Sorting Permutations: Games, Genomes, and Cycles

Permutation sorting, one of the fundamental steps in pre-processing data for the efficient application of other algorithms, has a long history in mathematical research literature and has numerous applications. Two special-purpose sorting operations are considered in this paper: context directed swap, abbreviated cds, and context directed reversal, abbreviated cdr. These are special cases of sorting operations that were studied in prior work on permutation sorting. Moreover, cds and cdr have been postulated to model molecular sorting events that occur in the genome maintenance program of certain species of single-celled organisms called ciliates. This paper investigates mathematical aspects of these two sorting operations. The main result of this paper is a generalization of previously discovered characterizations of cds-sortability of a permutation. The combinatorial structure underlying this generalization suggests natural combinatorial two-player games. These games are the main mathematical innovation of this paper.Comment: to appear in Discrete Mathematics, Algorithms and Application

C1q deficiency leads to the defective suppression of IFN-α in response to nucleoprotein containing immune complexes

Almost all humans with homozygous deficiency of C1q develop systemic lupus erythematosus (SLE). The precise cellular mechanism (s) by which C1q prevents the development of SLE remains unclear. In this study, we tested the role of C1q in the regulation of IFN-α induced by immune complexes (ICs) in vitro, as well as the consequences of lack of C1q in vivo. Our experiments revealed that C1q preferentially promotes the binding of SLE ICs to monocytes rather than plasmacytoid dendritic cells, but this inhibition was not due to the induction of inhibitory soluble factors. The presence of C1q also altered the trafficking of ICs within monocytes such that ICs persisted in early endosomes. In patients with C1q deficiency, serum and cerebrospinal fluid levels of IFN-α and IFN-γ–inducible protein-10 levels were elevated and strongly correlated with Ro autoantibodies, demonstrating the clinical significance of these observations. These studies therefore associate C1q deficiency with defective regulation of IFN-α and provide a better understanding of the cellular mechanisms by which C1q prevents the development of IC-stimulated autoimmunity

Assessing Expectations: Towards a Toolbox for an Ethics of Emerging Technologies

In recent years, several authors have argued that the desirability of novel technologies should be assessed early, when they are still emerging. Such an ethical assessment of emerging technologies is by definition focused on an elusive object. Usually promises, expectations, and visions of the technology are taken as a starting point. As Nordmann and Rip have pointed out in a recent article, however, ethicists should not take for granted the plausibility of such expectations and visions. In this paper, we explore how the quality of expectations on emerging technologies might be assessed when engaging in a reflection on the desirability of emerging technologies. We propose that an assessment of expectations’ plausibility should focus on statements on technological feasibility, societal usability, and desirability of the expected technology. Whereas the feasibility statement and, to a lesser extent, the usability statements are frequently quite futuristic, the claims on desirability, by contrast, often display a conservative stance towards the future. Assessing the quality of expectations and visions on behalf of emerging technologies requires, then, a careful and well-directed use of both skepticism and imagination. We conclude with a brief overview of the tools and methods ethicists could use to assess claims made on behalf of emerging technologies and improve the ethical reflection on them

First Dark Matter Limits from a Large-Mass, Low-Background Superheated Droplet Detector

We report on the fabrication aspects and calibration of the first large active mass ($\sim15$ g) modules of SIMPLE, a search for particle dark matter using Superheated Droplet Detectors (SDDs). While still limited by the statistical uncertainty of the small data sample on hand, the first weeks of operation in the new underground laboratory of Rustrel-Pays d'Apt already provide a sensitivity to axially-coupled Weakly Interacting Massive Particles (WIMPs) competitive with leading experiments, confirming SDDs as a convenient, low-cost alternative for WIMP detection.Comment: Final version, Phys. Rev. Lett. (in press

The vulnerability of public spaces: challenges for UK hospitals under the 'new' terrorist threat

This article considers the challenges for hospitals in the United Kingdom that arise from the threats of mass-casualty terrorism. Whilst much has been written about the role of health care as a rescuer in terrorist attacks and other mass-casualty crises, little has been written about health care as a victim within a mass-emergency setting. Yet, health care is a key component of any nation's contingency planning and an erosion of its capabilities would have a significant impact on the generation of a wider crisis following a mass-casualty event. This article seeks to highlight the nature of the challenges facing elements of UK health care, with a focus on hospitals both as essential contingency responders under the United Kingdom's civil contingencies legislation and as potential victims of terrorism. It seeks to explore the potential gaps that exist between the task demands facing hospitals and the vulnerabilities that exist within them

