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AimsThe pathology of heart failure is characterized by poorly contracting and dilated ventricles. At the cellular level, this is associated with lengthening of individual cardiomyocytes and loss of sarcomeres. While it is known that the transcription factor myocyte enhancer factor-2 (MEF2) is involved in this cardiomyocyte remodelling, the underlying mechanism remains to be elucidated. Here, we aim to mechanistically link MEF2 target genes with loss of sarcomeres during cardiomyocyte remodelling.Methods and resultsNeonatal rat cardiomyocytes overexpressing MEF2 elongated and lost their sarcomeric structure. We identified myotonic dystrophy protein kinase (DMPK) as direct MEF2 target gene involved in this process. Adenoviral overexpression of DMPK E, the isoform upregulated in heart failure, resulted in severe loss of sarcomeres in vitro, and transgenic mice overexpressing DMPK E displayed disruption of sarcomere structure and cardiomyopathy in vivo. Moreover, we found a decreased expression of sarcomeric genes following DMPK E gain-of-function. These genes are targets of the transcription factor serum response factor (SRF) and we found that DMPK E acts as inhibitor of SRF transcriptional activity.ConclusionOur data indicate that MEF2-induced loss of sarcomeres is mediated by DMPK via a decrease in sarcomeric gene expression by interfering with SRF transcriptional activity. Together, these results demonstrate an unexpected role for DMPK as a direct mediator of adverse cardiomyocyte remodelling and heart failure.

New experimental data for CO2 solubility in the aqueous solutions of N-methyldiethanolamine (MDEA) and 1-butylpyridinium tetrafluoroborate ([Bpy][BF4]) ionic liquid (IL) are reported. The experiments were conducted in a static high pressure equilibrium cell. Solubility measurement of CO2 was performed in various solution compositions of IL and MDEA in a wide temperature range of 298.15–343.15 K and pressures up to 4 MPa. The experimental results revealed that, by increasing the weight percent of IL, the absorption capacity of aqueous mixtures diminishes. It was also observed that the main capacity of CO2 loading in the absorbent solutions belonged to MDEA through chemical absorption, whereas its concentration was more effective than IL in gas solubility. The experimental results are correlated using a semiempirical model with good accuracy.

Solubility of CO2 in the hybrid solvents composed of aqueous N-methyldiethanolamine (MDEA) blended with 1-methyl-3-octyl-imidazolium tetrafluoroborate ([Omim][BF4]) ionic liquid (IL) was measured at temperatures from (298.15–343.15 K) and pressures of (0.2–4 MPa). The experimental trials were performed in a static high pressure equilibrium cell to determine the CO2 absorption capacity of novel absorbent solutions based on the isochoric saturation technique. The experimental data showed that, by rising the concentration of IL in the absorbent solutions’, the mole fraction of dissolved CO2 gas enhances gradually. Absorption capacity of these aqueous solutions was assessed and compared with pure ILs and alkanolamine solvents, which indicates the solutions studied in this research as better hybrid solvents in terms of CO2 loading. Furthermore, a semi empirical model is used to correlate the solubility data of this work, which presents a good agreement with an absolute average deviation (AAD %) of below 1%.

The RNA-binding protein Rbm24 has recently been identified as a pivotal splicing factor in the developing heart. Loss of Rbm24 in mice disrupts cardiac development by governing a large number of muscle-specific splicing events. Since Rbm24 knockout mice are embryonically lethal, the role of Rbm24 in the adult heart remained unexplored. Here, we used adeno-associated viruses (AAV9) to investigate the effect of increased Rbm24 levels in adult mouse heart. Using high-resolution microarrays, we found 893 differentially expressed genes and 1102 differential splicing events in 714 genes in hearts overexpressing Rbm24. We found splicing differences in cardiac genes, such as PDZ and Lim domain 5, Phospholamban, and Titin, but did not find splicing differences in previously identified embryonic splicing targets of Rbm24, such as skNAC, αNAC, and Coro6. Gene ontology enrichment analysis demonstrated increased expression of extracellular matrix (ECM)-related and immune response genes. Moreover, we found increased expression of Tgfβ-signaling genes, suggesting enhanced Tgfβ-signaling in these hearts. Ultimately, this increased activation of cardiac fibroblasts, as evidenced by robust expression of Periostin in the heart, and induced extensive cardiac fibrosis. These results indicate that Rbm24 may function as a regulator of cardiac fibrosis, potentially through the regulation of TgfβR1 and TgfβR2 expression.

