A theory of normed simulations

In existing simulation proof techniques, a single step in a lower-level specification may be simulated by an extended execution fragment in a higher-level one. As a result, it is cumbersome to mechanize these techniques using general purpose theorem provers. Moreover, it is undecidable whether a given relation is a simulation, even if tautology checking is decidable for the underlying specification logic. This paper introduces various types of normed simulations. In a normed simulation, each step in a lower-level specification can be simulated by at most one step in the higher-level one, for any related pair of states. In earlier work we demonstrated that normed simulations are quite useful as a vehicle for the formalization of refinement proofs via theorem provers. Here we show that normed simulations also have pleasant theoretical properties: (1) under some reasonable assumptions, it is decidable whether a given relation is a normed forward simulation, provided tautology checking is decidable for the underlying logic; (2) at the semantic level, normed forward and backward simulations together form a complete proof method for establishing behavior inclusion, provided that the higher-level specification has finite invisible nondeterminism.Comment: 31 pages, 10figure

Talking quiescence: a rigorous theory that supports parallel composition, action hiding and determinisation

The notion of quiescence - the absence of outputs - is vital in both behavioural modelling and testing theory. Although the need for quiescence was already recognised in the 90s, it has only been treated as a second-class citizen thus far. This paper moves quiescence into the foreground and introduces the notion of quiescent transition systems (QTSs): an extension of regular input-output transition systems (IOTSs) in which quiescence is represented explicitly, via quiescent transitions. Four carefully crafted rules on the use of quiescent transitions ensure that our QTSs naturally capture quiescent behaviour. We present the building blocks for a comprehensive theory on QTSs supporting parallel composition, action hiding and determinisation. In particular, we prove that these operations preserve all the aforementioned rules. Additionally, we provide a way to transform existing IOTSs into QTSs, allowing even IOTSs as input that already contain some quiescent transitions. As an important application, we show how our QTS framework simplifies the fundamental model-based testing theory formalised around ioco.Comment: In Proceedings MBT 2012, arXiv:1202.582

Lipidomic profiling of rat hepatic stellate cells during activation reveals a two-stage process accompanied by increased levels of lysosomal lipids

Hepatic stellate cells (HSCs) are liver-resident cells best known for their role in vitamin A storage under physiological conditions. Upon liver injury, HSCs activate into myofibroblast-like cells, a key process in the onset of liver fibrosis. Lipids play an important role during HSC activation. Here, we provide a comprehensive characterization of the lipidomes of primary rat HSCs during 17 days of activation in vitro. For lipidomic data interpretation, we expanded our previously described Lipid Ontology (LION) and associated web application (LION/Web) with the LION-PCA heatmap module, which generates heatmaps of the most typical LION-signatures in lipidomic datasets. Furthermore, we used LION to perform pathway analysis to determine the significant metabolic conversions in lipid pathways. Together, we identify two distinct stages of HSC activation. In the first stage, we observe a decrease of saturated phosphatidylcholine, sphingomyelin, and phosphatidic acid and an increase in phosphatidylserine and polyunsaturated bis(monoacylglycero)phosphate (BMP), a lipid class typically localized at endosomes and lysosomes. In the second activation stage, BMPs, hexosylceramides, and ether-linked phosphatidylcholines are elevated, resembling a lysosomal lipid storage disease profile. The presence of isomeric structures of BMP in HSCs was confirmed ex vivo in MS-imaging datasets of steatosed liver sections. Finally, treatment with pharmaceuticals targeting the lysosomal integrity led to cell death in primary HSCs but not in HeLa cells. In summary, our combined data suggest that lysosomes play a critical role during a two-stage activation process of HSCs

Weak Sequential Composition in Process Algebras

n this paper we study a special operator for sequential composition, which is defined relative to a dependency relation over the actions of a given system. The idea is that actions which are not dependent (intuitively because they share no common resources) do not have to wait for one another to proceed, even if they are composed sequentially. Such a notion has been studied before in a linear-time setting, but until recently there has been no systematic investigation in the context of process algebras. We give a structural operational semantics for a process algebraic language containing such a sequential composition operator, which shows some interesting interplay with choice. We give a complete axiomatisation of strong bisimilarity and we show consistency of the operational semantics with an event-based denotational semantics developed recently by the second author. The axiom system allows to derive the communication closed layers law, which in the linear time setting has been shown to be a very useful instrument in correctness preserving transformations. We conclude with a couple of examples

cGMP-Dependent Protein Kinase I Is Crucial for Angiogenesis and Postnatal Vasculogenesis

