Human Neutrophil Elastase Degrades SPLUNC1 and Impairs Airway Epithelial Defense against Bacteria

Background:Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a significant cause of mortality of COPD patients, and pose a huge burden on healthcare. One of the major causes of AECOPD is airway bacterial (e.g. nontypeable Haemophilus influenzae [NTHi]) infection. However, the mechanisms underlying bacterial infections during AECOPD remain poorly understood. As neutrophilic inflammation including increased release of human neutrophil elastase (HNE) is a salient feature of AECOPD, we hypothesized that HNE impairs airway epithelial defense against NTHi by degrading airway epithelial host defense proteins such as short palate, lung, and nasal epithelium clone 1 (SPLUNC1).Methodology/Main Results:Recombinant human SPLUNC1 protein was incubated with HNE to confirm SPLUNC1 degradation by HNE. To determine if HNE-mediated impairment of host defense against NTHi was SPLUNC1-dependent, SPLUNC1 protein was added to HNE-treated primary normal human airway epithelial cells. The in vivo function of SPLUNC1 in NTHi defense was investigated by infecting SPLUNC1 knockout and wild-type mice intranasally with NTHi. We found that: (1) HNE directly increased NTHi load in human airway epithelial cells; (2) HNE degraded human SPLUNC1 protein; (3) Recombinant SPLUNC1 protein reduced NTHi levels in HNE-treated human airway epithelial cells; (4) NTHi levels in lungs of SPLUNC1 knockout mice were increased compared to wild-type mice; and (5) SPLUNC1 was reduced in lungs of COPD patients.Conclusions:Our findings suggest that SPLUNC1 degradation by neutrophil elastase may increase airway susceptibility to bacterial infections. SPLUNC1 therapy likely attenuates bacterial infections during AECOPD. © 2013 Jiang et al

The Connection between Gamma-Ray Bursts and Extremely Metal-Poor Stars: Black Hole-forming Supernovae with Relativistic Jets

Long-duration gamma-ray bursts (GRBs) are thought to be connected to luminous and energetic supernovae (SNe), called hypernovae (HNe), resulting from the black-hole (BH) forming collapse of massive stars. For recent nearby GRBs~060505 and 060614, however, the expected SNe have not been detected. The upper limits to the SN brightness are about 100 times fainter than GRB-associated HNe (GRB-HNe), corresponding to the upper limits to the ejected $^{56}$Ni masses of $M({\rm ^{56}Ni})\sim 10^{-3}M_\odot$. SNe with a small amount of $^{56}$Ni ejection are observed as faint Type II SNe. HNe and faint SNe are thought to be responsible for the formation of extremely metal-poor (EMP) stars. In this Letter, a relativistic jet-induced BH forming explosion of the 40 $M_\odot$ star is investigated and hydrodynamic and nucleosynthetic models are presented. These models can explain both GRB-HNe and GRBs without bright SNe in a unified manner. Their connection to EMP stars is also discussed. We suggest that GRBs without bright SNe are likely to synthesize \Mni\sim 10^{-4} to $10^{-3}M_\odot$ or $\sim 10^{-6}M_\odot$.Comment: 7 pages, 3 figures. Accepted for publication in the Astrophysical Journal Letters (10 March 2007, v657n2 issue

The Connection between Gamma-Ray Bursts and Extremely Metal-Poor Stars as Nucleosynthetic Probes of the Early Universe

