On the Schoenberg Transformations in Data Analysis: Theory and Illustrations

The class of Schoenberg transformations, embedding Euclidean distances into higher dimensional Euclidean spaces, is presented, and derived from theorems on positive definite and conditionally negative definite matrices. Original results on the arc lengths, angles and curvature of the transformations are proposed, and visualized on artificial data sets by classical multidimensional scaling. A simple distance-based discriminant algorithm illustrates the theory, intimately connected to the Gaussian kernels of Machine Learning

Should Research Ethics Encourage the Production of Cost-Effective Interventions?

This project considers whether and how research ethics can contribute to the provision of cost-effective medical interventions. Clinical research ethics represents an underexplored context for the promotion of cost-effectiveness. In particular, although scholars have recently argued that research on less-expensive, less-effective interventions can be ethical, there has been little or no discussion of whether ethical considerations justify curtailing research on more expensive, more effective interventions. Yet considering cost-effectiveness at the research stage can help ensure that scarce resources such as tissue samples or limited subject popula- tions are employed where they do the most good; can support parallel efforts by providers and insurers to promote cost-effectiveness; and can ensure that research has social value and benefits subjects. I discuss and rebut potential objections to the consideration of cost-effectiveness in research, including the difficulty of predicting effectiveness and cost at the research stage, concerns about limitations in cost-effectiveness analysis, and worries about overly limiting researchers’ freedom. I then consider the advantages and disadvantages of having certain participants in the research enterprise, including IRBs, advisory committees, sponsors, investigators, and subjects, consider cost-effectiveness. The project concludes by qualifiedly endorsing the consideration of cost-effectiveness at the research stage. While incorporating cost-effectiveness considerations into the ethical evaluation of human subjects research will not on its own ensure that the health care system realizes cost-effectiveness goals, doing so nonetheless represents an important part of a broader effort to control rising medical costs

Current and prospective pharmacotherapies for the treatment of pleural mesothelioma

Introduction: Mesothelioma is a rare asbestos-linked cancer with an expected incidence peak between 2015–2030. Therapies remain ineffective, thus developing and testing novel treatments is important for both oncologists and researchers. Areas covered: After describing mesothelioma and the shortcomings of current therapies, the article discusses numerous therapies in turn such as immunotherapy (passive and active), gene therapy (such as suicide gene therapy) and targeted therapy such as tyrosine kinase inhibitors. The bases for different therapies and clinical trials at different phases are also described. The article concludes by detailing possible reasons for therapy failure. Expert opinion: Despite the many attempts to uncover new therapeutic options, mesothelioma is still an orphan disease, complicated by factors such as the inflammatory microenvironment and low mutational load. Our opinion is that uncovering the biological mechanisms behind mesothelioma development will assist therapy development. The lack of efficacy of tyrosine kinase inhibitors and modest anti-angiogenic activity indicates a less relevant role for tumor cell proliferation and neoangiogenesis, thus the shortcut of treating mesothelioma with therapies from other cancers may be unsound. Conversely, many lines of evidence indicate that focussing on the survival mechanisms that tumor cells exploit may yield better therapeutics, particularly nutrition and cellular machinery

Do red deer stags (Cervus elaphus) use roar fundamental frequency (F0) to assess rivals?

It is well established that in humans, male voices are disproportionately lower pitched than female voices, and recent studies suggest that this dimorphism in fundamental frequency (F0) results from both intrasexual (male competition) and intersexual (female mate choice) selection for lower pitched voices in men. However, comparative investigations indicate that sexual dimorphism in F0 is not universal in terrestrial mammals. In the highly polygynous and sexually dimorphic Scottish red deer Cervus elaphus scoticus, more successful males give sexually-selected calls (roars) with higher minimum F0s, suggesting that high, rather than low F0s advertise quality in this subspecies. While playback experiments demonstrated that oestrous females prefer higher pitched roars, the potential role of roar F0 in male competition remains untested. Here we examined the response of rutting red deer stags to playbacks of re-synthesized male roars with different median F0s. Our results show that stags’ responses (latencies and durations of attention, vocal and approach responses) were not affected by the F0 of the roar. This suggests that intrasexual selection is unlikely to strongly influence the evolution of roar F0 in Scottish red deer stags, and illustrates how the F0 of terrestrial mammal vocal sexual signals may be subject to different selection pressures across species. Further investigations on species characterized by different F0 profiles are needed to provide a comparative background for evolutionary interpretations of sex differences in mammalian vocalizations

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Discrete Information from CHL Black Holes

AdS_2/CFT_1 correspondence predicts that the logarithm of a Z_N twisted index over states carrying a fixed set of charges grows as 1/N times the entropy of the black hole carrying the same set of charges. In this paper we verify this explicitly by calculating the microscopic Z_N twisted index for a class of states in the CHL models. This demonstrates that black holes carry more information about the microstates than just the total degeneracy.Comment: LaTeX file, 24 pages; v2: references adde

Cooperation, Norms, and Revolutions: A Unified Game-Theoretical Approach

Cooperation is of utmost importance to society as a whole, but is often challenged by individual self-interests. While game theory has studied this problem extensively, there is little work on interactions within and across groups with different preferences or beliefs. Yet, people from different social or cultural backgrounds often meet and interact. This can yield conflict, since behavior that is considered cooperative by one population might be perceived as non-cooperative from the viewpoint of another. To understand the dynamics and outcome of the competitive interactions within and between groups, we study game-dynamical replicator equations for multiple populations with incompatible interests and different power (be this due to different population sizes, material resources, social capital, or other factors). These equations allow us to address various important questions: For example, can cooperation in the prisoner's dilemma be promoted, when two interacting groups have different preferences? Under what conditions can costly punishment, or other mechanisms, foster the evolution of norms? When does cooperation fail, leading to antagonistic behavior, conflict, or even revolutions? And what incentives are needed to reach peaceful agreements between groups with conflicting interests? Our detailed quantitative analysis reveals a large variety of interesting results, which are relevant for society, law and economics, and have implications for the evolution of language and culture as well

Rule-based knowledge aggregation for large-scale protein sequence analysis of influenza A viruses

Background: The explosive growth of biological data provides opportunities for new statistical and comparative analyses of large information sets, such as alignments comprising tens of thousands of sequences. In such studies, sequence annotations frequently play an essential role, and reliable results depend on metadata quality. However, the semantic heterogeneity and annotation inconsistencies in biological databases greatly increase the complexity of aggregating and cleaning metadata. Manual curation of datasets, traditionally favoured by life scientists, is impractical for studies involving thousands of records. In this study, we investigate quality issues that affect major public databases, and quantify the effectiveness of an automated metadata extraction approach that combines structural and semantic rules. We applied this approach to more than 90,000 influenza A records, to annotate sequences with protein name, virus subtype, isolate, host, geographic origin, and year of isolation. Results: Over 40,000 annotated Influenza A protein sequences were collected by combining information from more than 90,000 documents from NCBI public databases. Metadata values were automatically extracted, aggregated and reconciled from several document fields by applying user-defined structural rules. For each property, values were recovered from ≥88.8% of records, with accuracy exceeding 96% in most cases. Because of semantic heterogeneity, each property required up to six different structural rules to be combined. Significant quality differences between databases were found: GenBank documents yield values more reliably than documents extracted from GenPept. Using a simple set of semantic rules and a reasoner, we reconstructed relationships between sequences from the same isolate, thus identifying 7640 isolates. Validation of isolate metadata against a simple ontology highlighted more than 400 inconsistencies, leading to over 3,000 property value corrections. Conclusion: To overcome the quality issues inherent in public databases, automated knowledge aggregation with embedded intelligence is needed for large-scale analyses. Our results show that user-controlled intuitive approaches, based on combination of simple rules, can reliably automate various curation tasks, reducing the need for manual corrections to approximately 5% of the records. Emerging semantic technologies possess desirable features to support today's knowledge aggregation tasks, with a potential to bring immediate benefits to this field. © 2006 Brahmachary et al; licensee BioMed Central Ltd

Pleosporales

One hundred and five generic types of Pleosporales are described and illustrated. A brief introduction and detailed history with short notes on morphology, molecular phylogeny as well as a general conclusion of each genus are provided. For those genera where the type or a representative specimen is unavailable, a brief note is given. Altogether 174 genera of Pleosporales are treated. Phaeotrichaceae as well as Kriegeriella, Zeuctomorpha and Muroia are excluded from Pleosporales. Based on the multigene phylogenetic analysis, the suborder Massarineae is emended to accommodate five families, viz. Lentitheciaceae, Massarinaceae, Montagnulaceae, Morosphaeriaceae and Trematosphaeriaceae

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV