Self-stabilizing Leader Election in Population Protocols over Arbitrary Communication Graphs

This paper considers the fundamental problem of \emph{self-stabilizing leader election} ($\mathcal{SSLE}$) in the model of \emph{population protocols}. In this model, an unknown number of asynchronous, anonymous and finite state mobile agents interact in pairs over a given communication graph. $\mathcal{SSLE}$ has been shown to be impossible in the original model. This impossibility can been circumvented by a modular technique augmenting the system with an \emph{oracle} - an external module abstracting the added assumption about the system. Fischer and Jiang have proposed solutions to $\mathcal{SSLE}$, for complete communication graphs and rings, using an oracle $\Omega?$, called the \emph{eventual leader detector}. In this work, we present a solution for arbitrary graphs, using a \emph{composition} of two copies of $\Omega?$. We also prove that the difficulty comes from the requirement of self-stabilization, by giving a solution without oracle for arbitrary graphs, when an uniform initialization is allowed. Finally, we prove that there is no self-stabilizing \emph{implementation} of $\Omega?$ using $\mathcal{SSLE}$, in a sense we define precisely

Paxos Consensus, Deconstructed and Abstracted (Extended Version)

Lamport's Paxos algorithm is a classic consensus protocol for state machine replication in environments that admit crash failures. Many versions of Paxos exploit the protocol's intrinsic properties for the sake of gaining better run-time performance, thus widening the gap between the original description of the algorithm, which was proven correct, and its real-world implementations. In this work, we address the challenge of specifying and verifying complex Paxos-based systems by (a) devising composable specifications for implementations of Paxos's single-decree version, and (b) engineering disciplines to reason about protocol-aware, semantics-preserving optimisations to single-decree Paxos. In a nutshell, our approach elaborates on the deconstruction of single-decree Paxos by Boichat et al. We provide novel non-deterministic specifications for each module in the deconstruction and prove that the implementations refine the corresponding specifications, such that the proofs of the modules that remain unchanged can be reused across different implementations. We further reuse this result and show how to obtain a verified implementation of Multi-Paxos from a verified implementation of single-decree Paxos, by a series of novel protocol-aware transformations of the network semantics, which we prove to be behaviour-preserving.Comment: Accepted for publication in the 27th European Symposium on Programming (ESOP'18

Robustness in Interaction Systems

We treat the effect of absence/failure of ports or components on properties of component-based systems. We do so in the framework of interaction systems, a formalism for component-based systems that strictly separates the issues of local behavior and interaction, for which ideas to establish properties of systems where developed. We propose to adapt these ideas to analyze how the properties behave under absence or failure of certain components or merely some ports of components. We demonstrate our approach for the properties local and global deadlock-freedom as well as liveness and local progress

Correspondences in Arakelov geometry and applications to the case of Hecke operators on modular curves

In the context of arithmetic surfaces, Bost defined a generalized Arithmetic Chow Group (ACG) using the Sobolev space L^2_1. We study the behavior of these groups under pull-back and push-forward and we prove a projection formula. We use these results to define an action of the Hecke operators on the ACG of modular curves and to show that they are self-adjoint with respect to the arithmetic intersection product. The decomposition of the ACG in eigencomponents which follows allows us to define new numerical invariants, which are refined versions of the self-intersection of the dualizing sheaf. Using the Gross-Zagier formula and a calculation due independently to Bost and Kuehn we compute these invariants in terms of special values of L series. On the other hand, we obtain a proof of the fact that Hecke correspondences acting on the Jacobian of the modular curves are self-adjoint with respect to the N\'eron-Tate height pairing.Comment: 38 pages. Minor correction

Aberrant DNA hypermethylation of the ITIH5 tumor suppressor gene in acute myeloid leukemia

Epigenetic mechanisms such as DNA hypermethylation and modifications of histone amino acids are known to play an important role in the control of gene expression both in normal human development and tumorigenesis. Hypermethylation of CpG islands within promoter regions of tumor suppressor genes is associated with transcriptional inactivation and represents, in addition to genetic aberrations, an important mechanism of gene silencing in the pathogenesis of human cancer. Inter-α-trypsine inhibitors (ITIs) are a family of serine protease inhibitors consisting of one light chain (bikunin) and two heavy chains (ITI heavy chains, ITIHs). ITIHs stabilize the extracellular matrix (ECM) by interacting with hyaluronic acid, which is a major ECM component. Hypermethylation in the upstream region of the promoter-associated CpG island of ITIH5, the most recently described member of the ITIH family, has been previously detected in breast cancer and was associated with an adverse outcome. In this study, we determined the DNA methylation status of the promoter region near the transcription start site of the ITIH5 tumor suppressor gene in leukemia cell lines and primary samples from patients with acute myeloid leukemia (AML) as well as the potential use of demethylating agents to restore a demethylated state of the promoter. Aberrant ITIH5 promoter hypermethylation occurred in 15 of 104 (14.4%) diagnostic AML samples. There were no statistically significant correlations between the ITIH5 methylation status and clinical prognostic parameters. Our results indicate that aberrant ITIH5 promoter hypermethylation is a novel epigenetic event in AML

Differential responses of osteoblasts and macrophages upon Staphylococcus aureus infection

