Peroxidasin protein expression and enzymatic activity in metastatic melanoma cell lines are associated with invasive potential

Peroxidasin, a heme peroxidase, has been shown to play a role in cancer progression. mRNA expression has been reported to be upregulated in metastatic melanoma cell lines and connected to the invasive phenotype, but little is known about how peroxidasin acts in cancer cells. We have analyzed peroxidasin protein expression and activity in eight metastatic melanoma cell lines using an ELISA developed with an in-house peroxidasin binding protein. RNAseq data analysis confirmed high peroxidasin mRNA expression in the five cell lines classified as invasive and low expression in the three non-invasive cell lines. Protein levels of peroxidasin were higher in the cell lines with an invasive phenotype. Active peroxidasin was secreted to the cell culture medium, where it accumulated over time, and peroxidasin protein levels in the medium were also much higher in invasive than non-invasive cell lines. The only well-established physiological role of peroxidasin is in the formation of a sulfilimine bond, which cross-links collagen IV in basement membranes via catalyzed oxidation of bromide to hypobromous acid. We found that peroxidasin secreted from melanoma cells formed sulfilimine bonds in uncross-linked collagen IV, confirming peroxidasin activity and hypobromous acid formation. Moreover, 3-bromotyrosine, a stable product of hypobromous acid reacting with tyrosine residues, was detected in invasive melanoma cells, substantiating that their expression of peroxidasin generates hypobromous acid, and showing that it does not exclusively react with collagen IV, but also with other biomolecules

An Infinite-Dimensional Family of Black-Hole Microstate Geometries

We construct the first explicit, smooth, horizonless black-hole microstate geometry whose moduli space is described by an arbitrary function of one variable and is thus infinite-dimensional. This is achieved by constructing the scalar Green function on a simple D6 anti-D6 background, and using this Green function to obtain the fully back-reacted solution for a supertube with varying charge density in this background. We show that this supertube can store parametrically more entropy than in flat space, confirming the entropy enhancement mechanism that was predicted using brane probes. We also show that all the local properties of the fully back-reacted solution can, in fact, be obtained using the DBI action of an appropriate brane probe. In particular, the supergravity and the DBI analysis yield identical functional bubble equations that govern the relative locations of the centers. This indicates that there is a non-renormalization theorem that protects these functional equations as one moves in moduli space. Our construction creates configurations that are beyond the scope of recent arguments that appear to put strong limits on the entropy that can be found in smooth supergravity solutions.Comment: 46 pages, 1 figure, LaTe

Cluster M Mycobacteriophages Bongo, PegLeg, and Rey with Unusually Large Repertoires of tRNA Isotopes

Genomic analysis of a large set of phages infecting the common hostMycobacterium smegmatis mc2155 shows that they span considerable genetic diversity. There are more than 20 distinct types that lack nucleotide similarity with each other, and there is considerable diversity within most of the groups. Three newly isolated temperate mycobacteriophages, Bongo, PegLeg, and Rey, constitute a new group (cluster M), with the closely related phages Bongo and PegLeg forming subcluster M1 and the more distantly related Rey forming subcluster M2. The cluster M mycobacteriophages have siphoviral morphologies with unusually long tails, are homoimmune, and have larger than average genomes (80.2 to 83.7 kbp). They exhibit a variety of features not previously described in other mycobacteriophages, including noncanonical genome architectures and several unusual sets of conserved repeated sequences suggesting novel regulatory systems for both transcription and translation. In addition to containing transfer-messenger RNA and RtcB-like RNA ligase genes, their genomes encode 21 to 24 tRNA genes encompassing complete or nearly complete sets of isotypes. We predict that these tRNAs are used in late lytic growth, likely compensating for the degradation or inadequacy of host tRNAs. They may represent a complete set of tRNAs necessary for late lytic growth, especially when taken together with the apparent lack of codons in the same late genes that correspond to tRNAs that the genomes of the phages do not obviously encode