Aims Cardiac remodelling and heart failure are promoted by persistent sympathetic activity. We recently reported that nuclear receptor Nur77 may protect against sympathetic agonist-induced cardiac remodelling in mice. The sympathetic co-transmitter neuropeptide Y (NPY) is co-released with catecholamines and is a known cardiac modulator and predictor of heart failure mortality. Recently, transcriptome analyses revealed NPY as a putative target of Nur77. In this study, we assess whether Nur77 modulates adverse cardiac remodelling via NPY signalling. Methods and results Nur77 represses NPY expression in the PC12 adrenal chromaffin cell line. Accordingly, NPY levels are higher in adrenal gland, plasma, and heart from Nur77-KO compared to wild-type mice. Conditioned medium from Nur77-silenced chromaffin cells and serum from Nur77-KO mice induce marked hypertrophy in cultured neonatal rat cardiomyocytes, which is inhibited by the NPY type 1 receptor (NPY1R) antagonist BIBO3304. In cardiomyocytes from Nur77-KO mice, intracellular Ca2+ is increased partially via the NPY1R. This is independent from elevated circulating NPY since cardiomyocyte-specific Nur77-deficient mice (CM-KO) do not have elevated circulating NPY, but do exhibit BIBO3304-sensitive, increased cardiomyocyte intracellular Ca2+. In vivo, this translates to NPY1R antagonism attenuating cardiac calcineurin activity and isoproterenol-induced cardiomyocyte hypertrophy and fibrosis in full-body Nur77-KO mice, but not in CM-KO mice. Conclusions The cardioprotective action of Nur77 can be ascribed to both inhibition of circulating NPY levels and to cardiomyocyte-specific modulation of NPY-NPY1R signalling. These results reveal the underlying mechanism of Nur77 as a promising modifier gene in heart failure.

Background: Heart failure is associated with elongation of cardiomyocytes and loss of sarcomeres. Although the transcription factor myocyte enhancer factor-2 (MEF2) has an important role in this adverse remodeling, the mechanism underlying the structural changes of cardiomyocytes remains to be elucidated. In a screen for MEF2 target genes, we have recently identified myotonic dystrophy protein kinase (DMPK) as a potential mediator of adverse cardiomyocyte remodeling. However, it remains to be determined whether DMPK levels are increased in failing hearts and if DMPK is sufficient to induce structural remodeling of cardiomyocytes. Methods and Results: Since the DMPK gene is subject to extensive alternative splicing, we performed RT-PCR and QPCR analysis of known DMPK splice variants in hearts from mice subjected to transverse aortic constriction (TAC) or sham surgery. This demonstrated a 1.6 fold increase in the DMPK E isoform in failing mouse hearts compared to controls (P Conclusion: Our data indicate that the expression of DMPK E is increased in heart failure. Moreover, increased expression of this DMPK splice variant results in a decrease in sarcomeric gene expression by translocation and inhibition of SRF. Together, these results assign a novel function to DMPK in adverse cardiomyocyte remodeling during heart failure development.

Background— Tissue edema and endothelial barrier dysfunction as observed in sepsis and acute lung injury carry high morbidity and mortality, but currently lack specific therapy. In a recent case report, we described fast resolution of pulmonary edema on treatment with the tyrosine kinase inhibitor imatinib through an unknown mechanism. Here, we explored the effect of imatinib on endothelial barrier dysfunction and edema formation. Methods and Results— We evaluated the effect of imatinib on endothelial barrier function in vitro and in vivo. In human macro- and microvascular endothelial monolayers, imatinib attenuated endothelial barrier dysfunction induced by thrombin and histamine. Small interfering RNA knock-downs of the imatinib-sensitive kinases revealed that imatinib attenuates endothelial barrier dysfunction via inhibition of Abl-related gene kinase (Arg/Abl2), a previously unknown mediator of endothelial barrier dysfunction. Indeed, Arg was activated by endothelial stimulation with thrombin, histamine, and vascular endothelial growth factor. Imatinib limited Arg-mediated endothelial barrier dysfunction by enhancing Rac1 activity and enforcing adhesion of endothelial cells to the extracellular matrix. Using mouse models of vascular leakage as proof-of-concept, we found that pretreatment with imatinib protected against vascular endothelial growth factor–induced vascular leakage in the skin, and effectively prevented edema formation in the lungs. In a murine model of sepsis, imatinib treatment (6 hours and 18 hours after induction of sepsis) attenuated vascular leakage in the kidneys and the lungs (24 hours after induction of sepsis). Conclusions— Thus, imatinib prevents endothelial barrier dysfunction and edema formation via inhibition of Arg. These findings identify imatinib as a promising approach to permeability edema and indicate Arg as novel target for edema treatment.