The connection between the long GRBs and Type Ic Supernovae (SNe) has revealed the interesting diversity: (i) GRB-SNe, (ii) Non-GRB Hypernovae (HNe), (iii) X-Ray Flash (XRF)-SNe, and (iv) Non-SN GRBs (or dark HNe). We show that nucleosynthetic properties found in the above diversity are connected to the variation of the abundance patterns of extremely-metal-poor (EMP) stars, such as the excess of C, Co, Zn relative to Fe. We explain such a connection in a unified manner as nucleosynthesis of hyper-aspherical (jet-induced) explosions Pop III core-collapse SNe. We show that (1) the explosions with large energy deposition rate, $\dot{E}_{\rm dep}$, are observed as GRB-HNe and their yields can explain the abundances of normal EMP stars, and (2) the explosions with small $\dot{E}_{\rm dep}$ are observed as GRBs without bright SNe and can be responsible for the formation of the C-rich EMP (CEMP) and the hyper metal-poor (HMP) stars. We thus propose that GRB-HNe and the Non-SN GRBs (dark HNe) belong to a continuous series of BH-forming stellar deaths with the relativistic jets of different $\dot{E}_{\rm dep}$.Comment: 8 pages, 6 figures. To appear in "Massive Stars as Cosmic Engines", Proceedings of IAU Symposium 250 (December 2007, Kauai), eds. F. Bresolin, P.A. Crowther, & J. Puls (Cambridge Univ. Press

Nucleosynthesis in High-Entropy Hot-Bubbles of SNe and Abundance Patterns of Extremely Metal-Poor Stars

There have been suggestions that the abundance of Extremely Metal-Poor (EMP) stars can be reproduced by Hypernovae (HNe), not by normal supernovae (SNe). However, recently it was also suggested that if the innermost neutron-rich or proton-rich matter is ejected, the abundance patterns of ejected matter are changed, and normal SNe may also reproduce the observations of EMP stars. In this letter, we calculate explosive nucleosynthesis with various Ye and entropy, and investigate whether normal SNe with this innermost matter, which we call "hot-bubble" component, can reproduce the abundance of EMP stars. We find that neutron-rich (Ye = 0.45-0.49) and proton-rich (Ye = 0.51-0.55) matter can increase Zn/Fe and Co/Fe ratios as observed, but tend to overproduce other Fe-peak elements. In addition to it, we find that if slightly proton-rich matter with 0.50 <= Ye < 0.501 with s/kb ~ 15-40 is ejected as much as ~ 0.06 Msolar, even normal SNe can reproduce the abundance of EMP stars, though it requires fine-tuning of Ye. On the other hand, HNe can more easily reproduce the observations of EMP stars without fine-tuning. Our results imply that HNe are the most possible origin of the abundance pattern of EMP stars.Comment: 10 pages, 3 figures, Accepted to ApJL; modified reference

ActiveHNE: Active Heterogeneous Network Embedding

Heterogeneous network embedding (HNE) is a challenging task due to the diverse node types and/or diverse relationships between nodes. Existing HNE methods are typically unsupervised. To maximize the profit of utilizing the rare and valuable supervised information in HNEs, we develop a novel Active Heterogeneous Network Embedding (ActiveHNE) framework, which includes two components: Discriminative Heterogeneous Network Embedding (DHNE) and Active Query in Heterogeneous Networks (AQHN). In DHNE, we introduce a novel semi-supervised heterogeneous network embedding method based on graph convolutional neural network. In AQHN, we first introduce three active selection strategies based on uncertainty and representativeness, and then derive a batch selection method that assembles these strategies using a multi-armed bandit mechanism. ActiveHNE aims at improving the performance of HNE by feeding the most valuable supervision obtained by AQHN into DHNE. Experiments on public datasets demonstrate the effectiveness of ActiveHNE and its advantage on reducing the query cost.Comment: Accepted to IJCAI201

Discrete Effects in Stellar Feedback: Individual Supernovae, Hypernovae, and IMF Sampling in Dwarf Galaxies

