Rate of Convergence of Increasing Path-Vector Routing Protocols

A good measure of the rate of convergence of path-vector protocols is the number of synchronous iterations required for convergence in the worst case. From an algebraic perspective, the rate of convergence depends on the expressive power of the routing algebra associated with the protocol. For example in a network of $n$ nodes, shortest-path protocols are guaranteed to converge in $O(n)$ iterations. In contrast the algebra underlying the Border Gateway Protocol (BGP) is in some sense too expressive and the protocol is not guaranteed to converge. There is significant interest in finding well-behaved algebras that still have enough expressive power to satisfy network operators. Recent theoretical results have shown that by constraining routing algebras to those that are ``strictly increasing'' we can guarantee the convergence of path-vector protocols. Currently the best theoretical worst-case upper bound for the convergence of such algebras is $O(n!)$ iterations. However in practice it is difficult to find examples that do not converge in $n$ iterations. In this paper we close this gap. We first present a family of network configurations that converges in $\Theta(n^2)$ iterations, demonstrating that the worst case is $\Omega(n^2)$ iterations. We then prove that path-vector protocols with a strictly increasing algebra are guaranteed to converge in $O(n^2)$ iterations. Together these results establish a tight $\Theta(n^2)$ bound. This is another piece of the puzzle in showing that ``strictly increasing" is, at least on a technical level, a reasonable constraint for practical policy-rich protocols. {In memory of Abha Ahuja

Asynchronous Convergence of Policy-Rich Distributed Bellman-Ford Routing Protocols

We present new results in the theory of asynchronous convergence for the Distributed Bellman-Ford (DBF) family of routing protocols which includes distance-vector protocols (e.g. RIP) and path-vector protocols (e.g. BGP). We take the \emph{strictly increasing} conditions of Sobrinho and make three main new contributions. First, we show that the conditions are sufficient to guarantee that the protocols will converge to a \emph{unique} solution, preventing the possibility of BGP wedgies. Second, we decouple the computation from the asynchronous context in which it occurs, allowing us to reason about a more relaxed model of asynchronous computation in which routing messages can be lost, reordered, and duplicated. Third, our theory and results have been fully formalised in the Agda theorem prover and the resulting library is publicly available for others to use and extend. This is in line with the increasing emphasis on formal verification of software for critical infrastructure

Automated Analysis of Cryptococcal Macrophage Parasitism Using GFP-Tagged Cryptococci

The human fungal pathogens Cryptococcus neoformans and C. gattii cause life-threatening infections of the central nervous system. One of the major characteristics of cryptococcal disease is the ability of the pathogen to parasitise upon phagocytic immune effector cells, a phenomenon that correlates strongly with virulence in rodent models of infection. Despite the importance of phagocyte/Cryptococcus interactions to disease progression, current methods for assaying virulence in the acrophage system are both time consuming and low throughput. Here, we introduce the first stable and fully characterised GFP–expressing derivatives of two widely used cryptococcal strains: C. neoformans serotype A type strain H99 and C. gattii serotype B type strain R265. Both strains show unaltered responses to environmental and host stress conditions and no deficiency in virulence in the macrophage model system. In addition, we report the development of a method to effectively and rapidly investigate macrophage parasitism by flow cytometry, a technique that preserves the accuracy of current approaches but offers a four-fold improvement in speed

AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL

Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) are caused by the BCR-ABL oncogene. Imatinib inhibits the tyrosine kinase activity of the BCR-ABL protein and is an effective, frontline therapy for chronic-phase CML. However, accelerated or blast-crisis phase CML patients and Ph+ ALL patients often relapse due to drug resistance resulting from the emergence of imatinib-resistant point mutations within the BCR-ABL tyrosine kinase domain. This has stimulated the development of new kinase inhibitors that are able to over-ride resistance to imatinib. The novel, selective BCR-ABL inhibitor, AMN107, was designed to fit into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib. In addition to being more potent than imatinib (IC50<30 nM) against wild-type BCR-ABL, AMN107 is also significantly active against 32/33 imatinib-resistant BCR-ABL mutants. In preclinical studies, AMN107 demonstrated activity in vitro and in vivo against wild-type and imatinib-resistant BCR-ABL-expressing cells. In phase I/II clinical trials, AMN107 has produced haematological and cytogenetic responses in CML patients, who either did not initially respond to imatinib or developed imatinib resistance. Dasatinib (BMS-354825), which inhibits Abl and Src family kinases, is another promising new clinical candidate for CML that has shown good efficacy in CML patients. In this review, the early characterisation and development of AMN107 is discussed, as is the current status of AMN107 in clinical trials for imatinib-resistant CML and Ph+ ALL. Future trends investigating prediction of mechanisms of resistance to AMN107, and how and where AMN107 is expected to fit into the overall picture for treatment of early-phase CML and imatinib-refractory and late-stage disease are discussed

The ends justifies the means: A global research agenda for political marketing and public affairs

This is the peer reviewed version of the following article: Harris, P., & Sun, H. (2017). The ends justify the means: A global research agenda for political marketing and public affairs. Journal of Public Affairs, 14(4), e1693 which has been published in final form at http://dx.doi.org/10.1002/pa.1693 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Political marketing has developed into an increasingly mainstream discipline in universities globally over the last decade. There are many schools of political marketing with different approaches, such as the North American approach, the Western and Eastern European perspectives, and the Asian position. The study and application of political marketing has been categorised with different perspectives, such as electoral, governmental, and international aspects. It is becoming increasingly evident that political marketing needs further classification like any matured and established discipline. A close analysis of political marketing practices and academic research leads one to perceive two distinct areas of political exchanges in two different markets: the intranational market and the international market

Globally convergent evolution strategies for constrained optimization

International audienceIn this paper we propose, analyze, and test algorithms for constrained optimization when no use of derivatives of the objective function is made. The proposed methodology is built upon the globally convergent evolution strategies previously introduced by the authors for unconstrained optimization. Two approaches are encompassed to handle the constraints. In a first approach, feasibility is first enforced by a barrier function and the objective function is then evaluated directly at the feasible generated points. A second approach projects first all the generated points onto the feasible domain before evaluating the objective function.The resulting algorithms enjoy favorable global convergence properties (convergence to stationarity from arbitrary starting points), regardless of the linearity of the constraints.The algorithmic implementation (i) includes a step where previously evaluated points are used to accelerate the search (by minimizing quadratic models) and (ii) addresses the particular cases of bounds on the variables and linear constraints. Our solver is compared to others, and the numerical results confirm its competitiveness in terms of efficiency and robustness

Nuclear localization and cytosolic overexpression of LASP-1 correlates with tumor size and nodal-positivity of human breast carcinoma

<p>Abstract</p> <p>Background</p> <p>LIM and SH3 protein 1 (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell proliferation and migration, which was reported to be overexpressed in 8–12 % of human breast cancers and thought to be exclusively located in cytoplasm.</p> <p>Methods</p> <p>In the present work we analyzed the cellular and histological expression pattern of LASP-1 and its involvement in biological behavior of human breast cancer through correlation with standard clinicopathological parameters and expression of c-erbB2 (HER-2/neu), estrogen- (ER) and progesterone-receptors (PR). For this purpose immunohistochemical staining intensity and percentage of stained cells were semi-quantitatively rated to define a LASP-1 immunoreactive score (LASP-1-IRS). LASP-1-IRS was determined in 83 cases of invasive ductal breast carcinomas, 25 ductal carcinomas in situ (DCIS) and 18 fibroadenomas. Cellular LASP-1 distribution and expression pattern was visualized by immunofluorescence and confocal microscopy and assessed through separate Western blots of nuclear and cytosol preparations of BT-20, MCF-7, MDA-MB231, and ZR-75/1 breast cancer cells.</p> <p>Results</p> <p>Statistical analysis revealed that the resulting LASP-1-IRS was significantly higher in invasive carcinomas compared to fibroadenomas (p = 0.0176). Strong cytoplasmatic expression of LASP-1 was detected in 55.4 % of the invasive carcinomas, which correlated significantly with nuclear LASP-1-positivity (p = 0.0014), increased tumor size (p = 0.0159) and rate of nodal-positivity (p = 0.0066). However, levels of LASP-1 expression did not correlate with average age at time point of diagnosis, histological tumor grading, c-erbB2-, ER- or PR-expression.</p> <p>Increased nuclear localization and cytosolic expression of LASP-1 was found in breast cancer with higher tumor stage as well as in rapidly proliferating epidermal basal cells. Confocal microscopy and separate Western blots of cytosolic and nuclear preparations confirmed nuclear localization of LASP-1.</p> <p>Conclusion</p> <p>The current data provide evidence that LASP-1 is not exclusively a cytosolic protein, but is also detectable within the nucleus. Increased expression of LASP-1 in vivo is present in breast carcinomas with higher tumor stage and therefore may be related with worse prognosis concerning patients' overall survival.</p

Enteric Neural Crest Differentiation in Ganglioneuromas Implicates Hedgehog Signaling in Peripheral Neuroblastic Tumor Pathogenesis

Peripheral neuroblastic tumors (PNTs) share a common origin in the sympathetic nervous system, but manifest variable differentiation and growth potential. Malignant neuroblastoma (NB) and benign ganglioneuroma (GN) stand at opposite ends of the clinical spectrum. We hypothesize that a common PNT progenitor is driven to variable differentiation by specific developmental signaling pathways. To elucidate developmental pathways that direct PNTs along the differentiation spectrum, we compared the expression of genes related to neural crest development in GN and NB. In GNs, we found relatively low expression of sympathetic markers including adrenergic biosynthesis enzymes, indicating divergence from sympathetic fate. In contrast, GNs expressed relatively high levels of enteric neuropeptides and key constituents of the Hedgehog (HH) signaling pathway, including Dhh, Gli1 and Gli3. Predicted HH targets were also differentially expressed in GN, consistent with transcriptional response to HH signaling. These findings indicate that HH signaling is specifically active in GN. Together with the known role of HH activity in enteric neural development, these findings further suggested a role for HH activity in directing PNTs away from the sympathetic lineage toward a benign GN phenotype resembling enteric ganglia. We tested the potential for HH signaling to advance differentiation in PNTs by transducing NB cell lines with Gli1 and determining phenotypic and transcriptional response. Gli1 inhibited proliferation of NB cells, and induced a pattern of gene expression that resembled the differential pattern of gene expression of GN, compared to NB (p<0.00001). Moreover, the transcriptional response of SY5Y cells to Gli1 transduction closely resembled the transcriptional response to the differentiation agent retinoic acid (p<0.00001). Notably, Gli1 did not induce N-MYC expression in neuroblastoma cells, but strongly induced RET, a known mediator of RA effect. The decrease in NB cell proliferation induced by Gli1, and the similarity in the patterns of gene expression induced by Gli1 and by RA, corroborated by closely matched gene sets in GN tumors, all support a model in which HH signaling suppresses PNT growth by promoting differentiation along alternative neural crest pathways

The Last Post: British Press Representations of Veterans of the Great War

Harry Patch (1898–2009) was the last surviving soldier to have fought in the trenches of the Western Front, entering the media spotlight in 1998 when he was approached to contribute to the BBC documentary Veterans. Media coverage of Patch and the cultivation of his totemic status were particularly prodigious in anticipating and marking his death, producing a range of reflections on its historical, social and cultural significance. Focusing on the British popular press, this article examines media coverage of the last decade of Patch’s life. It considers the way in which the Great War is memorialised in the space of public history of the media in terms of the personalisation and sentimentalisation of Patch, exploring how he serves as a synecdoche for the millions of others who fought, how he embodies ideas of generational and social change, and how the iconography of the Great War’s contemporaneous representation works in the space of its memorialisation