Routing in MANETs becomes a more sophisticated issue especially when a certain QoS requirement is to be satisfied. One of the most important QoS metrics is end-to-end reliability. Multi-path routing can be considered as an effective method to support end-to-end reliability. However, the path discovery in current multi-path routing algorithms considering reliability relies mostly on local link availability information at intermediate nodes to perform the route request message forwarding. Selecting a reliable link at an intermediate node solely based on local information may not necessarily lead to finding a satisfactory reliable end-to-end path. To mitigate this problem, in this paper we have proposed an Enhanced Multi-Path Dynamic Source Routing Algorithm (EMP-DSR) which is an enhanced version of MP-DSR. The proposed method uses an ant-colony optimization method to provide global information. The simulation results show that the EMP-DSR outperforms MP-DSR both in finding reliable paths and end-to-end delay with a little tolerable overhead.

Despite the emphasis on removing gap between software models and implementation code, there has been made little effort to apply software tools to enforce access control models directly into program code. In this paper the design and implementation of an access control policy enforcement environment is described. Within this environment, view-based access control policies defined in XML Metadata Interchange format are translated into view policy language. The view policy language primitives are then easily translated into Java primitives. At last, these primitives are enforced into Java program code to be secured. Two major benefits of applying the proposed approach for modeling and enforcement of access control policies are rapid development of view-based customized applications and secure enforcement of ordered chain of methods' executions.

One of the primary challenges in IDS alerts analysis is controlling and archiving the huge amount of alerts that have been triggered mainly in attack periods. We have developed a self-adaptive controlling mechanism which archives the Snort generated alerts in a well-formed abstracted format. An appropriate hashing technique along with a full-automated time-based hierarchical archiving approach has been used to reach this end. The developed system prevents the Snort database size to grow uncontrollably and unexpectedly. Results obtained from experiments and test cases show that especially in critical attack situations the system responds to queries well in a reasonable amount of time. The developed analyzer with new archiving approach is also able to compress the generated alerts effectively and generate statistical reports fast. The developed system is platform independent and can be deployed on mid-range servers and workstations. Also employing it does not require much degree of security expertise.

Applying access control is a well-known approach for securing programs. Access control policies can be modeled and then enforced into the existing program code. A major difficulty is to translate policy models into compatible format with the program code to be secured. In this paper, a new approach for automatic translation and enforcement of View-based access control policies into Java program text is presented.

Security is one of the most important concerns for both developers and consumers in the Information Technology (IT) world. Developing secure IT products demands some standards to assure the security level of the products. Common Criteria (CC) standard is formed to achieve this goal. But like other standards, CC has its own problems. In this paper, we address two of these problems: abstraction and time problems. Abstraction in the context of Common Criteria evaluation methodology is one of the most significant problems in the IT product evaluation process. Furthermore, the other problem of evaluation process based on Common Criteria is that it is a time consuming process, so it eventually makes the process a costly one. To solve these two problems, we decompose the tasks mentioned in the CC standard into finer ones. Moreover, we propose various expertises and task parallelism for performing aforementioned finer tasks.

Computing least-cost multicast routing tree while satisfying QoS constraints has become a key issue especially by growing communication networks. To solve this problem, a triplex algorithm called GASANT which is based on Ant Colony Optimization (ACO), Genetic Algorithm (GA), and Simulated Annealing (SA) has been proposed in this paper. Through ACO, we have both provided improved initial population to feed GA and reduced search process. Besides, SA has been deployed to refrain GA from getting stuck into local optimum solutions. Simulation results assert that GASANT not only has high speed convergence time, but also generates least-cost multicast routing trees of high QoS.