The Fastest Flights in Nature: High-Speed Spore Discharge Mechanisms among Fungi

BACKGROUND: A variety of spore discharge processes have evolved among the fungi. Those with the longest ranges are powered by hydrostatic pressure and include "squirt guns" that are most common in the Ascomycota and Zygomycota. In these fungi, fluid-filled stalks that support single spores or spore-filled sporangia, or cells called asci that contain multiple spores, are pressurized by osmosis. Because spores are discharged at such high speeds, most of the information on launch processes from previous studies has been inferred from mathematical models and is subject to a number of errors. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have used ultra-high-speed video cameras running at maximum frame rates of 250,000 fps to analyze the entire launch process in four species of fungi that grow on the dung of herbivores. For the first time we have direct measurements of launch speeds and empirical estimates of acceleration in these fungi. Launch speeds ranged from 2 to 25 m s(-1) and corresponding accelerations of 20,000 to 180,000 g propelled spores over distances of up to 2.5 meters. In addition, quantitative spectroscopic methods were used to identify the organic and inorganic osmolytes responsible for generating the turgor pressures that drive spore discharge. CONCLUSIONS/SIGNIFICANCE: The new video data allowed us to test different models for the effect of viscous drag and identify errors in the previous approaches to modeling spore motion. The spectroscopic data show that high speed spore discharge mechanisms in fungi are powered by the same levels of turgor pressure that are characteristic of fungal hyphae and do not require any special mechanisms of osmolyte accumulation

The Atacama Cosmology Telescope: Detection of mm-wave transient sources

We report on the serendipitous discovery of three transient mm-wave sources using data from the Atacama Cosmology Telescope. The first, detected at RA = 273.8138, dec = -49.4628 at ${\sim}50\sigma$ total, brightened from less than 5 mJy to at least 1100 mJy at 150 GHz with an unknown rise time shorter than thirteen days, during which the increase from 250 mJy to 1100 mJy took only 8 minutes. Maximum flux was observed on 2019-11-8. The source's spectral index in flux between 90 and 150 GHz was positive, $\alpha = 1.5\pm0.2$. The second, detected at RA = 105.1584, dec = -11.2434 at ${\sim}20\sigma$ total, brightened from less than 20 mJy to at least 300 mJy at 150 GHz with an unknown rise time shorter than eight days. Maximum flux was observed on 2019-12-15. Its spectral index was also positive, $\alpha = 1.8\pm0.2$. The third, detected at RA = 301.9952, dec = 16.1652 at ${\sim}40\sigma$ total, brightened from less than 8 mJy to at least 300 mJy at 150 GHz over a day or less but decayed over a few days. Maximum flux was observed on 2018-9-11. Its spectrum was approximately flat, with a spectral index of $\alpha = -0.2\pm0.1$. None of the sources were polarized to the limits of these measurements. The two rising-spectrum sources are coincident in position with M and K stars, while the third is coincident with a G star.Comment: 8 pages, 4 figures, 1 tabl

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

The Atacama Cosmology Telescope: Microwave Intensity and Polarization Maps of the Galactic Center

We present arcminute-resolution intensity and polarization maps of the Galactic center made with the Atacama Cosmology Telescope (ACT). The maps cover a 32 deg$^2$ field at 98, 150, and 224 GHz with $\vert l\vert\le4^\circ$, $\vert b\vert\le2^\circ$. We combine these data with Planck observations at similar frequencies to create coadded maps with increased sensitivity at large angular scales. With the coadded maps, we are able to resolve many known features of the Central Molecular Zone (CMZ) in both total intensity and polarization. We map the orientation of the plane-of-sky component of the Galactic magnetic field inferred from the polarization angle in the CMZ, finding significant changes in morphology in the three frequency bands as the underlying dominant emission mechanism changes from synchrotron to dust emission. Selected Galactic center sources, including Sgr A*, the Brick molecular cloud (G0.253+0.016), the Mouse pulsar wind nebula (G359.23-0.82), and the Tornado supernova remnant candidate (G357.7-0.1), are examined in detail. These data illustrate the potential for leveraging ground-based Cosmic Microwave Background polarization experiments for Galactic science.Comment: 26 pages, 14 figures, accepted for publication in Ap

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure