Modal Logics with Hard Diamond-free Fragments

We investigate the complexity of modal satisfiability for certain combinations of modal logics. In particular we examine four examples of multimodal logics with dependencies and demonstrate that even if we restrict our inputs to diamond-free formulas (in negation normal form), these logics still have a high complexity. This result illustrates that having D as one or more of the combined logics, as well as the interdependencies among logics can be important sources of complexity even in the absence of diamonds and even when at the same time in our formulas we allow only one propositional variable. We then further investigate and characterize the complexity of the diamond-free, 1-variable fragments of multimodal logics in a general setting.Comment: New version: improvements and corrections according to reviewers' comments. Accepted at LFCS 201

The inhibitor of differentiation-2 promotes synovial fibroblast-dependent osteoclastogenesis in rheumatoid arthritis

Objectives: Despite indirect evidence suggesting that low oxygen levels might occur in the rheumatoid arthritis (RA) synovium, direct proof of the presence of hypoxia in the arthritic synovium as well as the relevance of low oxygen levels for joint destruction is lacking. The aim of this study was to analyse the distribution of hypoxia in arthritic joints and to evaluate the molecular effects of the hypoxic environment on the phenotype of RA synovial fibroblasts (SF).<p></p> Methods: The hypoxia marker EF-5 was applied in mice with the collagen-induced arthritis (CIA). Expression profile analysis with hypoxic and normoxic SF was performed using subtractive hybridization and microarray. The expression of the inhibitor of differentiation-2 (Id-2), CD68 (macrophage marker) and prolyl hydroxylase (fibroblast marker) was evaluated by immunohistochemistry on synovial tissues from RA, osteoarthritis patients and CIA mice. To evaluate the function of Id-2 in SF, cells were transfected with the pcDNA3.1 containing cDNA for Id-2 or Id-2-specific siRNA or mock controls. The expression of Id-2 and genes regulated by Id-2 in transfected SF was evaluated by SYBR Green real-time PCR and western blot. SF stably transfected with Id-2 were cocultured with bone marrow cells in a transwell system. The expression of the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin were measured by real-time PCR. The development of osteoclasts was evaluated by visualization of the activity of tartrate-resistant acid phosphatase.<p></p> Results: Using the hypoxia marker EF-5 we found that in mice with CIA, synovial cells invading bone and cartilage are exposed to reduced oxygen levels. Expression profile studies identified Id-2 as being upregulated under low oxygen conditions. In addition, IL-1beta stimulation increased the expression of Id-2 in these cells. Histological studies of RA synovium and CIA synovium showed strong expression of Id-2 in SF at sites of synovial invasion into bone. Overproduction of Id-2 in SF by stable transfection triggered the expression of several genes promoting osteoclastogenesis, including BMP-2, PTHrP, Wnt5a and vascular endothelial growth factor. Conversely, the suppression of endogenous Id-2 led to the downregulation of the expression of these molecules. Consistent with these findings coculture of Id-2 transfected SF with bone marrow cells increased the expression of the osteoclast differentiation factor RANKL, and decreased the expression of the osteoclast inhibitory factor osteoprotegerin in bone marrow stromal cells, which was followed by an increase in the number of osteoclasts.<p></p> Conclusion: Taken together, our data provide evidence that hypoxia is present at sites of synovial invasion in RA and that Id-2 induced by hypoxia contributes at these sites to joint destruction by promoting SF-dependent osteoclastogenesis

A Hierarchy of Polynomial Kernels

In parameterized algorithmics, the process of kernelization is defined as a polynomial time algorithm that transforms the instance of a given problem to an equivalent instance of a size that is limited by a function of the parameter. As, afterwards, this smaller instance can then be solved to find an answer to the original question, kernelization is often presented as a form of preprocessing. A natural generalization of kernelization is the process that allows for a number of smaller instances to be produced to provide an answer to the original problem, possibly also using negation. This generalization is called Turing kernelization. Immediately, questions of equivalence occur or, when is one form possible and not the other. These have been long standing open problems in parameterized complexity. In the present paper, we answer many of these. In particular, we show that Turing kernelizations differ not only from regular kernelization, but also from intermediate forms as truth-table kernelizations. We achieve absolute results by diagonalizations and also results on natural problems depending on widely accepted complexity theoretic assumptions. In particular, we improve on known lower bounds for the kernel size of compositional problems using these assumptions

A Dichotomy Result for Ramsey Quantifiers

Abstract. Ramsey quantifiers are a natural object of study not only for logic and computer science, but also for formal semantics of natu-ral language. Restricting attention to finite models leads to the natural question whether all Ramsey quantifiers are either polynomial-time com-putable or NP-hard, and whether we can give a natural characterization of the polynomial-time computable quantifiers. In this paper, we first show that there exist intermediate Ramsey quantifiers and then we prove a dichotomy result for a large and natural class of Ramsey quantifiers, based on a reasonable and widely-believed complexity assumption. We show that the polynomial-time computable quantifiers in this class are exactly the constant-log-bounded Ramsey quantifiers.

Phylodynamic assessment of intervention strategies for the West African Ebola virus outbreak

Genetic analyses have provided important insights into Ebola virus spread during the recent West African outbreak, but their implications for specific intervention scenarios remain unclear. Here, we address this issue using a collection of phylodynamic approaches. We show that long-distance dispersal events were not crucial for epidemic expansion and that preventing viral lineage movement to any given administrative area would, in most cases, have had little impact. However, major urban areas were critical in attracting and disseminating the virus: preventing viral lineage movement to all three capitals simultaneously would have contained epidemic size to one-third. We also show that announcements of border closures were followed by a significant but transient effect on international virus dispersal. By quantifying the hypothetical impact of different intervention strategies, as well as the impact of barriers on dispersal frequency, our study illustrates how phylodynamic analyses can help to address specific epidemiological and outbreak control questions.info:eu-repo/semantics/publishe

Secretion of Genome-Free Hepatitis B Virus – Single Strand Blocking Model for Virion Morphogenesis of Para-retrovirus

As a para-retrovirus, hepatitis B virus (HBV) is an enveloped virus with a double-stranded (DS) DNA genome that is replicated by reverse transcription of an RNA intermediate, the pregenomic RNA or pgRNA. HBV assembly begins with the formation of an “immature” nucleocapsid (NC) incorporating pgRNA, which is converted via reverse transcription within the maturing NC to the DS DNA genome. Only the mature, DS DNA-containing NCs are enveloped and secreted as virions whereas immature NCs containing RNA or single-stranded (SS) DNA are not enveloped. The current model for selective virion morphogenesis postulates that accumulation of DS DNA within the NC induces a “maturation signal” that, in turn, triggers its envelopment and secretion. However, we have found, by careful quantification of viral DNA and NCs in HBV virions secreted in vitro and in vivo, that the vast majority of HBV virions (over 90%) contained no DNA at all, indicating that NCs with no genome were enveloped and secreted as empty virions (i.e., enveloped NCs with no DNA). Furthermore, viral mutants bearing mutations precluding any DNA synthesis secreted exclusively empty virions. Thus, viral DNA synthesis is not required for HBV virion morphogenesis. On the other hand, NCs containing RNA or SS DNA were excluded from virion formation. The secretion of DS DNA-containing as well as empty virions on one hand, and the lack of secretion of virions containing single-stranded (SS) DNA or RNA on the other, prompted us to propose an alternative, “Single Strand Blocking” model to explain selective HBV morphogenesis whereby SS nucleic acid within the NC negatively regulates NC envelopment, which is relieved upon second strand DNA synthesis