A general lower bound for collaborative tree exploration

We consider collaborative graph exploration with a set of $k$ agents. All agents start at a common vertex of an initially unknown graph and need to collectively visit all other vertices. We assume agents are deterministic, vertices are distinguishable, moves are simultaneous, and we allow agents to communicate globally. For this setting, we give the first non-trivial lower bounds that bridge the gap between small ($k \leq \sqrt n$) and large ($k \geq n$) teams of agents. Remarkably, our bounds tightly connect to existing results in both domains. First, we significantly extend a lower bound of $\Omega(\log k / \log\log k)$ by Dynia et al. on the competitive ratio of a collaborative tree exploration strategy to the range $k \leq n \log^c n$ for any $c \in \mathbb{N}$. Second, we provide a tight lower bound on the number of agents needed for any competitive exploration algorithm. In particular, we show that any collaborative tree exploration algorithm with $k = Dn^{1+o(1)}$ agents has a competitive ratio of $\omega(1)$, while Dereniowski et al. gave an algorithm with $k = Dn^{1+\varepsilon}$ agents and competitive ratio $O(1)$, for any $\varepsilon > 0$ and with $D$ denoting the diameter of the graph. Lastly, we show that, for any exploration algorithm using $k = n$ agents, there exist trees of arbitrarily large height $D$ that require $\Omega(D^2)$ rounds, and we provide a simple algorithm that matches this bound for all trees

Anonymous Graph Exploration with Binoculars

International audienceWe investigate the exploration of networks by a mobile agent. It is long known that, without global information about the graph, it is not possible to make the agent halts after the exploration except if the graph is a tree. We therefore endow the agent with binoculars, a sensing device that can show the local structure of the environment at a constant distance of the agent current location.We show that, with binoculars, it is possible to explore and halt in a large class of non-tree networks. We give a complete characterization of the class of networks that can be explored using binoculars using standard notions of discrete topology. This class is much larger than the class of trees: it contains in particular chordal graphs, plane triangulations and triangulations of the projective plane. Our characterization is constructive, we present an Exploration algorithm that is universal; this algorithm explores any network explorable with binoculars, and never halts in non-explorable networks

Mobile agent rendezvous: A survey

Abstract. Recent results on the problem of mobile agent rendezvous on distributed networks are surveyed with an emphasis on outlining the various approaches taken by researchers in the theoretical computer science community.

International longitudinal registry of patients with atrial fibrillation and treated with rivaroxaban: RIVaroxaban Evaluation in Real life setting (RIVER)

Background Real-world data on non-vitamin K oral anticoagulants (NOACs) are essential in determining whether evidence from randomised controlled clinical trials translate into meaningful clinical benefits for patients in everyday practice. RIVER (RIVaroxaban Evaluation in Real life setting) is an ongoing international, prospective registry of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) and at least one investigator-determined risk factor for stroke who received rivaroxaban as an initial treatment for the prevention of thromboembolic stroke. The aim of this paper is to describe the design of the RIVER registry and baseline characteristics of patients with newly diagnosed NVAF who received rivaroxaban as an initial treatment. Methods and results Between January 2014 and June 2017, RIVER investigators recruited 5072 patients at 309 centres in 17 countries. The aim was to enroll consecutive patients at sites where rivaroxaban was already routinely prescribed for stroke prevention. Each patient is being followed up prospectively for a minimum of 2-years. The registry will capture data on the rate and nature of all thromboembolic events (stroke / systemic embolism), bleeding complications, all-cause mortality and other major cardiovascular events as they occur. Data quality is assured through a combination of remote electronic monitoring and onsite monitoring (including source data verification in 10% of cases). Patients were mostly enrolled by cardiologists (n = 3776, 74.6%), by internal medicine specialists 14.2% (n = 718) and by primary care/general practice physicians 8.2% (n = 417). The mean (SD) age of the population was 69.5 (11.0) years, 44.3% were women. Mean (SD) CHADS2 score was 1.9 (1.2) and CHA2DS2-VASc scores was 3.2 (1.6). Almost all patients (98.5%) were prescribed with once daily dose of rivaroxaban, most commonly 20 mg (76.5%) and 15 mg (20.0%) as their initial treatment; 17.9% of patients received concomitant antiplatelet therapy. Most patients enrolled in RIVER met the recommended threshold for AC therapy (86.6% for 2012 ESC Guidelines, and 79.8% of patients according to 2016 ESC Guidelines). Conclusions The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients in the real world

