Testing A (Stringy) Model of Quantum Gravity

I discuss a specific model of space-time foam, inspired by the modern non-perturbative approach to string theory (D-branes). The model views our world as a three brane, intersecting with D-particles that represent stringy quantum gravity effects, which can be real or virtual. In this picture, matter is represented generically by (closed or open) strings on the D3 brane propagating in such a background. Scattering of the (matter) strings off the D-particles causes recoil of the latter, which in turn results in a distortion of the surrounding space-time fluid and the formation of (microscopic, i.e. Planckian size) horizons around the defects. As a mean-field result, the dispersion relation of the various particle excitations is modified, leading to non-trivial optical properties of the space time, for instance a non-trivial refractive index for the case of photons or other massless probes. Such models make falsifiable predictions, that may be tested experimentally in the foreseeable future. I describe a few such tests, ranging from observations of light from distant gamma-ray-bursters and ultra high energy cosmic rays, to tests using gravity-wave interferometric devices and terrestrial particle physics experients involving, for instance, neutral kaons.Comment: 25 pages LATEX, four figures incorporated, uses special proceedings style. Invited talk at the third international conference on Dark Matter in Astro and Particle Physics, DARK2000, Heidelberg, Germany, July 10-15 200

Observational and Physical Classification of Supernovae

This chapter describes the current classification scheme of supernovae (SNe). This scheme has evolved over many decades and now includes numerous SN Types and sub-types. Many of these are universally recognized, while there are controversies regarding the definitions, membership and even the names of some sub-classes; we will try to review here the commonly-used nomenclature, noting the main variants when possible. SN Types are defined according to observational properties; mostly visible-light spectra near maximum light, as well as according to their photometric properties. However, a long-term goal of SN classification is to associate observationally-defined classes with specific physical explosive phenomena. We show here that this aspiration is now finally coming to fruition, and we establish the SN classification scheme upon direct observational evidence connecting SN groups with specific progenitor stars. Observationally, the broad class of Type II SNe contains objects showing strong spectroscopic signatures of hydrogen, while objects lacking such signatures are of Type I, which is further divided to numerous subclasses. Recently a class of super-luminous SNe (SLSNe, typically 10 times more luminous than standard events) has been identified, and it is discussed. We end this chapter by briefly describing a proposed alternative classification scheme that is inspired by the stellar classification system. This system presents our emerging physical understanding of SN explosions, while clearly separating robust observational properties from physical inferences that can be debated. This new system is quantitative, and naturally deals with events distributed along a continuum, rather than being strictly divided into discrete classes. Thus, it may be more suitable to the coming era where SN numbers will quickly expand from a few thousands to millions of events.Comment: Extended final draft of a chapter in the "SN Handbook". Comments most welcom

Strategies of a parasite of the ant–Acacia mutualism

Mutualisms can be exploited by parasites—species that obtain resources from a partner but provide no services. Though the stability of mutualisms in the presence of such parasites is under intensive investigation, we have little information on life history traits that allow a species to be a successful mutualist or rather a parasite, particularly in cases where both are closely related. We studied the exploitation of Acacia myrmecophytes by the ant, Pseudomyrmex gracilis, contrasting with the mutualistic ant Pseudomyrmex ferrugineus. P. gracilis showed no host-defending behavior and had a negative effect on plant growth. By preventing the mutualist from colonization, P. gracilis imposes opportunity costs on the host plant. P. gracilis produced smaller colonies with a higher proportion of alates than did the mutualist and thus showed an “r-like” strategy. This appears to be possible because P. gracilis relies less on host-derived food resources than does the mutualist, as shown by behavioral and stable isotope studies. We discuss how this system allows the identification of strategies that characterize parasites of mutualisms

Aspects of coverage in medical DNA sequencing

<p>Abstract</p> <p>Background</p> <p>DNA sequencing is now emerging as an important component in biomedical studies of diseases like cancer. Short-read, highly parallel sequencing instruments are expected to be used heavily for such projects, but many design specifications have yet to be conclusively established. Perhaps the most fundamental of these is the redundancy required to detect sequence variations, which bears directly upon genomic coverage and the consequent resolving power for discerning somatic mutations.</p> <p>Results</p> <p>We address the medical sequencing coverage problem via an extension of the standard mathematical theory of haploid coverage. The expected diploid multi-fold coverage, as well as its generalization for aneuploidy are derived and these expressions can be readily evaluated for any project. The resulting theory is used as a scaling law to calibrate performance to that of standard BAC sequencing at 8× to 10× redundancy, i.e. for expected coverages that exceed 99% of the unique sequence. A differential strategy is formalized for tumor/normal studies wherein tumor samples are sequenced more deeply than normal ones. In particular, both tumor alleles should be detected at least twice, while both normal alleles are detected at least once. Our theory predicts these requirements can be met for tumor and normal redundancies of approximately 26× and 21×, respectively. We explain why these values do not differ by a factor of 2, as might intuitively be expected. Future technology developments should prompt even deeper sequencing of tumors, but the 21× value for normal samples is essentially a constant.</p> <p>Conclusion</p> <p>Given the assumptions of standard coverage theory, our model gives pragmatic estimates for required redundancy. The differential strategy should be an efficient means of identifying potential somatic mutations for further study.</p

PADB : Published Association Database

<p>Abstract</p> <p>Background</p> <p>Although molecular pathway information and the International HapMap Project data can help biomedical researchers to investigate the aetiology of complex diseases more effectively, such information is missing or insufficient in current genetic association databases. In addition, only a few of the environmental risk factors are included as gene-environment interactions, and the risk measures of associations are not indexed in any association databases.</p> <p>Description</p> <p>We have developed a published association database (PADB; <url>http://www.medclue.com/padb</url>) that includes both the genetic associations and the environmental risk factors available in PubMed database. Each genetic risk factor is linked to a molecular pathway database and the HapMap database through human gene symbols identified in the abstracts. And the risk measures such as odds ratios or hazard ratios are extracted automatically from the abstracts when available. Thus, users can review the association data sorted by the risk measures, and genetic associations can be grouped by human genes or molecular pathways. The search results can also be saved to tab-delimited text files for further sorting or analysis. Currently, PADB indexes more than 1,500,000 PubMed abstracts that include 3442 human genes, 461 molecular pathways and about 190,000 risk measures ranging from 0.00001 to 4878.9.</p> <p>Conclusion</p> <p>PADB is a unique online database of published associations that will serve as a novel and powerful resource for reviewing and interpreting huge association data of complex human diseases.</p

Role of HPV Genotype, Multiple Infections, and Viral Load on the Risk of High-Grade Cervical Neoplasia

Background:HPV testing provides a much more sensitive method of detection for high-grade lesions than cytology, but specificity is low. Here we explore the extent to which full HPV genotyping, viral load and multiplicity of types can be used to improve specificity. Methods:A population-based sample of 47,120 women undergoing cervical screening were tested for 13 high-risk HPV genotypes. Positive predictive values (PPV) for CIN grade 2 or worse (CIN2+; N=3449) and CIN3 or worse (CIN3+; N=1475) over three years of follow-up were estimated for HPV genotype and viral load. Weighted multivariate logistic regression models were used to estimate the odds of CIN2+ or CIN3+ according to genotype, multiplicity of types and viral load. Results:High-risk HPV was detected in 15.4% of women. A hierarchy of HPV genotypes based on sequentially maximizing PPVs for CIN3+ found HPV16>33>31 to be the most predictive, followed sequentially by HPV18>35>58>45>52>59>51>39>56>68. After adjusting for higher ranked genotypes, multiple HPV infections added little to risk prediction. High viral loads for HPV18, 35, 52 and 58 carried more risk than low viral loads for HPV16, 31 and 33. High viral load for HPV16 was significantly more associated with CIN3+ than low viral load. Conclusions:HPV genotype and viral load, but not multiplicity of HPV infections, are important predictors of CIN2+ and CIN3+. Impact:The ability to identify women at higher risk of CIN2+ and CIN3+ based on both HPV genotype and viral load could be important for individualising triage plans, particularly as HPV becomes the primary screening test

A Neutralizing RNA Aptamer against EGFR Causes Selective Apoptotic Cell Death

Nucleic acid aptamers have been developed as high-affinity ligands that may act as antagonists of disease-associated proteins. Aptamers are non immunogenic and characterised by high specificity and low toxicity thus representing a valid alternative to antibodies or soluble ligand receptor traps/decoys to target specific cancer cell surface proteins in clinical diagnosis and therapy. The epidermal growth factor receptor (EGFR) has been implicated in the development of a wide range of human cancers including breast, glioma and lung. The observation that its inhibition can interfere with the growth of such tumors has led to the design of new drugs including monoclonal antibodies and tyrosine kinase inhibitors currently used in clinic. However, some of these molecules can result in toxicity and acquired resistance, hence the need to develop novel kinds of EGFR-targeting drugs with high specificity and low toxicity. Here we generated, by a cell-Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach, a nuclease resistant RNA-aptamer that specifically binds to EGFR with a binding constant of 10 nM. When applied to EGFR-expressing cancer cells the aptamer inhibits EGFR-mediated signal pathways causing selective cell death. Furthermore, at low doses it induces apoptosis even of cells that are resistant to the most frequently used EGFR-inhibitors, such as gefitinib and cetuximab, and inhibits tumor growth in a mouse xenograft model of human non-small-cell lung cancer (NSCLC). Interestingly, combined treatment with cetuximab and the aptamer shows clear synergy in inducing apoptosis in vitro and in vivo. In conclusion, we demonstrate that this neutralizing RNA-aptamer is a promising bio-molecule that can be developed as a more effective alternative to the repertoire of already existing EGFR-inhibitors

P130Cas Attenuates Epidermal Growth Factor (EGF) Receptor Internalization by Modulating EGF-Triggered Dynamin Phosphorylation

BACKGROUND: Endocytosis controls localization-specific signal transduction via epidermal growth factor receptor (EGFR), as well as downregulation of that receptor. Extracellular matrix (ECM)-integrin coupling induces formation of macromolecular complexes that include EGFR, integrin, Src kinase and p130Cas, resulting in EGFR activation. In addition, cell adhesion to ECM increases EGFR localization at the cell surface and reduces EGFR internalization. The molecular mechanisms involved are not yet well understood. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the molecular mechanism by which p130Cas affects the endocytic regulation of EGFR. Biochemical quantification revealed that cell adhesion to fibronectin (FN) increases total EGFR levels and its phosphorylation, and that p130Cas is required for this process. Measurements of Texas Red-labeled EGF uptake and cell surface EGFR revealed that p130Cas overexpression reduces EGF-induced EGFR internalization, while p130Cas depletion enhances it. In addition, both FN-mediated cell adhesion and p130Cas overexpression reduce EGF-stimulated dynamin phosphorylation, which is necessary for EGF-induced EGFR internalization. Coimmunoprecipitation and GST pull-down assays confirmed the interaction between p130Cas and dynamin. Moreover, a SH3-domain-deleted form of p130Cas, which shows diminished binding to dynamin, inhibits dynamin phosphorylation and EGF uptake less effectively than wild-type p130Cas. CONCLUSIONS/SIGNIFICANCE: Our results show that p130Cas plays an inhibitory role in EGFR internalization via its interaction with dynamin. Given that the EGFR internalization process determines signaling density and specificity in the EGFR pathway, these findings suggest that the interaction between p130Cas and dynamin may regulate EGFR trafficking and signaling in the same manner as other endocytic regulatory proteins related to EGFR endocytosis