Model-based prototyping of an interoperability protocol for mobile ad-hoc networks

We present an industrial project conducted at Ericsson Danmark A/S, Telebit where formal methods in the form of Coloured Petri Nets (CP-nets or CPNs) have been used for the specification of an interoperability protocol for routing packets between fixed core networks and mobile ad-hoc networks. The interoperability protocol ensures that a packet flow between a host in a core network and a mobile node in an ad-hoc network is always relayed via one of the closest gateways connecting the core network and the mobile ad-hoc network. This paper shows how integrated use of CP-nets and application-specific visualisation have been applied to build a model-based prototype of the interoperability protocol. The prototype consists of two parts: a CPN model that formally specifies the protocol mechanisms and a graphical user interface for experimenting with the protocol. The project demonstrates that the use of formal modelling combined with the use of application-specific visualisation can be an effective approach to rapidly construct an executable prototype of a communication protocol

Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration

BACKGROUND AND PURPOSE: The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism. EXPERIMENTAL APPROACH: Female APOE*3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin-4. KEY RESULTS: Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (-33%), accompanied by a reduction in monocyte adhesion to the vessel wall (-42%) and macrophage content in the plaque (-44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68(+) (-18%) and F4/80(+) (-25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1(+) macrophage content was decreased (-36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor. CONCLUSIONS AND IMPLICATIONS: Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously

A single night of sleep curtailment increases plasma acylcarnitines: Novel insights in the relationship between sleep and insulin resistance.

We have previously shown that acute sleep curtailment induces insulin resistance, both in healthy individuals as well as in patients with type 1 diabetes, suggesting a causal role for sleep disturbances in pathogenesis of insulin resistance, independent of endogenous insulin production. However, the underlying mechanisms remain unclear. This study aimed to explore the metabolic pathways affected by sleep loss using targeted metabolomics in human fasting plasma samples. Healthy individuals (n = 9) and patients with type 1 diabetes (n = 7) were studied after a single night of short sleep (4 h) versus normal sleep (8 h) in a cross-over design. Strikingly, one night of short sleep specifically increased the plasma levels of acylcarnitines, essential intermediates in mitochondrial fatty acid oxidation (FAO). Specifically, short sleep increased plasma levels of tetradecenoyl-l-carnitine (C14:1) (+32%, p = 2.67*10(-4)), octadecanoyl-l-carnitine (C18:1) (+22%, p = 1.92*10(-4)) and octadecadienyl-l-carnitine (C18:2) (+27%, p = 1.32*10(-4)). Since increased plasma acylcarnitine levels could be a sign of disturbed FAO, it is possible that sleep curtailment acutely induces inefficient mitochondrial function. Our observations provide a basis for further research into the role of acylcarnitines as a potential mechanistic pathway by which sleep deprivation - even short term - causes adverse metabolic effects, such as insulin resistance

Hepatocyte-specific IKKbeta expression aggravates atherosclerosis development in APOE*3-Leiden mice

Item does not contain fulltextOBJECTIVE: The liver is the key organ involved in systemic inflammation, but the relation between hepatic inflammation and atherogenesis is poorly understood. Since nuclear factor-kappaB (NF-kappaB) is a central regulator of inflammatory processes, we hypothesized that chronically enhanced hepatic NF-kappaB activation, through hepatocyte-specific expression of IkappaB kinase-beta (IKKbeta) (LIKK), will aggravate atherosclerosis development in APOE*3-Leiden (E3L) mice. METHODS AND RESULTS: E3L.LIKK and E3L control littermates were fed a Western-type diet for 24 weeks. E3L.LIKK mice showed a 2.3-fold increased atherosclerotic lesion area and more advanced atherosclerosis in the aortic root with less segments without atherosclerotic lesions (11% vs. 42%), and more segments with mild (63% vs. 44%) and severe (26% vs. 14%) lesions. Expression of LIKK did not affect basal levels of inflammatory parameters, but plasma cytokine levels tended to be higher in E3L.LIKK mice after lipopolysaccharide (LPS) administration. E3L.LIKK mice showed transiently increased plasma cholesterol levels, confined to (V)LDL. This transient character resulted in a mild (+17%) increased cumulative plasma cholesterol exposure. CONCLUSION: We conclude that selective activation of NF-kappaB in hepatocytes considerably promotes atherosclerosis development which is (at least partly) explained by an increased sensitivity to proinflammatory triggers and transiently increased plasma cholesterol levels