Background Staphylococcus aureus (S. aureus) is one of the primary causes of bone infections which are often chronic and difficult to eradicate. Bacteria like S. aureus may survive upon internalization in cells and may be responsible for chronic and recurrent infections. In this study, we compared the responses of a phagocytic cell (i.e. macrophage) to a non-phagocytic cell (i.e. osteoblast) upon S. aureus internalization. Results We found that upon internalization, S. aureus could survive for up to 5 and 7 days within macrophages and osteoblasts, respectively. Significantly more S. aureus was internalized in macrophages compared to osteoblasts and a significantly higher (100 fold) level of live intracellular S. aureus was detected in macrophages compared to osteoblasts. However, the percentage of S. aureus survival after infection was significantly lower in macrophages compared to osteoblasts at post-infection days 1–6. Interestingly, macrophages had relatively lower viability in shorter infection time periods (i.e. 0.5-4 h; significant at 2 h) but higher viability in longer infection time periods (i.e. 6–8 h; significant at 8 h) compared to osteoblasts. In addition, S. aureusinfection led to significant changes in reactive oxygen species production in both macrophages and osteoblasts. Moreover, infected osteoblasts had significantly lower alkaline phosphatase activity at post-infection day 7 and infected macrophages had higher phagocytosis activity compared to non-infected cells. Conclusions S. aureus was found to internalize and survive within osteoblasts and macrophages and led to differential responses between osteoblasts and macrophages. These findings may assist in evaluation of the pathogenesis of chronic and recurrent infections which may be related to the intracellular persistence of bacteria within host cells

MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma

<p>ABSTRACT</p> <p>Background</p> <p>Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system and accounts for 15% of childhood cancer mortalities. With regards to the role of miRNAs in neuroblastoma, miR-34a, mapping to a chromosome 1p36 region that is commonly deleted, has been found to act as a tumor suppressor through targeting of numerous genes associated with cell proliferation and apoptosis.</p> <p>Methods</p> <p>A synthetic miR-34a (or negative control) precursor molecule was transfected into NB1691^lucand SK-N-AS^lucneuroblastoma cells. Quantitative PCR was used to verify increased miR-34a levels in NB1691^lucand SK-N-AS^luccell lines prior to <it>in vitro </it>and <it>in vivo </it>analysis. <it>In vitro </it>analysis of the effects of miR-34a over expression on cell growth, cell cycle and phosphoprotein activation in signal transduction pathways was performed. Neuroblastoma cells over expressing miR-34a were injected retroperitoneally into immunocompromised CB17-SCID mice and tumor burden was assessed over a 21 day period by measuring bioluminescence (photons/sec/cm²).</p> <p>Results</p> <p>Over expression of miR-34a in both NB1691^lucand SK-N-AS^lucneuroblastoma cell lines led to a significant decrease in cell number relative to premiR-negative control treated cells over a 72 hour period. Flow cytometry results indicated that miR-34a induced cell cycle arrest and subsequent apoptosis activation. Phosphoprotein analysis highlighted key elements involved in signal transduction, whose activation was dysregulated as a result of miR-34a introduction into cells. As a potential mechanism of miR-34a action on phosphoprotein levels, we demonstrate that miR-34a over-expression results in a significant reduction of <it>MAP3K9 </it>mRNA and protein levels. Although <it>MAP3K9 </it>is a predicted target of miR-34a, direct targeting could not be validated with luciferase reporter assays. Despite this fact, any functional effects of reduced MAP3K9 expression as a result of miR-34a would be expected to be similar regardless of the mechanism involved. Most notably, <it>in vivo </it>studies showed that tumor growth was significantly repressed after exogenous miR-34a administration in retroperitoneal neuroblastoma tumors.</p> <p>Conclusion</p> <p>We demonstrate for the first time that miR-34a significantly reduces tumor growth in an <it>in vivo </it>orthotopic murine model of neuroblastoma and identified novel effects that miR-34a has on phospho-activation of key proteins involved with apoptosis.</p

Cesarean delivery on maternal request: Can the ethical problem be solved by the principlist approach?

In this article, we use the principlist approach to identify, analyse and attempt to solve the ethical problem raised by a pregnant woman's request for cesarean delivery in absence of medical indications

Staphylococcus aureus Protein A Binds to Osteoblasts and Triggers Signals That Weaken Bone in Osteomyelitis

Osteomyelitis is a debilitating infectious disease of the bone. It is predominantly caused by S. aureus and is associated with significant morbidity and mortality. It is characterised by weakened bones associated with progressive bone loss. Currently the mechanism through which either bone loss or bone destruction occurs in osteomyelitis patients is poorly understood. We describe here for the first time that the major virulence factor of S. aureus, protein A (SpA) binds directly to osteoblasts. This interaction prevents proliferation, induces apoptosis and inhibits mineralisation of cultured osteoblasts. Infected osteoblasts also increase the expression of RANKL, a key protein involved in initiating bone resorption. None of these effects was seen in a mutant of S. aureus lacking SpA. Complementing the SpA-defective mutant with a plasmid expressing spa or using purified protein A resulted in attachment to osteoblasts, inhibited proliferation and induced apoptosis to a similar extent as wildtype S. aureus. These events demonstrate mechanisms through which loss of bone formation and bone weakening may occur in osteomyelitis patients. This new information may pave the way for the development of new and improved therapeutic agents to treat this disease

Manganese Enhances Prion Protein Survival in Model Soils and Increases Prion Infectivity to Cells

Prion diseases are considered to be transmissible. The existence of sporadic forms of prion diseases such as scrapie implies an environmental source for the infectious agent. This would suggest that under certain conditions the prion protein, the accepted agent of transmission, can survive in the environment. We have developed a novel technique to extract the prion protein from soil matrices. Previous studies have suggested that environmental manganese is a possible risk factor for prion diseases. We have shown that exposure to manganese is a soil matrix causes a dramatic increase in prion protein survival (∼10 fold) over a two year period. We have also shown that manganese increases infectivity of mouse passaged scrapie to culture cells by 2 logs. These results clearly verify that manganese is a risk factor for both the survival of the infectious agent in the environment and its transmissibility