Cyclin G associated kinase interacts with interleukin 12 receptor beta2 and suppresses interleukin 12 induced IFN-gamma production.

BACKGROUND: Although severe encephalopathy has been proposed as a possible contraindication to the use of noninvasive positive-pressure ventilation (NPPV), increasing clinical reports showed it was effective in patients with impaired consciousness and even coma secondary to acute respiratory failure, especially hypercapnic acute respiratory failure (HARF). To further evaluate the effectiveness and safety of NPPV for severe hypercapnic encephalopathy, a prospective case-control study was conducted at a university respiratory intensive care unit (RICU) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) during the past 3 years. METHODS: Forty-three of 68 consecutive AECOPD patients requiring ventilatory support for HARF were divided into 2 groups, which were carefully matched for age, sex, COPD course, tobacco use and previous hospitalization history, according to the severity of encephalopathy, 22 patients with Glasgow coma scale (GCS) <10 served as group A and 21 with GCS = 10 as group B. RESULTS: Compared with group B, group A had a higher level of baseline arterial partial CO2 pressure ((102 +/- 27) mmHg vs (74 +/- 17) mmHg, P <0.01), lower levels of GCS (7.5 +/- 1.9 vs 12.2 +/- 1.8, P <0.01), arterial pH value (7.18 +/- 0.06 vs 7.28 +/- 0.07, P <0.01) and partial O(2) pressure/fraction of inspired O(2) ratio (168 +/- 39 vs 189 +/- 33, P <0.05). The NPPV success rate and hospital mortality were 73% (16/22) and 14% (3/22) respectively in group A, which were comparable to those in group B (68% (15/21) and 14% (3/21) respectively, all P > 0.05), but group A needed an average of 7 cm H2O higher of maximal pressure support during NPPV, and 4, 4 and 7 days longer of NPPV time, RICU stay and hospital stay respectively than group B (P <0.05 or P <0.01). NPPV therapy failed in 12 patients (6 in each group) because of excessive airway secretions (7 patients), hemodynamic instability (2), worsening of dyspnea and deterioration of gas exchange (2), and gastric content aspiration (1). CONCLUSIONS: Selected patients with severe hypercapnic encephalopathy secondary to HARF can be treated as effectively and safely with NPPV as awake patients with HARF due to AECOPD; a trial of NPPV should be instituted to reduce the need of endotracheal intubation in patients with severe hypercapnic encephalopathy who are otherwise good candidates for NPPV due to AECOPD.

Dust and the Type II-Plateau Supernova 2004et

We present mid-infrared (MIR) observations of the Type II-plateau supernova (SN) 2004et, obtained with the Spitzer Space Telescope between 64 and 1406 days past explosion. Late-time optical spectra are also presented. For the period 300-795 days past explosion, we argue that the spectral energy distribution (SED) of SN 2004et comprises (1) a hot component due to emission from optically thick gas, as well as free-bound radiation; (2) a warm component due to newly formed, radioactively heated dust in the ejecta; and (3) a cold component due to an IR echo from the interstellar-medium dust of the host galaxy, NGC 6946. There may also have been a small contribution to the IR SED due to free-free emission from ionized gas in the ejecta. We reveal the first-ever spectroscopic evidence for silicate dust formed in the ejecta of a supernova. This is supported by our detection of a large, but progressively declining, mass of SiO. However, we conclude that the mass of directly detected ejecta dust grew to no more than a few times 10(-4) M-circle dot. We also provide evidence that the ejecta dust formed in comoving clumps of fixed size. We argue that, after about two years past explosion, the appearance of wide, box-shaped optical line profiles was due to the impact of the ejecta on the progenitor circumstellar medium and that the subsequent formation of a cool, dense shell was responsible for a later rise in the MIR flux. This study demonstrates the rich, multifaceted ways in which a typical core-collapse supernova and its progenitor can produce and/or interact with dust grains. The work presented here adds to the growing number of studies that do not support the contention that SNe are responsible for the large mass of observed dust in high-redshift galaxies.