Using high-resolution simulations from the FIRE-2 (Feedback In Realistic Environments) project, we study the effects of discreteness in stellar feedback processes on the evolution of galaxies and the properties of the interstellar medium (ISM). We specifically consider the discretization of supernovae (SNe), including hypernovae (HNe), and sampling the initial mass function (IMF). We study these processes in cosmological simulations of dwarf galaxies with $z=0$ stellar masses $M_{\ast}\sim 10^{4}-3\times10^{6}\,M_\odot$ (halo masses $\sim 10^{9}-10^{10}\,M_\odot$). We show that the discrete nature of individual SNe (as opposed to a model in which their energy/momentum deposition is continuous over time, similar to stellar winds) is crucial in generating a reasonable ISM structure and galactic winds and in regulating dwarf stellar masses. However, once SNe are discretized, accounting for the effects of IMF sampling on continuous mechanisms such as radiative feedback and stellar mass-loss (as opposed to adopting IMF-averaged rates) has weak effects on galaxy-scale properties. We also consider the effects of rare HNe events with energies $\sim 10^{53}\,{\rm erg}$. The effects of HNe are similar to the effects of clustered explosions of SNe -- which are already captured in our default simulation setup -- and do not quench star formation (provided that the HNe do not dominate the total SNe energy budget), which suggests that HNe yield products should be observable in ultra-faint dwarfs today.Comment: 9 pages, 4 figure

Apc mutation induces resistance of colonic cells to lipoperoxide-triggered apoptosis induced by faecal water from haem-fed rats

Recent epidemiological studies suggest that high meat intake is associated with promotion of colon cancer linked to haem-iron intake. We previously reported that dietary haem, in the form of either haemoglobin or meat, promotes precancerous lesions in the colon of rats given a low-calcium diet. The mechanism of promotion by haem is not known, but is associated with increased lipid peroxidation in faecal water and strong cytotoxic activity of faecal water on a cancerous mouse colonic epithelial cell line. To better understand the involvement of faecal water components of haem-fed rats in colon cancer promotion, we explored the effect of faecal water on normal (Apc +/+) or premalignant cells (Apc Min/+). Further, we tested if this effect was correlated to lipoperoxidation and 4-hydroxynonenal (HNE). We show here for the first time that heterozygote Apc mutation represents a strong selective advantage, via resistance to apoptosis induction (caspase 3 pathway), for colonic cells exposed to a haem-iron induced lipoperoxidation. The fact that HNE treatment of the cells provoked the same effects as the faecal water of rats fed the haem-rich diet suggests that this compound triggers apoptosis in those cells. We propose that this mechanism could be involved in the promotion of colon carcinogenesis by haem in vivo

Nucleosynthesis in Core-Collapse Supernovae and GRB--Metal-Poor Star Connection

We review the nucleosynthesis yields of core-collapse supernovae (SNe) for various stellar masses, explosion energies, and metallicities. Comparison with the abundance patterns of metal-poor stars provides excellent opportunities to test the explosion models and their nucleosynthesis. We show that the abundance patterns of extremely metal-poor (EMP) stars, e.g., the excess of C, Co, Zn relative to Fe, are in better agreement with the yields of hyper-energetic explosions (Hypernovae, HNe) rather than normal supernovae. We note that the variation of the abundance patterns of EMP stars are related to the diversity of the Supernova-GRB connection. We summarize the diverse properties of (1) GRB-SNe, (2) Non-GRB HNe/SNe, (3) XRF-SN, and (4) Non-SN GRB. In particular, the Non-SN GRBs (dark hypernovae) have been predicted in order to explain the origin of C-rich EMP stars. We show that these variations and the connection can be modeled in a unified manner with the explosions induced by relativistic jets. Finally, we examine whether the most luminous supernova 2006gy can be consistently explained with the pair-instability supernova model.Comment: 15 pages, 9 figures. To appear in "Supernova 1987A: 20 Years After: Supernovae and Gamma-Ray Bursters", eds. S. Immler, K. Weiler, & R. McCray (American Institute of Physics) (2007

