Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology.

Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and decorin, play pivotal roles in the regulation of these vital cellular pathways and, as such, are intrinsically involved in cancer initiation and progression. In this minireview, we will address novel functions of biglycan and decorin in inflammation and autophagy, and analyze new emerging signaling events triggered by these proteoglycans, which directly or indirectly modulate these processes. We will critically discuss the dual role of proteoglycan-driven inflammation and autophagy in tumor biology, and delineate the potential mechanisms through which soluble extracellular matrix constituents affect the microenvironment associated with inflammatory and neoplastic diseases

Discovery of Reflection Nebulosity Around Five Vega-like Stars

Coronagraphic optical observations of six Vega-like stars reveal reflection nebulosities, five of which were previously unknown. The nebulosities illuminated by HD 4881, HD 23362, HD 23680, HD 26676, and HD 49662 resemble that of the Pleiades, indicating an interstellar origin for dust grains. The reflection nebulosity around HD 123160 has a double-arm morphology, but no disk-like feature is seen as close as 2.5 arcsec from the star in K-band adaptive optics data. We demonstrate that uniform density dust clouds surrounding HD 23362, HD 23680 and HD 123160 can account for the observed 12-100 micron spectral energy distributions. For HD 4881, HD 26676, and HD 49662 an additional emission source, such as from a circumstellar disk or non-equilibrium grain heating, is required to fit the 12-25 micron data. These results indicate that in some cases, particularly for Vega-like stars located beyond the Local Bubble (>100 pc), the dust responsible for excess thermal emission may originate from the interstellar medium rather than from a planetary debris system.Comment: The Astrophysical Journal, in press for March, 2002 (32 pages, 13 figures

Mid-infrared Imaging of a Circumstellar Disk Around HR 4796: Mapping the Debris of Planetary Formation

We report the discovery of a circumstellar disk around the young A0 star, HR 4796, in thermal infrared imaging carried out at the W.M. Keck Observatory. By fitting a model of the emission from a flat dusty disk to an image at lambda=20.8 microns, we derive a disk inclination, i = 72 +6/-9 deg from face on, with the long axis of emission at PA 28 +/-6 deg. The intensity of emission does not decrease with radius as expected for circumstellar disks but increases outward from the star, peaking near both ends of the elongated structure. We simulate this appearance by varying the inner radius in our model and find an inner hole in the disk with radius R_in = 55+/-15 AU. This value corresponds to the radial distance of our own Kuiper belt and may suggest a source of dust in the collision of cometesimals. By contrast with the appearance at 20.8 microns, excess emission at lambda = 12.5 microns is faint and concentrated at the stellar position. Similar emission is also detected at 20.8 microns in residual subtraction of the best-fit model from the image. The intensity and ratio of flux densities at the two wavelengths could be accounted for by a tenuous dust component that is confined within a few AU of the star with mean temperature of a few hundred degrees K, similar to that of zodiacal dust in our own solar system. The morphology of dust emission from HR 4796 (age 10 Myr) suggests that its disk is in a transitional planet-forming stage, between that of massive gaseous proto-stellar disks and more tenuous debris disks such as the one detected around Vega.Comment: 9 pages, 4 figures as LaTex manuscript and postscript files in gzipped tar file. Accepted for publication in Astrophysical Journal Letters. http://upenn5.hep.upenn.edu/~davidk/hr4796.htm

New sub-millimeter limits on dust in the 55 Cancri planetary system

We present new, high-sensitivity sub-millimeter observations towards 55 Cancri, a nearby G8 star with one, or possibly two, known planetary companion(s). Our 850 $\mu$m map, obtained with the SCUBA instrument on the James Clerk Maxwell Telescope, shows three peaks of emission at the 2.5 mJy level in the vicinity of the star's position. However, the observed peaks are 25\arcsec--40\arcsec away from the star and a deep $R$-band optical image reveals faint point sources that coincide with two of the sub-millimeter peaks. Thus, we do not find evidence for dust emission spatially associated with 55 Cancri. The excess 60 $\mu$m emission detected with ISO may originate from one or more of the 850 $\mu$m peaks that we attribute to background sources. Our new results, together with the HST/NICMOS coronographic images in the near-infrared, place stringent limits on the amount of dust in this planetary system, and argue against the existence of a detectable circumstellar dust disk around 55 Cnc.Comment: 11 pages, 2 PostScript figures, to appear in The Astrophysical Journal Letter

Giant Impacts and Debris Disk Morphology

Certain debris disks have non-axisymmetric shapes in scattered light which are unexplained. The appearance of a disk depends on how its constituent Keplerian ellipses are arranged. The more the ellipses align apsidally, the more non-axisymmetric the disk. Apsidal alignment is automatic for fragments released from a catastrophic collision between solid bodies. We synthesize scattered light images, and thermal emission images, of such giant impact debris. Depending on the viewing geometry, and if and how the initial apsidal alignment is perturbed, the remains of a giant impact can appear in scattered light as a one-sided or two-sided "fork", a lopsided "needle", or a set of "double wings". Double wings are difficult to reproduce in other scenarios involving gravitational forcing or gas drag, which do not align orbits as well. We compare our images with observations and offer a scorecard assessing whether the scattered light asymmetries in HD 15115, HD 32297, HD 61005, HD 111520, HD 106906, beta Pic, and AU Mic are best explained by giant impacts, gravitational perturbations, or sculpting by the interstellar medium.Comment: Final ApJ-proofed version with updated references to summary Table 1. Animations available at https://github.com/joshwajones/jones_etal_animations

Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection

Significance The emergence of multidrug-resistant bacteria, including uropathogenic Escherichia coli (UPEC), makes the development of targeted antivirulence therapeutics a critical focus of research. During urinary tract infections (UTIs), UPEC uses chaperone–usher pathway pili tipped with an array of adhesins that recognize distinct receptors with sterochemical specificity to facilitate persistence in various tissues and habitats. We used an interdisciplinary approach driven by structural biology and synthetic glycoside chemistry to design and optimize glycomimetic inhibitors of the UPEC adhesin FmlH. These inhibitors competitively blocked FmlH in vitro, in in vivo mouse UTI models, and in ex vivo healthy human kidney tissue. This work demonstrates the utility of structure-driven drug design in the effort to develop antivirulence therapeutic compounds. </jats:p

Adaptation of arginine synthesis among uropathogenic branches of the Escherichia coli phylogeny reveals adjustment to the urinary tract habitat

Urinary tract infections (UTIs) are predominantly caused by uropathogeni

mAb Das-1 recognizes 3\u27-Sulfated Lewis A/C, which is aberrantly expressed during metaplastic and oncogenic transformation of several gastrointestinal epithelia

INTRODUCTION: Multiple previous studies have shown the monoclonal antibody Das-1 (formerly called 7E12H12) is specifically reactive towards metaplastic and carcinomatous lesions in multiple organs of the gastrointestinal system (e.g. Barrett\u27s esophagus, intestinal-type metaplasia of the stomach, gastric adenocarcinoma, high-grade pancreatic intraepithelial neoplasm, and pancreatic ductal adenocarcinoma) as well as in other organs (bladder and lung carcinomas). Beyond being a useful biomarker in tissue, mAb Das-1 has recently proven to be more accurate than current paradigms for identifying cysts harboring advanced neoplasia. Though this antibody has been used extensively for clinical, basic science, and translational applications for decades, its epitope has remained elusive. METHODS: In this study, we chemically deglycosylated a standard source of antigen, which resulted in near complete loss of the signal as measured by western blot analysis. The epitope recognized by mAb Das-1 was determined by affinity to a comprehensive glycan array and validated by inhibition of a direct ELISA. RESULTS: The epitope recognized by mAb Das-1 is 3\u27-Sulfo-Lewis A/C (3\u27-Sulfo-LeA/C). 3\u27-Sulfo-LeA/C is broadly reexpressed across numerous GI epithelia and elsewhere during metaplastic and carcinomatous transformation. DISCUSSION: 3\u27-Sulfo-LeA/C is a clinically important antigen that can be detected both intracellularly in tissue using immunohistochemistry and extracellularly in cyst fluid and serum by ELISA. The results open new avenues for tumorigenic risk stratification of various gastrointestinal lesions

Evolutionary fine-tuning of conformational ensembles in FimH during host-pathogen interactions

Positive selection in the two-domain type 1 pilus adhesin FimH enhances Escherichia coli fitness in urinary tract infection (UTI). We report a comprehensive atomic-level view of FimH in two-state conformational ensembles in solution, composed of one low-affinity tense (T) and multiple high-affinity relaxed (R) conformations. Positively selected residues allosterically modulate the equilibrium between these two conformational states, each of which engages mannose through distinct binding orientations. A FimH variant that only adopts the R state is severely attenuated early in a mouse model of uncomplicated UTI but is proficient at colonizing catheterized bladders in vivo or bladder transitional-like epithelial cells in vitro. Thus, the bladder habitat has barrier(s) to R state–mediated colonization possibly conferred by the terminally differentiated bladder epithelium and/or decoy receptors in urine. Together, our studies reveal the conformational landscape in solution, binding mechanisms, and adhesive strength of an allosteric two-domain adhesin that evolved “moderate” affinity to optimize persistence in the bladder during UTI

Collisional Cascades in Planetesimal Disks I. Stellar Flybys

We use a new multiannulus planetesimal accretion code to investigate the evolution of a planetesimal disk following a moderately close encounter with a passing star. The calculations include fragmentation, gas and Poynting-Robertson drag, and velocity evolution from dynamical friction and viscous stirring. We assume that the stellar encounter increases planetesimal velocities to the shattering velocity, initiating a collisional cascade in the disk. During the early stages of our calculations, erosive collisions damp particle velocities and produce substantial amounts of dust. For a wide range of initial conditions and input parameters, the time evolution of the dust luminosity follows a simple relation, L_d/L_{\star} = L_0 / [alpha + (t/t_d)^{beta}]. The maximum dust luminosity L_0 and the damping time t_d depend on the disk mass, with L_0 proportional to M_d and t_d proportional to M_d^{-1}. For disks with dust masses of 1% to 100% of the `minimum mass solar nebula' (1--100 earth masses at 30--150 AU), our calculations yield t_d approx 1--10 Myr, alpha approx 1--2, beta = 1, and dust luminosities similar to the range observed in known `debris disk' systems, L_0 approx 10^{-3} to 10^{-5}. Less massive disks produce smaller dust luminosities and damp on longer timescales. Because encounters with field stars are rare, these results imply that moderately close stellar flybys cannot explain collisional cascades in debris disk systems with stellar ages of 100 Myr or longer.Comment: 33 pages of text, 12 figures, and an animation. The paper will appear in the March 2002 issue of the Astronmomical Journal. The animation and a copy of the paper with full resolution figures are at S. Kenyon's planet formation website: http://cfa-www.harvard.edu/~kenyon/p