Type II-P supernovae as standardized candles: improvements using near-infrared data

We present the first near-infrared Hubble diagram for Type II-P supernovae (SNe), to further explore their value as distance indicators. We use a modified version of the standardized candle method, which relies on the tight correlation between the absolute magnitudes of Type II-P SNe and their expansion velocities during the plateau phase. Although our sample contains only 12 II-P SNe and they are necessarily local (z

The death of massive stars - I. Observational constraints on the progenitors of Type II-P supernovae

We present the results of a 10.5-yr, volume-limited (28-Mpc) search for supernova (SN) progenitor stars. In doing so we compile all SNe discovered within this volume (132, of which 27 per cent are Type Ia) and determine the relative rates of each subtype from literature studies. The core-collapse SNe break down into 59 per cent II-P and 29 per cent Ib/c, with the remainder being IIb (5 per cent), IIn (4 per cent) and II-L (3 per cent). There have been 20 II-P SNe with high-quality optical or near-infrared pre-explosion images that allow a meaningful search for the progenitor stars. In five cases they are clearly red supergiants, one case is unconstrained, two fall on compact coeval star clusters and the other twelve have no progenitor detected. We review and update all the available data for the host galaxies and SN environments (distance, metallicity and extinction) and determine masses and upper mass estimates for these 20 progenitor stars using the STARS stellar evolutionary code and a single consistent homogeneous method. A maximum likelihood calculation suggests that the minimum stellar mass for a Type II-P to form is m(min) = 8.5(-1.5)(+1) M-circle dot and the maximum mass for II-P progenitors is m(max) = 16.5 +/- 1.5 M-circle dot, assuming a Salpeter initial mass function holds for the progenitor population (in the range Gamma = -1.35(-0.7)(+0.3)). The minimum mass is consistent with current estimates for the upper limit to white dwarf progenitor masses, but the maximum mass does not appear consistent with massive star populations in Local Group galaxies. Red supergiants in the Local Group have masses up to 25 M-circle dot and the minimum mass to produce a Wolf-Rayet star in single star evolution (between solar and LMC metallicity) is similarly 25-30 M-circle dot. The reason we have not detected any high-mass red supergiant progenitors above 17 M-circle dot is unclear, but we estimate that it is statistically significant at 2.4 sigma confidence. Two simple reasons for this could be that we have systematically underestimated the progenitor masses due to dust extinction or that stars between 17-25 M-circle dot produce other kinds of SNe which are not II-P. We discuss these possibilities and find that neither provides a satisfactory solution. We term this discrepancy the 'red supergiant problem' and speculate that these stars could have core masses high enough to form black holes and SNe which are too faint to have been detected. We compare the Ni-56 masses ejected in the SNe to the progenitor mass estimates and find that low-luminosity SNe with low Ni-56 production are most likely to arise from explosions of low-mass progenitors near the mass threshold that can produce a core-collapse.

Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline

Much recent attention has focused on the GLP-1 receptor as a potential target for antidiabetic drugs. Enzyme resistant GLP-1 mimetics such as exenatide are now employed for the treatment of type 2 diabetes, but must be administered by injection. The present study has examined and compared the in vitro and in vivo metabolic actions of a small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB), with native GLP-1, exenatide and liraglutide. DMB significantly stimulated in vitro insulin secretion from BRIN-BD11 cells but with decreased molar potency compared to native GLP-1 or related mimetics. Administration of DMB in combination with glucose to mice significantly (P