Designing a Good Life: A Matrix for the Technological Mediation of Morality

Technologies fulfill a social role in the sense that they influence the moral actions of people, often in unintended and unforeseen ways. Scientists and engineers are already accepting much responsibility for the technological, economical and environmental aspects of their work. This article asks them to take an extra step, and now also consider the social role of their products. The aim is to enable engineers to take a prospective responsibility for the future social roles of their technologies by providing them with a matrix that helps to explore in advance how emerging technologies might plausibly affect the reasons behind people’s (moral) actions. On the horizontal axis of the matrix, we distinguished the three basic types of reasons that play a role in practical judgment: what is the case, what can be done and what should be done. On the vertical axis we distinguished the morally relevant classes of issues: stakeholders, consequences and the good life. To illustrate how this matrix may work in practice, the final section applies the matrix to the case of the Google PowerMeter

Observation of hard scattering in photoproduction events with a large rapidity gap at HERA

Events with a large rapidity gap and total transverse energy greater than 5 GeV have been observed in quasi-real photoproduction at HERA with the ZEUS detector. The distribution of these events as a function of the $\gamma p$ centre of mass energy is consistent with diffractive scattering. For total transverse energies above 12 GeV, the hadronic final states show predominantly a two-jet structure with each jet having a transverse energy greater than 4 GeV. For the two-jet events, little energy flow is found outside the jets. This observation is consistent with the hard scattering of a quasi-real photon with a colourless object in the proton.Comment: 19 pages, latex, 4 figures appended as uuencoded fil

The C-Type Lectin of the Aggrecan G3 Domain Activates Complement

Excessive complement activation contributes to joint diseases such as rheumatoid arthritis and osteoarthritis during which cartilage proteins are fragmented and released into the synovial fluid. Some of these proteins and fragments activate complement, which may sustain inflammation. The G3 domain of large cartilage proteoglycan aggrecan interacts with other extracellular matrix proteins, fibulins and tenascins, via its C-type lectin domain (CLD) and has important functions in matrix organization. Fragments containing G3 domain are released during normal aggrecan turnover, but increasingly so in disease. We now show that the aggrecan CLD part of the G3 domain activates the classical and to a lesser extent the alternative pathway of complement, via binding of C1q and C3, respectively. The complement control protein (CCP) domain adjacent to the CLD showed no effect on complement initiation. The binding of C1q to G3 depended on ionic interactions and was decreased in D2267N mutant G3. However, the observed complement activation was attenuated due to binding of complement inhibitor factor H to CLD and CCP domains. This was most apparent at the level of deposition of terminal complement components. Taken together our observations indicate aggrecan CLD as one factor involved in the sustained inflammation of the joint

Analysis of the putative role of CR1 in Alzheimer’s disease: Genetic association, expression and function

Chronic activation of the complement system and induced inflammation are associated with neuropathology in Alzheimer's disease (AD). Recent large genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the C3b/C4b receptor (CR1 or CD35) that are associated with late onset AD. Here, anti-CR1 antibodies (Abs) directed against different epitopes of the receptor, were used to localize CR1 in brain, and relative binding affinities of the CR1 ligands, C1q and C3b, were assessed by ELISA. Most Abs tested stained red blood cells in blood vessels but showed no staining in brain parenchyma. However, two monoclonal anti-CR1 Abs labeled astrocytes in all of the cases tested, and this reactivity was preabsorbed by purified recombinant human CR1. Human brain-derived astrocyte cultures were also reactive with both mAbs. The amount of astrocyte staining varied among the samples, but no consistent difference was conferred by diagnosis or the GWAS-identified SNPs rs4844609 or rs6656401. Plasma levels of soluble CR1 did not correlate with diagnosis but a slight increase was observed with rs4844609 and rs6656401 SNP. There was also a modest but statistically significant increase in relative binding activity of C1q to CR1 with the rs4844609 SNP compared to CR1 without the SNP, and of C3b to CR1 in the CR1 genotypes containing the rs6656401 SNP (also associated with the larger isoform of CR1) regardless of clinical diagnosis. These results suggest that it is unlikely that astrocyte CR1 expression levels or C1q or C3b binding activity are the cause of the GWAS identified association of CR1 variants with AD. Further careful functional studies are needed to determine if the variant-dictated number of CR1 expressed on red blood cells contributes to the role of this receptor in the progression of AD, or if another mechanism is involved