Comparison of Peptide Array Substrate Phosphorylation of c-Raf and Mitogen Activated Protein Kinase Kinase Kinase 8

Kinases are pivotal regulators of cellular physiology. The human genome contains more than 500 putative kinases, which exert their action via the phosphorylation of specific substrates. The determinants of this specificity are still only partly understood and as a consequence it is difficult to predict kinase substrate preferences from the primary structure, hampering the understanding of kinase function in physiology and prompting the development of technologies that allow easy assessment of kinase substrate consensus sequences. Hence, we decided to explore the usefulness of phosphorylation of peptide arrays comprising of 1176 different peptide substrates with recombinant kinases for determining kinase substrate preferences, based on the contribution of individual amino acids to total array phosphorylation. Employing this technology, we were able to determine the consensus peptide sequences for substrates of both c-Raf and Mitogen Activated Protein Kinase Kinase Kinase 8, two highly homologous kinases with distinct signalling roles in cellular physiology. The results show that although consensus sequences for these two kinases identified through our analysis share important chemical similarities, there is still some sequence specificity that could explain the different biological action of the two enzymes. Thus peptide arrays are a useful instrument for deducing substrate consensus sequences and highly homologous kinases can differ in their requirement for phosphorylation events

Kinase Activity Profiling of Pneumococcal Pneumonia

Background: Pneumonia represents a major health burden. Previous work demonstrated that although the induction of inflammation is important for adequate host defense against pneumonia, an inability to regulate the host's inflammatory response within the lung later during infection can be detrimental. Intracellular signaling pathways commonly rely on activation of kinases, and kinases play an essential role in the regulation of the inflammatory response of immune cells. Methodology/Principal Findings: Pneumonia was induced in mice via intranasal instillation of Streptococcus (S.) pneumoniae. Kinomics peptide arrays, exhibiting 1024 specific consensus sequences for protein kinases, were used to produce a systems biology analysis of cellular kinase activity during the course of pneumonia. Several differences in kinase activity revealed by the arrays were validated in lung homogenates of individual mice using western blot. We identified cascades of activated kinases showing that chemotoxic stress and a T helper 1 response were induced during the course of pneumococcal pneumonia. In addition, our data point to a reduction in WNT activity in lungs of S. pneumoniae infected mice. Moreover, this study demonstrated a reduction in overall CDK activity implying alterations in cell cycle biology. Conclusions/Significance: This s

Evidence for a Minimal Eukaryotic Phosphoproteome?

BACKGROUND: Reversible phosphorylation catalysed by kinases is probably the most important regulatory mechanism in eukaryotes. METHODOLOGY/PRINCIPAL FINDINGS: We studied the in vitro phosphorylation of peptide arrays exhibiting the majority of PhosphoBase-deposited protein sequences, by factors in cell lysates from representatives of various branches of the eukaryotic species. We derived a set of substrates from the PhosphoBase whose phosphorylation by cellular extracts is common to the divergent members of different kingdoms and thus may be considered a minimal eukaryotic phosphoproteome. The protein kinases (or kinome) responsible for phosphorylation of these substrates are involved in a variety of processes such as transcription, translation, and cytoskeletal reorganisation. CONCLUSIONS/SIGNIFICANCE: These results indicate that the divergence in eukaryotic kinases is not reflected at the level of substrate phosphorylation, revealing the presence of a limited common substrate space for kinases in eukaryotes and suggests the presence of a set of kinase substrates and regulatory mechanisms in an ancestral eukaryote that has since remained constant in eukaryotic life

Ordering heuristics for parallel graph coloring

This paper introduces the largest-log-degree-first (LLF) and smallest-log-degree-last (SLL) ordering heuristics for paral-lel greedy graph-coloring algorithms, which are inspired by the largest-degree-first (LF) and smallest-degree-last (SL) serial heuristics, respectively. We show that although LF and SL, in prac-tice, generate colorings with relatively small numbers of colors, they are vulnerable to adversarial inputs for which any paralleliza-tion yields a poor parallel speedup. In contrast, LLF and SLL allow for provably good speedups on arbitrary inputs while, in practice, producing colorings of competitive quality to their serial analogs. We applied LLF and SLL to the parallel greedy coloring algo-rithm introduced by Jones and Plassmann, referred to here as JP. Jones and Plassman analyze the variant of JP that processes the ver-tices of a graph in a random order, and show that on an O(1)-degree graph G = (V,E), this JP-R variant has an expected parallel run-ning time of O(lgV / lg lgV) in a PRAM model. We improve this bound to show, using work-span analysis, that JP-R, augmented to handle arbitrary-degree graphs, colors a graph G = (V,E) with degree ∆ using Θ(V +E) work and O(lgV + lg ∆ ·min{√E,∆+ lg ∆ lgV / lg lgV}) expected span. We prove that JP-LLF and JP-SLL — JP using the LLF and SLL heuristics, respectively — execute with the same asymptotic work as JP-R and only logarith-mically more span while producing higher-quality colorings than JP-R in practice. We engineered an efficient implementation of JP for modern shared-memory multicore computers and evaluated its performance on a machine with 12 Intel Core-i7 (Nehalem) processor cores. Our implementation of JP-LLF achieves a geometric-mean speedup of 7.83 on eight real-world graphs and a geometric-mean speedup of 8.08 on ten synthetic graphs, while our implementation using SLL achieves a geometric-mean speedup of 5.36 on these real-world graphs and a geometric-mean speedup of 7.02 on these synthetic graphs. Furthermore, on one processor, JP-LLF is slightly faster than a well-engineered serial greedy algorithm using LF, and like-wise, JP-SLL is slightly faster than the greedy algorithm using SL

Identification of c-Src Tyrosine Kinase Substrates Using Mass Spectrometry and Peptide Microarrays

Udgivelsesdato: 2008-Sepc-Src tyrosine kinase plays a critical role in signal transduction downstream of growth factor receptors, integrins and G protein-coupled receptors. We used stable isotope labeling with amino acids in cell culture (SILAC) approach to identify additional substrates of c-Src tyrosine kinase in human embryonic kidney 293T cells. We have identified 10 known substrates and interactors of c-Src and Src family kinases along with 26 novel substrates. We have experimentally validated 4 of the novel proteins (NICE-4, RNA binding motif 10, FUSE-binding protein 1 and TRK-fused gene) as direct substrates of c-Src using in vitro kinase assays and cotransfection experiments. Significantly, using a c-Src specific inhibitor, we were also able to implicate 3 novel substrates (RNA binding motif 10, EWS1 and Bcl-2 associated transcription factor) in PDGF signaling. Finally, to identify the exact tyrosine residues that are phosphorylated by c-Src on the novel c-Src substrates, we designed custom peptide microarrays containing all possible tyrosine-containing peptides (312 unique peptides) and their mutant counterparts containing a Tyr --> Phe substitution from 14 of the identified substrates. Using this platform, we identified 34 peptides that are phosphorylated by c-Src. We have demonstrated that SILAC-based quantitative proteomics approach is suitable for identification of substrates of nonreceptor tyrosine kinases and can be coupled with peptide microarrays for high-throughput identification of substrate phosphopeptides

Mast cells disrupt the function of the esophageal epithelial barrier

Mast cells (MCs) accumulate in the epithelium of patients with eosinophilic esophagitis (EoE), an inflammatory disorder characterized by extensive esophageal eosinophilic infiltration. Esophageal barrier dysfunction plays an important role in the pathophysiology of EoE. We hypothesized that MCs contribute to the observed impaired esophageal epithelial barrier. Herein, we demonstrate that coculture of differentiated esophageal epithelial cells with immunoglobulin E-activated MCs significanly decreased epithelial resistance by 30% and increased permeability by 22% compared with non-activated MCs. These changes were associated with decreased messenger RNA expression of barrier proteins filaggrin, desmoglein-1 and involucrin, and antiprotease serine peptidase inhibitor kazal type 7. Using targeted proteomics, we detected various cytokines in coculture supernatants, most notably granulocyte-macrophage colony-stimulating factor and oncostatin M (OSM). OSM expression was increased by 12-fold in active EoE and associated with MC marker genes. Furthermore, OSM receptor-expressing esophageal epithelial cells were found in the esophageal tissue of patients with EoE, suggesting that the epithelial cells may respond to OSM. Stimulation of esophageal epithelial cells with OSM resulted in a dose-dependent decrease in barrier function and expression of filaggrin and desmoglein-1 and an increase in protease calpain-14. Taken together, these data suggest a role for MCs in decreasing esophageal epithelial barrier function in EoE, which may in part be mediated by OSM