Dust and the type II-Plateau supernova 2004dj

We present mid-infrared (MIR) spectroscopy of a Type II-plateau supernova, SN 2004dj, obtained with the Spitzer Space Telescope, spanning 106--1393d after explosion. MIR photometry plus optical/near-IR observations are also reported. An early-time MIR excess is attributed to emission from non-silicate dust formed within a cool dense shell (CDS). Most of the CDS dust condensed between 50d and 165d, reaching a mass of $0.3x^(-5)Msun. Throughout the observations much of the longer wavelength (>10microns) part of the continuum is explained as an IR echo from interstellar dust. The MIR excess strengthened at later times. We show that this was due to thermal emission from warm, non-silicate dust formed in the ejecta. Using optical/near-IR line-profiles and the MIR continua, we show that the dust was distributed as a disk whose radius appeared to be slowly shrinking. The disk radius may correspond to a grain destruction zone caused by a reverse shock which also heated the dust. The dust-disk lay nearly face-on, had high opacities in the optical/near-IR regions, but remained optically thin in the MIR over much of the period studied. Assuming a uniform dust density, the ejecta dust mass by 996d was 0.5+/-0.1 x 10^(-4)Msun, and exceeded 10^(-4)Msun by 1393d. For a dust density rising toward the center the limit is higher. Nevertheless, this study suggests that the amount of freshly-synthesized dust in the SN 2004dj ejecta is consistent with that found from previous studies, and adds further weight to the claim that such events could not have been major contributors to the cosmic dust budget.

The Yellow Supergiant Progenitor of the Type II Supernova 2011dh in M51

We present the detection of the putative progenitor of the Type IIb SN 2011dh in archival pre-explosion Hubble Space Telescope images. Using post-explosion Adaptive Optics imaging with Gemini NIRI+ALTAIR, the position of the supernova (SN) in the pre-explosion images was determined to within 23 mas. The progenitor candidate is consistent with an F8 supergiant star (logL/L sun = 4.92 ± 0.20 and T eff = 6000 ± 280 K). Through comparison with stellar evolution tracks, this corresponds to a single star at the end of core C-burning with an initial mass of M ZAMS = 13 ± 3 M sun. The possibility of the progenitor source being a cluster is rejected, on the basis of: (1) the source not being spatially extended, (2) the absence of excess Ha emission, and (3) the poor fit to synthetic cluster spectral energy distributions (SEDs). It is unclear if a binary companion is contributing to the observed SED, although given the excellent correspondence of the observed photometry to a single star SED we suggest that the companion does not contribute significantly. Early photometric and spectroscopic observations show fast evolution similar to the transitional Type IIb SN 2008ax and suggest that a large amount of the progenitor's hydrogen envelope was removed before explosion. Late-time observations will reveal if the yellow supergiant or the putative companion star were responsible for this SN explosion.

ON THE PROGENITOR AND EARLY EVOLUTION OF THE TYPE II SUPERNOVA 2009kr

We identify a source coincident with SN 2009kr in Hubble Space Telescope pre-explosion images. The object appears to be a single point source with an intrinsic color V - I = 1.1 +/- 0.25 and M-V = -7.6 +/- 0.6. If this is a single star, it would be a yellow supergiant of log L/L-circle dot similar to 5.1 and a mass of 15(-4)(+5) M-circle dot. The spatial resolution does not allow us yet to definitively determine if the progenitor object is a single star, a binary system, or a compact cluster. We show that the early light curve is similar to a Type IIL SN, but the prominent H alpha P-Cygni profiles and the signature of the end of a recombination phase are reminiscent of a Type IIP. The evolution of the expanding ejecta will play an important role in understanding the progenitor object.

VLT DETECTION OF A RED SUPERGIANT PROGENITOR OF THE TYPE II-P SUPERNOVA 2008bk

We report the identification of a source coincident with the position of the nearby Type II-P supernova (SN) 2008bk in high-quality optical and near-infrared preexplosion images from the ESO Very Large Telescope (VLT). The SN position in the optical and near-infrared preexplosion images is identified to within about +/- 70 and +/- 40 mas, respectively, using postexplosion-band images obtained with the NAOS CONICA adaptive optics system K-s on the VLT. The preexplosion source detected in four different bands is precisely coincident with SN 2008bk and is consistent with being dominated by a single point source. We determine the nature of the point source using the STARS stellar evolutionary models and find that its colors and luminosity are consistent with the source being a red supergiant progenitor of SN 2008bk with an initial mass of 8.5 +/- 1.0 M-circle dot.