Background Endothelium-derived nitric oxide plays an important role for the bone marrow microenvironment. Since several important effects of nitric oxide are mediated by cGMP-dependent pathways, we investigated the role of the cGMP downstream effector cGMP-dependent protein kinase I (cGKI) on postnatal neovascularization. Methodology/Principal Findings In a disc neovascularization model, cGKI -/- mice showed an impaired neovascularization as compared to their wild-type (WT) littermates. Infusion of WT, but not cGKI -/- bone marrow progenitors rescued the impaired ingrowth of new vessels in cGKI-deficient mice. Bone marrow progenitors from cGKI -/- mice showed reduced proliferation and survival rates. In addition, we used cGKI alpha leucine zipper mutant (LZM) mice as model for cGKI deficiency. LZM mice harbor a mutation in the cGKI alpha leucine zipper that prevents interaction with downstream signaling molecules. Consistently, LZM mice exhibited reduced numbers of vasculogenic progenitors and impaired neovascularization following hindlimb ischemia compared to WT mice. Conclusions/Significance Our findings demonstrate that the cGMP-cGKI pathway is critical for postnatal neovascularization and establish a new role for cGKI in vasculogenesis, which is mediated by bone marrow-derived progenitors

Retinoids in health and disease : A role for hepatic stellate cells in affecting retinoid levels

Vitamin A (retinol) is important for normal growth, vision and reproduction. It has a role in the immune response and the development of metabolic syndrome. Most of the retinol present in the body is stored as retinyl esters within lipid droplets in hepatic stellate cells (HSCs). In case of liver damage, HSCs release large amounts of stored retinol, which is partially converted to retinoic acid (RA). This surge of RA can mediate the immune response and enhance the regeneration of the liver. If the damage persists activated HSCs change into myofibroblast-like cells producing extracellular matrix, which increases the chance of tumorigenesis to occur. RA has been shown to decrease proliferation and metastasis of hepatocellular carcinoma. The levels of RA and RA signaling are influenced by the possibility to esterify retinol towards retinyl esters. This suggests a complex regulation between different retinoids, with an important regulatory role for HSCs

Interphase FISH detection of BCL2 rearrangement in follicular lymphoma using breakpoint-flanking probes

Rearrangement of the BCL2 gene is an important parameter for the differential diagnosis of non-Hodgkin lymphomas. Although a relatively large proportion of breakpoints is clustered, many are missed by standard PCR. A FISH assay is therefore desired. Up to now, a lack of probes flanking the BCL2 gene has limited the possibilities for a FISH assay to an approach based on colocalization of probes for BCL2 and the immunoglobulin heavy chain (IGH) locus. Intrinsically high rates of false positive nuclei and high interobserver variability make such assays unsuitable for use on lymphoma tissue samples, where tumor cells often form only a minority of the cell population. Using YAC end cloning techniques and screening of a PAC library, we have isolated PAC clones flanking the BCL2 gene. Using these PACs, and several cosmid clones in the second BCL2 intron, we developed a segregation-based interphase FISH assay with two probe combinations enabling separate detection of 5' and 3' (mbr/mcr) breakpoints. The assay was applied to a series of 40 follicular lymphomas. To evaluate the results, the same lymphomas were analyzed by DNA fiber FISH with a 600-kb set of BCL2 DNA clones labeled in alternating colors in combination with a color barcode covering the IGH locus. This approach allowed precise mapping of BCL2 breakpoints, and simultaneously showed juxtaposition of IGH genes to BCL2. Comparison of the results of interphase and fiber FISH showed complete correlation. Five cases were negative with both FISH techniques as well as with Southern blotting. Interestingly, all of these 5 cases lacked BCL2 overexpression as determined by immunohistochemistry, against 3 of 35 rearrangement-positive follicular lymphomas. Furthermore, absence of t(14;18) seemed to be correlated with a higher histologic grade (grades 2 and 3 according to Berard). These data indicate that the segregation-based interphase FISH assay detects 100% of BCL2 rearrangements. Because interpretation of the results is straightforward and requires no extensive experience, this assay may be the best available diagnostic test for BCL2 rearrangement. Genes Chromosomes Cancer 27:85-94, 2000