New Approximability Results for the Robust k-Median Problem

We consider a robust variant of the classical $k$-median problem, introduced by Anthony et al. \cite{AnthonyGGN10}. In the \emph{Robust $k$-Median problem}, we are given an $n$-vertex metric space $(V,d)$ and $m$ client sets $\set{S_i \subseteq V}_{i=1}^m$. The objective is to open a set $F \subseteq V$ of $k$ facilities such that the worst case connection cost over all client sets is minimized; in other words, minimize $\max_{i} \sum_{v \in S_i} d(F,v)$. Anthony et al.\ showed an $O(\log m)$ approximation algorithm for any metric and APX-hardness even in the case of uniform metric. In this paper, we show that their algorithm is nearly tight by providing $\Omega(\log m/ \log \log m)$ approximation hardness, unless ${\sf NP} \subseteq \bigcap_{\delta >0} {\sf DTIME}(2^{n^{\delta}})$. This hardness result holds even for uniform and line metrics. To our knowledge, this is one of the rare cases in which a problem on a line metric is hard to approximate to within logarithmic factor. We complement the hardness result by an experimental evaluation of different heuristics that shows that very simple heuristics achieve good approximations for realistic classes of instances.Comment: 19 page

Evaluating practical negotiating agents: Results and analysis of the 2011 international competition

This paper presents an in-depth analysis and the key insights gained from the Second International Automated Negotiating Agents Competition (ANAC 2011). ANAC is an international competition that challenges researchers to develop successful automated negotiation agents for scenarios where there is no information about the strategies and preferences of the opponents. The key objectives of this competition are to advance the state-of-the-art in the area of practical bilateral multi-issue negotiations, and to encourage the design of agents that are able to operate effectively across a variety of scenarios. Eighteen teams from seven different institutes competed. This paper describes these agents, the setup of the tournament, including the negotiation scenarios used, and the results of both the qualifying and final rounds of the tournament. We then go on to analyse the different strategies and techniques employed by the participants using two methods: (i) we classify the agents with respect to their concession behaviour against a set of standard benchmark strategies and (ii) we employ empirical game theory (EGT) to investigate the robustness of the strategies. Our analysis of the competition results allows us to highlight several interesting insights for the broader automated negotiation community. In particular, we show that the most adaptive negotiation strategies, while robu

Overcoming the blood–brain barrier: the role of nanomaterials in treating neurological diseases

Therapies directed toward the central nervous system remain difficult to translate into improved clinical outcomes. This is largely due to the blood–brain barrier (BBB), arguably the most tightly regulated interface in the human body, which routinely excludes most therapeutics. Advances in the engineering of nanomaterials and their application in biomedicine (i.e., nanomedicine) are enabling new strategies that have the potential to help improve our understanding and treatment of neurological diseases. Herein, the various mechanisms by which therapeutics can be delivered to the brain are examined and key challenges facing translation of this research from benchtop to bedside are highlighted. Following a contextual overview of the BBB anatomy and physiology in both healthy and diseased states, relevant therapeutic strategies for bypassing and crossing the BBB are discussed. The focus here is especially on nanomaterial‐based drug delivery systems and the potential of these to overcome the biological challenges imposed by the BBB. Finally, disease‐targeting strategies and clearance mechanisms are explored. The objective is to provide the diverse range of researchers active in the field (e.g., material scientists, chemists, engineers, neuroscientists, and clinicians) with an easily accessible guide to the key opportunities and challenges currently facing the nanomaterial‐mediated treatment of neurological diseases

Expression profiling in transgenic FVB/N embryonic stem cells overexpressing STAT3

BACKGROUND: The transcription factor STAT3 is a downstream target of the LIF signalling cascade. LIF signalling or activation is sufficient to maintain embryonic stem (ES) cells in an undifferentiated and pluripotent state. To further investigate the importance of STAT3 in the establishment of ES cells we have in a first step derived stable pluripotent embryonic stem cells from transgenic FVB mice expressing a conditional tamoxifen dependent STAT3-MER fusion protein. In a second step, STAT3-MER overexpressing cells were used to identify STAT3 pathway-related genes by expression profiling in order to identify new key-players involved in maintenance of pluripotency in ES cells. RESULTS: Transgenic STAT3-MER blastocysts yielded pluripotent germline-competent ES cells at a high frequency in the absence of LIF when established in tamoxifen-containing medium. Expression profiling of tamoxifen-induced transgenic FVB ES cell lines revealed a set of 26 genes that were markedly up- or down-regulated when compared with wild type cells. The expression of four of the up-regulated genes (Hexokinase II, Lefty2, Pramel7, PP1rs15B) was shown to be restricted to the inner cell mass (ICM) of the blastocysts. These differentially expressed genes represent potential candidates for the maintenance of pluripotency of ES cells. We finally overexpressed two candidate genes, Pem/Rhox5 and Pramel7, in ES cells and demonstrated that their overexpression is sufficient for the maintenance of expression of ES cell markers as well as of the typical morphology of pluripotent ES cells in absence of LIF. CONCLUSION: Overexpression of STAT3-MER in the inner cell mass of blastocyst facilitates the establishment of ES cells and induces the upregulation of potential candidate genes involved in the maintenance of pluripotency. Two of them, Pem/Rhox5 and Pramel7, when overexpressed in ES cells are able to maintain the embryonic stem cells in a pluripotent state in a LIF independent manner as STAT3 or Nanog

SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair

Breaking and sealing one strand of DNA is an inherent feature of chromosome metabolism to overcome torsional barriers. Failure to reseal broken DNA strands results in protein-linked DNA breaks, causing neurodegeneration in humans. This is typified by defects in tyrosyl DNA phosphodiesterase 1 (TDP1), which removes stalled topoisomerase 1 peptides from DNA termini. Here we show that TDP1 is a substrate for modification by the small ubiquitin-like modifier SUMO. We purify SUMOylated TDP1 from mammalian cells and identify the SUMOylation site as lysine 111. While SUMOylation exhibits no impact on TDP1 catalytic activity, it promotes its accumulation at sites of DNA damage. A TDP1 SUMOylation-deficient mutant displays a reduced rate of repair of chromosomal single-strand breaks arising from transcription-associated topoisomerase 1 activity or oxidative stress. These data identify a role for SUMO during single-strand break repair, and suggest a mechanism for protecting the nervous system from genotoxic stress

Autonomy and Its Role in English Language Learning: Practice and Research

This chapter picks up discussion in the previous edition of this handbook of how the concept of autonomy has influenced language education and applied linguistics in recent years. It begins by discussing the philosophical and practical origins of learner autonomy in language education and particularly in English language teaching and how these have developed over the last 10 years. Key practical initiatives and research findings are reviewed to illuminate how autonomy has been interpreted in relation to learners, teachers, and the learning situation; how it has been linked or contrasted with other constructs; and how fostering autonomy has been seen as a part of pedagogy. Recent developments from the earlier edition are discussed regarding metacognition and, in particular, various contextual dimensions of learner autonomy. Other emerging topics are also reviewed, including learner autonomy in the world of digital/social media, learner autonomy in curriculum design and published materials, and the relation of learner autonomy to plurilingual perspectives. The chapter discusses issues in each of these areas, potential strategies for developing autonomy and effective learning, and possible future directions for research and practice