SN 2004A: another type II-P supernova with a red supergiant progenitor

We present a monitoring study of SN 2004A and probable discovery of a progenitor star in pre-explosion Hubble Space Telescope (HST) images. The photometric and spectroscopic monitoring of SN 2004A show that it was a normal Type II-P which was discovered in NGC 6207 about two weeks after explosion. We compare SN 2004A to the similar Type II-P SN 1999em and estimate an explosion epoch of 2004 January 6. We also calculate three new distances to NGC 6207 of 21.0 +/- 4.3, 21.4 +/- 3.5 and 25.1 +/- 1.7 Mpc. The former was calculated using the Standard Candle Method (SCM) for SNe II-P, and the latter two from the brightest supergiants method (BSM). We combine these three distances with existing kinematic distances, to derive a mean value of 20.3 +/- 3.4 Mpc. Using this distance, we estimate that the ejected nickel mass in the explosion is 0.046(-0.017)(+0.031) M-circle dot. The progenitor of SN 2004A is identified in pre-explosion WFPC2 F814W images with a magnitude of m(F814W) = 24.3 +/- 0.3, but is below the detection limit of the F606W images. We show that this was likely a red supergiant (RSG) with a mass of 9(-2)(+3) M-circle dot. The object is detected at 4.7 sigma above the background noise. Even if this detection is spurious, the 5 sigma upper limit would give a robust upper mass limit of 12M(circle dot) for a RSG progenitor. These initial masses are very similar to those of two previously identified RSG progenitors of the Type II-P SNe 2004gd (8(-2)(+4) M circle dot) and 2005cs (9(-2)(+3) M-circle dot).

An upper mass limit for the progenitor of the Type II-P supernova SN 1999gi

Masses and progenitor evolutionary states of Type II supernovae remain almost unconstrained by direct observations. Only one robust observation of a progenitor (SN 1987A) and one plausible observation (SN 1993J) are available. Neither matched theoretical predictions, and in this Letter we report limits on a third progenitor (SN 1999gi). The Hubble Space Telescope (HST) has imaged the site of the Type II-P supernova SN 1999gi with the Wide Field Planetary Camera 2 (WFPC2) in two filters (F606W and F300W) prior to explosion. The distance to the host galaxy (NGC 3184) of 7.9 Mpc means that the most luminous, massive stars are resolved as single objects in the archive images. The supernova occurred in a resolved, young OB association 2.3 kpc from the center of NGC 3184 with an association age of about 4 Myr. Follow-up images of SN 1999gi with WFPC2 taken 14 months after discovery determine the precise position of the supernova on the preexplosion frames. An upper limit of the absolute magnitude of the progenitor is estimated (M-v greater than or equal to -5.1). By comparison with stellar evolutionary tracks, this can be interpreted as a stellar mass, and we determine an upper mass limit of 9(-2)(+3) M.. We discuss the possibility of determining the masses or mass limits for numerous nearby core-collapse supernovae using the HST archive enhanced by our current SNAP program.

Burkholderia cenocepacia Type VI Secretion System Mediates Escape of Type II Secreted Proteins into the Cytoplasm of Infected Macrophages

Burkholderia cenocepacia is an opportunistic pathogen that survives intracellularly in macrophages and causes serious respiratory infections in patients with cystic fibrosis. We have previously shown that bacterial survival occurs in bacteria-containing membrane vacuoles (BcCVs) resembling arrested autophagosomes. Intracellular bacteria stimulate IL-1ß secretion in a caspase-1-dependent manner and induce dramatic changes to the actin cytoskeleton and the assembly of the NADPH oxidase complex onto the BcCV membrane. A Type 6 secretion system (T6SS) is required for these phenotypes but surprisingly it is not required for the maturation arrest of the BcCV. Here, we show that macrophages infected with B. cenocepacia employ the NLRP3 inflammasome to induce IL-1ß secretion and pyroptosis. Moreover, IL-1ß secretion by B. cenocepacia-infected macrophages is suppressed in deletion mutants unable to produce functional Type VI, Type IV, and Type 2 secretion systems (SS). We provide evidence that the T6SS mediates the disruption of the BcCV membrane, which allows the escape of proteins secreted by the T2SS into the macrophage cytoplasm. This was demonstrated by the activity of fusion derivatives of the T2SS-secreted metalloproteases ZmpA and ZmpB with adenylcyclase. Supporting this notion, ZmpA and ZmpB are required for efficient IL-1ß secretion in a T6SS dependent manner. ZmpA and ZmpB are also required for the maturation arrest of the BcCVs and bacterial intra-macrophage survival in a T6SS-independent fashion. Our results uncover a novel mechanism for inflammasome activation that involves cooperation between two bacterial secretory pathways, and an unanticipated role for T2SS-secreted proteins in intracellular bacterial survival.

The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense

Toll-like receptors (TLRs) are crucial in the innate immune response to pathogens, in that they recognize and respond to pathogen associated molecular patterns, which leads to activation of intracellular signaling pathways and altered gene expression. Vaccinia virus (VV), the poxvirus used to vaccinate against smallpox, encodes proteins that antagonize important components of host antiviral defense. Here we show that the VV protein A52R blocks the activation of the transcription factor nuclear factor kappa B (NF-kappa B) by multiple TLRs, including TLR3, a recently identified receptor for viral RNA. A52R associates with both interleukin 1 receptor-associated kinase 2 (IRAK2) and tumor necrosis factor receptor-associated factor 6 (TRAF6), two key proteins important in TLR signal transduction. Further, A52R could disrupt signaling complexes containing these proteins. A virus deletion mutant lacking the A52R gene was attenuated compared with wild-type and revertant controls in a murine intranasal model of infection. This study reveals a novel mechanism used by VV to suppress the host immunity. We demonstrate viral disabling of TLRs, providing further evidence for an important role for this family of receptors in the antiviral response.

SN 2009N: linking normal and subluminous Type II-P Sne

We present ultraviolet, optical, near-infrared photometry and spectroscopy of SN 2009N in NGC 4487. This object is a Type II-P supernova with spectra resembling those of subluminous II-P supernovae, while its bolometric luminosity is similar to that of the intermediate-luminosity SN 2008in. We created SYNOW models of the plateau phase spectra for line identification and to measure the expansion velocity. In the near-infrared spectra we find signs indicating possible weak interaction between the supernova ejecta and the pre-existing circumstellar material. These signs are also present in the previously unpublished near-infrared spectra of SN 2008in. The distance to SN 2009N is determined via the expanding photosphere method and the standard candle method as D = 21.6 ± 1.1 Mpc. The produced nickel-mass is estimated to be ∼0.020 ± 0.004 M⊙. We infer the physical properties of the progenitor at the explosion through hydrodynamical modelling of the observables. We find the values of the total energy as ∼0.48 × 1051 erg, the ejected mass as ∼11.5 M⊙, and the initial radius as ∼287 R⊙.

LSQ13fn: A type II-Plateau supernova with a possibly low metallicity progenitor that breaks the standardised candle relation∗

We present optical imaging and spectroscopy of supernova (SN) LSQ13fn, a type II supernova with several hitherto-unseen properties. Although it initially showed strong symmetric spectral emission features attributable to He ii, N iii, and C iii, reminiscent of some interacting SNe, it transitioned into an object that would fall more naturally under a type II-Plateau (IIP) classification. However, its spectral evolution revealed several unusual properties: metal lines appeared later than expected, were weak, and some species were conspicuous by their absence. Furthermore, the line velocities were found to be lower than expected given the plateau brightness, breaking the SN IIP standardised candle method for distance estimates. We found that, in combination with a short phase of early-time ejecta-circumstellar material interaction, metal-poor ejecta, and a large progenitor radius could reasonably account for the observed behaviour. Comparisons with synthetic model spectra of SNe IIP of a given progenitor mass would imply a progenitor star metallicity as low as 0.1 Z_⊙. LSQ13fn highlights the diversity of SNe II and the many competing physical effects that come into play towards the final stages of massive star evolution immediately preceding core-collapse.