A Relativistic Type Ibc Supernova Without a Detected Gamma-ray Burst

Long duration gamma-ray bursts (GRBs) mark the explosive death of some massive stars and are a rare sub-class of Type Ibc supernovae (SNe Ibc). They are distinguished by the production of an energetic and collimated relativistic outflow powered by a central engine (an accreting black hole or neutron star). Observationally, this outflow is manifested in the pulse of gamma-rays and a long-lived radio afterglow. To date, central engine-driven SNe have been discovered exclusively through their gamma-ray emission, yet it is expected that a larger population goes undetected due to limited satellite sensitivity or beaming of the collimated emission away from our line-of-sight. In this framework, the recovery of undetected GRBs may be possible through radio searches for SNe Ibc with relativistic outflows. Here we report the discovery of luminous radio emission from the seemingly ordinary Type Ibc SN 2009bb, which requires a substantial relativistic outflow powered by a central engine. The lack of a coincident GRB makes SN 2009bb the first engine-driven SN discovered without a detected gamma-ray signal. A comparison with our extensive radio survey of SNe Ibc reveals that the fraction harboring central engines is low, ~1 percent, measured independently from, but consistent with, the inferred rate of nearby GRBs. Our study demonstrates that upcoming optical and radio surveys will soon rival gamma-ray satellites in pinpointing the nearest engine-driven SNe. A similar result for a different supernova is reported independently.Comment: To appear in Nature on Jan 28 2010. Embargoed for discussion in the press until 13:00 US Eastern Time on Jan 27 (Accepted version, 27 pages, Manuscript and Suppl. Info.

Induction and regulation of matrix metalloproteinase-12in human airway smooth muscle cells

BACKGROUND: The elastolytic enzyme matrix metalloproteinase (MMP)-12 has been implicated in the development of airway inflammation and remodeling. We investigated whether human airway smooth muscle cells could express and secrete MMP-12, thereby participating in the pathogenesis of airway inflammatory diseases. METHODS: Laser capture microdissection was used to collect smooth muscle cells from human bronchial biopsy sections. MMP-12 mRNA expression was analysed by quantitative real-time RT-PCR. MMP-12 protein expression and secretion from cultured primary airway smooth muscle cells was further analysed by Western blot. MMP-12 protein localization in bronchial tissue sections was detected by immunohistochemistry. MMP-12 activity was determined by zymography. The TransAM AP-1 family kit was used to measure c-Jun activation and nuclear binding. Analysis of variance was used to determine statistical significance. RESULTS: We provide evidence that MMP-12 mRNA and protein are expressed by in-situ human airway smooth muscle cells obtained from bronchial biopsies of normal volunteers, and of patients with asthma, COPD and chronic cough. The pro-inflammatory cytokine, interleukin (IL)-1β, induced a >100-fold increase in MMP-12 gene expression and a >10-fold enhancement in MMP-12 activity of primary airway smooth muscle cell cultures. Selective inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase and phosphatidylinositol 3-kinase reduced the activity of IL-1β on MMP-12, indicating a role for these kinases in IL-1β-induced induction and release of MMP-12. IL-1β-induced MMP-12 activity and gene expression was down-regulated by the corticosteroid dexamethasone but up-regulated by the inflammatory cytokine tumour necrosis factor (TNF)-α through enhancing activator protein-1 activation by IL-1β. Transforming growth factor-β had no significant effect on MMP-12 induction. CONCLUSION: Our findings indicate that human airway smooth muscle cells express and secrete MMP-12 that is up-regulated by IL-1β and TNF-α. Bronchial smooth muscle cells may be an important source of elastolytic activity, thereby participating in remodeling in airway diseases such as COPD and chronic asthma

Broad-Spectrum Matrix Metalloproteinase Inhibition Curbs Inflammation and Liver Injury but Aggravates Experimental Liver Fibrosis in Mice

Background Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-α-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury.Methodology/Principal Findings Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-α receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-α receptors exhibited an 80% reduction of serum ALT, confirming the hepatoprotective effects of Marimastat via the TNF-signaling pathway.Conclusions/Significance Inhibition of MMP and TACE activity with Marimastat during chronic CCl4administration counterbalanced any beneficial anti-inflammatory effect, resulting in a positive balance of collagen deposition. Since effective inhibition of MMPs accelerates fibrosis progression, MMP inhibitors should be used with caution in patients with chronic liver diseases

In pursuit of delay-related brain activity for anticipatory eye movements

How the brain stores motion information and subsequently uses it to follow a moving target is largely unknown. This is mainly due to previous fMRI studies using paradigms in which the eye movements cannot be segregated from the storage of this motion information. To avoid this problem we used a novel paradigm designed in our lab in which we interlaced a delay (2, 4 or 6 seconds) between the 1st and 2nd presentation of a moving stimulus. Using this design we could examine brain activity during a delay period using fMRI and have subsequently found a number of brain areas that reveal sustained activity during predictive pursuit. These areas include, the V5 complex and superior parietal lobe. This study provides new evidence for the network involved in the storage of visual information to generate early motor responses in pursuit

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