Nucleosomes and neutrophil extracellular traps in septic and burn patients

NETosis is a host defense mechanism associated with inflammation and tissue damage. Experimental models show that platelets and von Willebrand factor (VWF) are key elements for intravascular NETosis. We determined NETosis in septic and burn patients at 1 and 4days post-admission (dpa). Nucleosomes were elevated in patients. In septics, they correlated with Human Neutrophil Elastase (HNE)-DNA complexes and SOFA score at 1dpa, and were associated with mortality. Patient´s neutrophils had spontaneous NETosis and were unresponsive to stimulation. Although platelet P-selectin and TNF-α were increased in both groups, higher platelet TLR4 expression, VWF levels and IL-6 were found in septics at 1dpa. Neither platelet activation markers nor cytokines correlated with nucleosomes or HNE-DNA. Nucleosomes could be indicators of organ damage and predictors of mortality in septic but not in burn patients. Platelet activation, VWF and cytokines do not appear to be key mediators of NETosis in these patient groups.Fil: Kaufman, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Magosevich, Débora. Clínica Sagrado Corazón; ArgentinaFil: Moreno, María Carolina. Clínica Bazterrica; ArgentinaFil: Guzman, María Alejandra. Gobiernos de la Ciudad de Buenos Aires. Hospital de Quemados Dr. Arturo Umberto Illia; ArgentinaFil: D'Atri, Lina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Carestia, Agostina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fandiño, María Eugenia. Clínica Sagrado Corazón; ArgentinaFil: Fondevila, Carlos. Clínica Bazterrica; ArgentinaFil: Schattner, Mirta Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Nova metoda za dokazivanje HNE-histidinskih konjugata u {takorskim upalnim stanicama

Oxidative stress, excessive production of reactive oxygen species, is considered an important part of different disorders, as well as of physiological processes (inflammation). The difference between physiological and pathological oxidative stress is often the occurrence of lipid peroxidation and its final toxic products, among which is 4-hydroxy-2-nonenal (HNE), a reactive aldehyde that forms protein conjugates. The aim of this study was to determine the distribution of HNE-histidine conjugates in leukocytes during systemic inflammation. We used genuine monoclonal antibodies against HNE-histidine conjugates for immuno-cytochemical, immuno- histochemical and immuno-electronmicroscopical analyses of HNE in inflammatory cells. Spleen tissue, leukocytes from blood and macrophages from the peritoneum of rats intraperitoneally (i.p.) injected with micronized zeolite (MZ) were analyzed. HNE-histidine conjugates were predominantly detected near cell membranes, phagosomes and macrophage granules. Immunodetection of HNE-histidine conjugates may be used as an analytical immunochemical method to study HNE formation in pathological and physiological processes and for pathomorphological diagnostic procedures.Oksidacijski stres, stanje prekomjernoga stvaranja reaktivnih kisikovih tvari, bitna je sastavnica različitih bolesti, ali i fizioloških procesa (upala). Često je razlika između fiziološkoga i patološkoga oksidacijskoga stresa pojava lipidne peroksidacije i njenih završnih toksičnih produkata, među kojima posebnu ulogu ima 4-hidroksi- 2-nonenal (HNE), reaktivni aldehid koji tvori konjugate s bjelančevinama. Cilj ovoga istraživanja bio je utvrditi distribuciju HNE-histidinskih konjugata u leukocitima tijekom nespecifične upalne reakcije. Rabili smo izvorna monoklonalna protutijela na HNE-histidinski konjugat, za imuno-citokemijsko, histokemijsko i elektronskomikroskopsko dokazivanje HNE-a u upalnim stanicama. Analizirano je tkivo slezene, leukociti iz krvi te makrofazi štakora kojima je intraperitonealno injiciran mikronizirani zeolit (MZ). HNE-histidinski konjugati pretežito su uočeni uz stanične membrane te pored fagosoma i makrofagnih granula. Imunodetekcija HNE-histidinskih konjugata mogla bi se stoga rabiti kao analitička imunokemijska metoda za istraživanja fizioloških i patoloških procesa te u patomorfološkim dijagnostičkim postupcima