission, is C > 0.86, on average. The global covering factor, which is the fraction of emission intercepted by the absorber averaged over all lines of sight, is C > 0.5.Comment: 56 pages, Latex, includes 4 figures (encapsulated postscript), Fig. 1 has 2 parts and Fig. 2 has 3 parts, to appear in the Astrophysical Journa

Genetic and genomic architecture in eight strains of the laboratory opossum Monodelphis domestica

The gray short-tailed opossum (Monodelphis domestica) is an established laboratory-bred marsupial model for biomedical research. It is a critical species for comparative genomics research, providing the pivotal phylogenetic outgroup for studies of derived vs ancestral states of genomic/epigenomic characteristics for eutherian mammal lineages. To characterize the current genetic profile of this laboratory marsupial, we examined 79 individuals from eight established laboratory strains. Double digest restriction site-associated DNA sequencing and whole-genome resequencing experiments were performed to investigate the genetic architecture in these strains. A total of 66,640 highquality single nucleotide polymorphisms (SNPs) were identified. We analyzed SNP density, average heterozygosity, nucleotide diversity, and population differentiation parameter Fst within and between the eight strains. Principal component and population structure analysis clearly resolve the strains at the level of their ancestral founder populations, and the genetic architecture of these strains correctly reflects their breeding history. We confirmed the successful establishment of the first inbred laboratory opossum strain LSD (inbreeding coefficient F \u3e 0.99) and a nearly inbred strain FD2M1 (0.98 \u3c F \u3c 0.99), each derived from a different ancestral background. These strains are suitable for various experimental protocols requiring controlled genetic backgrounds and for intercrosses and backcrosses that can generate offspring with informative SNPs for studying a variety of genetic and epigenetic processes. Together with recent advances in reproductive manipulation and CRISPR/Cas9 techniques for Monodelphis domestica, the existence of distinctive inbred strains will enable genome editing on different genetic backgrounds, greatly expanding the utility of this marsupial model for biomedical research