Black Hole Production by Cosmic Rays

Ultra-high energy cosmic rays create black holes in scenarios with extra dimensions and TeV-scale gravity. In particular, cosmic neutrinos will produce black holes deep in the atmosphere, initiating quasi-horizontal showers far above the standard model rate. At the Auger Observatory, hundreds of black hole events may be observed, providing evidence for extra dimensions and the first opportunity for experimental study of microscopic black holes. If no black holes are found, the fundamental Planck scale must be above 2 TeV for any number of extra dimensions.Comment: 4 pages, 4 figures, PRL versio

VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research

Accurate variant calling in next generation sequencing (NGS) is critical to understand cancer genomes better. Here we present VarDict, a novel and versatile variant caller for both DNA- and RNA-sequencing data. VarDict simultaneously calls SNV, MNV, InDels, complex and structural variants, expanding the detected genetic driver landscape of tumors. It performs local realignments on the fly for more accurate allele frequency estimation. VarDict performance scales linearly to sequencing depth, enabling ultra-deep sequencing used to explore tumor evolution or detect tumor DNA circulating in blood. In addition, VarDict performs amplicon aware variant calling for polymerase chain reaction (PCR)-based targeted sequencing often used in diagnostic settings, and is able to detect PCR artifacts. Finally, VarDict also detects differences in somatic and loss of heterozygosity variants between paired samples. VarDict reprocessing of The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma dataset called known driver mutations in KRAS, EGFR, BRAF, PIK3CA and MET in 16% more patients than previously published variant calls. We believe VarDict will greatly facilitate application of NGS in clinical cancer research

A comparison of collision cross section values obtained via travelling wave ion mobility-mass spectrometry and ultra high performance liquid chromatography-ion mobility-mass spectrometry : application to the characterisation of metabolites in rat urine

A comprehensive Collision Cross Section (CCS) library was obtained via Travelling Wave Ion Guide mobility measurements through direct infusion (DI). The library consists of CCS and Mass Spectral (MS) data in negative and positive ElectroSpray Ionisation (ESI) mode for 463 and 479 endogenous metabolites, respectively. For both ionisation modes combined, TWCCSN2 data were obtained for 542 non-redundant metabolites. These data were acquired on two different ion mobility enabled orthogonal acceleration QToF MS systems in two different laboratories, with the majority of the resulting TWCCSN2 values (from detected compounds) found to be within 1% of one another. Validation of these results against two independent, external TWCCSN2 data sources and predicted TWCCSN2 values indicated to be within 1-2% of these other values. The same metabolites were then analysed using a rapid reversed-phase ultra (high) performance liquid chromatographic (U(H)PLC) separation combined with IM and MS (IM-MS) thus providing retention time (tr), m/z and TWCCSN2 values (with the latter compared with the DI-IM-MS data). Analytes for which TWCCSN2 values were obtained by U(H)PLC-IM-MS showed good agreement with the results obtained from DI-IM-MS. The repeatability of the TWCCSN2 values obtained for these metabolites on the different ion mobility QToF systems, using either DI or LC, encouraged the further evaluation of the U(H)PLC-IM-MS approach via the analysis of samples of rat urine, from control and methotrexate-treated animals, in order to assess the potential of the approach for metabolite identification and profiling in metabolic phenotyping studies. Based on the database derived from the standards 63 metabolites were identified in rat urine, using positive ESI, based on the combination of tr, TWCCSN2 and MS data.</p

A Powassan virus domain III nanoparticle immunogen elicits neutralizing and protective antibodies in mice

Powassan virus (POWV) is an emerging tick borne flavivirus (TBFV) that causes severe neuroinvasive disease. Currently, there are no approved treatments or vaccines to combat POWV infection. Here, we generated and characterized a nanoparticle immunogen displaying domain III (EDIII) of the POWV E glycoprotein. Immunization with POWV EDIII presented on nanoparticles resulted in significantly higher serum neutralizing titers against POWV than immunization with monomeric POWV EDIII. Furthermore, passive transfer of EDIII-reactive sera protected against POWV challenge in vivo. We isolated and characterized a panel of EDIII-specific monoclonal antibodies (mAbs) and identified several that potently inhibit POWV infection and engage distinct epitopes within the lateral ridge and C-C\u27 loop of the EDIII. By creating a subunit-based nanoparticle immunogen with vaccine potential that elicits antibodies with protective activity against POWV infection, our findings enhance our understanding of the molecular determinants of antibody-mediated neutralization of TBFVs

The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

Detecting Microscopic Black Holes with Neutrino Telescopes

If spacetime has more than four dimensions, ultra-high energy cosmic rays may create microscopic black holes. Black holes created by cosmic neutrinos in the Earth will evaporate, and the resulting hadronic showers, muons, and taus may be detected in neutrino telescopes below the Earth's surface. We simulate such events in detail and consider black hole cross sections with and without an exponential suppression factor. We find observable rates in both cases: for conservative cosmogenic neutrino fluxes, several black hole events per year are observable at the IceCube detector; for fluxes at the Waxman-Bahcall bound, tens of events per year are possible. We also present zenith angle and energy distributions for all three channels. The ability of neutrino telescopes to differentiate hadrons, muons, and possibly taus, and to measure these distributions provides a unique opportunity to identify black holes, to experimentally constrain the form of black hole production cross sections, and to study Hawking evaporation.Comment: 20 pages, 9 figure

A methodology for automatic classification of breast cancer immunohistochemical data using semi-supervised fuzzy c-means

Previously, a semi-manual method was used to identify six novel and clinically useful classes in the Nottingham Tenovus Breast Cancer dataset. 663 out of 1,076 patients were classified. The objectives of our work is three folds. Firstly, our primary objective is to use one single automatic method (post-initialisation) to reproduce the six classes for the 663 patients and to classify the remaining 413 patients. Secondly, we explore using semi-supervised fuzzy c-means with various distance metrics and initialisation techniques to achieve this. Thirdly, the clinical characteristics of the 413 patients are examined by comparing with the 663 patients. Our experiments use various amount of labelled data and 10-fold cross validation to reproduce and evaluate the classification. ssFCM with Euclidean distance and initialisation technique by Katsavounidis et al. produced the best results. It is then used to classify the 413 patients. Visual evaluation of the 413 patients’ classifications revealed common characteristics as those previously reported. Examination of clinical characteristics indicates significant associations between classification and clinical parameters. More importantly, association between classification and survival based on the survival curves is shown