Adenosine metabolized from extracellular ATP ameliorates organ injury by triggering A2BR signaling

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A2BR. The aim of this study was to evaluate the role of CD39 and CD73 delivering adenosine to A2BRs in regulating the host's response to T/HS. METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A2BR) and conditional knockout (intestinal epithelial cell-specific deficient VillinCre-A2BRfl/fl) mice. At 3 three hours after resuscitation, blood and tissue samples were collected to analyze organ injury. RESULTS: T/HS upregulated the expression of CD39, CD73, and the A2BR in organs. ATP and adenosine levels increased after T/HS in bronchoalveolar lavage fluid. CD39, CD73, and A2BR mimics/agonists alleviated lung and liver injury. Antagonists or the CD39, CD73, and A2BR knockout (KO) exacerbated lung injury, inflammatory cytokines, and chemokines as well as macrophage and neutrophil infiltration and accumulation in the lung. Agonists reduced the levels of the liver enzymes aspartate transferase and alanine transaminase in the blood, whereas antagonist administration or CD39, CD73, and A2BR KO enhanced enzyme levels. In addition, intestinal epithelial cell-specific deficient VillinCre-A2BRfl/fl mice showed increased intestinal injury compared to their wild-type VillinCre controls. CONCLUSION: In conclusion, the CD39-CD73-A2BR axis protects against T/HS-induced multiple organ failure

Adenosine Metabolized From Extracellular ATP Ameliorates Organ Injury by Triggering A2BR Signaling

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5\u27 triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A RESULTS: T/HS upregulated the expression of CD39, CD73, and the A CONCLUSION: In conclusion, the CD39-CD73-

Attacks on quantum key distribution protocols that employ non-ITS authentication

We demonstrate how adversaries with unbounded computing resources can break Quantum Key Distribution (QKD) protocols which employ a particular message authentication code suggested previously. This authentication code, featuring low key consumption, is not Information-Theoretically Secure (ITS) since for each message the eavesdropper has intercepted she is able to send a different message from a set of messages that she can calculate by finding collisions of a cryptographic hash function. However, when this authentication code was introduced it was shown to prevent straightforward Man-In-The-Middle (MITM) attacks against QKD protocols. In this paper, we prove that the set of messages that collide with any given message under this authentication code contains with high probability a message that has small Hamming distance to any other given message. Based on this fact we present extended MITM attacks against different versions of BB84 QKD protocols using the addressed authentication code; for three protocols we describe every single action taken by the adversary. For all protocols the adversary can obtain complete knowledge of the key, and for most protocols her success probability in doing so approaches unity. Since the attacks work against all authentication methods which allow to calculate colliding messages, the underlying building blocks of the presented attacks expose the potential pitfalls arising as a consequence of non-ITS authentication in QKD-postprocessing. We propose countermeasures, increasing the eavesdroppers demand for computational power, and also prove necessary and sufficient conditions for upgrading the discussed authentication code to the ITS level.Comment: 34 page

CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion.

Targeting cannabinoid-2 (CB(2)) receptors with selective agonists may represent a novel therapeutic avenue in various inflammatory diseases, but the mechanisms by which CB(2) activation exerts its anti-inflammatory effects and the cellular targets are elusive. Here, we investigated the effects of CB(2)-receptor activation on TNF-alpha-induced signal transduction in human coronary artery endothelial cells in vitro and on endotoxin-induced vascular inflammatory response in vivo. TNF-alpha induced NF-kappaB and RhoA activation and upregulation of adhesion molecules ICAM-1 and VCAM-1, increased expression of monocyte chemoattractant protein, enhanced transendothelial migration of monocytes, and augmented monocyte-endothelial adhesion. Remarkably, all of the above-mentioned effects of TNF-alpha were attenuated by CB(2) agonists. CB(2) agonists also decreased the TNF-alpha- and/or endotoxin-induced ICAM-1 and VCAM-1 expression in isolated aortas and the adhesion of monocytes to aortic vascular endothelium. CB(1) and CB(2) receptors were detectable in human coronary artery endothelial cells by Western blotting, RT-PCR, real-time PCR, and immunofluorescence staining. Because the above-mentioned TNF-alpha-induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis, our findings suggest that targeting CB(2) receptors on endothelial cells may offer a novel approach in the treatment of these pathologies

Interacting spinor and scalar fields in Bianchi type-I Universe filled with viscous fluid: exact and numerical solutions

We consider a self-consistent system of spinor and scalar fields within the framework of a Bianchi type I gravitational field filled with viscous fluid in presence of a $\Lambda$ term. Exact self-consistent solutions to the corresponding spinor, scalar and BI gravitational field equations are obtained in terms of $\tau$, where $\tau$ is the volume scale of BI universe. System of equations for $\tau$ and \ve, where \ve is the energy of the viscous fluid, is deduced. Some special cases allowing exact solutions are thoroughly studied.Comment: 18 pages, 6 figure

Nonlinear spinor field in Bianchi type-I Universe filled with viscous fluid: numerical solutions

We consider a system of nonlinear spinor and a Bianchi type I gravitational fields in presence of viscous fluid. The nonlinear term in the spinor field Lagrangian is chosen to be $\lambda F$, with $\lambda$ being a self-coupling constant and $F$ being a function of the invariants $I$ an $J$ constructed from bilinear spinor forms $S$ and $P$. Self-consistent solutions to the spinor and BI gravitational field equations are obtained in terms of $\tau$, where $\tau$ is the volume scale of BI universe. System of equations for $\tau$ and \ve, where \ve is the energy of the viscous fluid, is deduced. This system is solved numerically for some special cases.Comment: 15 pages, 4 figure

Compensated right ventricular function of the onset of pulmonary hypertension in a rat model depends on chamber remodeling and contractile augmentation.

Right-ventricular function is a good indicator of pulmonary arterial hypertension (PAH) prognosis; however, how the right ventricle (RV) adapts to the pressure overload is not well understood. Here, we aimed at characterizing the time course of RV early remodeling and discriminate the contribution of ventricular geometric remodeling and intrinsic changes in myocardial mechanical properties in a monocrotaline (MCT) animal model. In a longitudinal study of PAH, ventricular morphology and function were assessed weekly during the first four weeks after MCT exposure. Using invasive measurements of RV pressure and volume, heart performance was evaluated at end of systole and diastole to quantify contractility (end-systolic elastance) and chamber stiffness (end-diastolic elastance). To distinguish between morphological and intrinsic mechanisms, a computational model of the RV was developed and used to determine the level of prediction when accounting for wall masses and unloaded volume measurements changes. By four weeks, mean pulmonary arterial pressure and elastance rose significantly. RV pressures rose significantly after the second week accompanied by significant RV hypertrophy, but RV stroke volume and cardiac output were maintained. The model analysis suggested that, after two weeks, this compensation was only possible due to a significant increase in the intrinsic inotropy of RV myocardium. We conclude that this MCT-PAH rat is a model of RV compensation during the first month after treatment, where geometric remodeling on EDPVR and increased myocardial contractility on ESPVR are the major mechanisms by which stroke volume is preserved in the setting of elevated pulmonary arterial pressure. The mediators of this compensation might themselves promote longer-term adverse remodeling and decompensation in this animal model

Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential