Reconstructing particle masses from pairs of decay chains

A method is proposed for determining the masses of the new particles N,X,Y,Z in collider events containing a pair of effectively identical decay chains Z to Y+jet, Y to X+l_1, X to N+l_2, where l_1, l_2 are opposite-sign same-flavour charged leptons and N is invisible. By first determining the upper edge of the dilepton invariant mass spectrum, we reduce the problem to a curve for each event in the 3-dimensional space of mass-squared differences. The region through which most curves pass then determines the unknown masses. A statistical approach is applied to take account of mismeasurement of jet and missing momenta. The method is easily visualized and rather robust against combinatorial ambiguities and finite detector resolution. It can be successful even for small event samples, since it makes full use of the kinematical information from every event.Comment: 12 pages, 5 figure

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment

A Modified Coupled Enzyme Method for O-linked GlcNAc Transferase Activity Assay

In order to determine the activity of O-linked GlcNAc transferase (OGT), a modified coupled enzyme method was proposed. This method was based on the measurement of uridine 5'-(trihydrogen diphosphate) (UDP), a product generated in transglycosylation reaction. In the assay, UDP was coupled to the conversion of phosphoenolpyruvate to pyruvate using pyruvate kinase. Using a commercial pyruvate assay kit, the pyruvate was converted to a red terminal product, which could be photometrically measured at 570 nm or fluorometrically measured at 587 nm (Em = 535 nm) on a microplate reader. Kinetic study of a truncated recombinant mOGT and quantitative analysis of OGT in two biological samples indicated that this method was practical and competitive for quantitative analysis of OGT

Serratamolide is a hemolytic factor produced by Serratia marcescens

Serratia marcescens is a common contaminant of contact lens cases and lenses. Hemolytic factors of S. marcescens contribute to the virulence of this opportunistic bacterial pathogen. We took advantage of an observed hyper-hemolytic phenotype of crp mutants to investigate mechanisms of hemolysis. A genetic screen revealed that swrW is necessary for the hyper-hemolysis phenotype of crp mutants. The swrW gene is required for biosynthesis of the biosurfactant serratamolide, previously shown to be a broad-spectrum antibiotic and to contribute to swarming motility. Multicopy expression of swrW or mutation of the hexS transcription factor gene, a known inhibitor of swrW expression, led to an increase in hemolysis. Surfactant zones and expression from an swrW-transcriptional reporter were elevated in a crp mutant compared to the wild type. Purified serratamolide was hemolytic to sheep and murine red blood cells and cytotoxic to human airway and corneal limbal epithelial cells in vitro. The swrW gene was found in the majority of contact lens isolates tested. Genetic and biochemical analysis implicate the biosurfactant serratamolide as a hemolysin. This novel hemolysin may contribute to irritation and infections associated with contact lens use. © 2012 Shanks et al

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

VaxiJen: a server for prediction of protective antigens, tumour antigens and subunit vaccines

BACKGROUND: Vaccine development in the post-genomic era often begins with the in silico screening of genome information, with the most probable protective antigens being predicted rather than requiring causative microorganisms to be grown. Despite the obvious advantages of this approach – such as speed and cost efficiency – its success remains dependent on the accuracy of antigen prediction. Most approaches use sequence alignment to identify antigens. This is problematic for several reasons. Some proteins lack obvious sequence similarity, although they may share similar structures and biological properties. The antigenicity of a sequence may be encoded in a subtle and recondite manner not amendable to direct identification by sequence alignment. The discovery of truly novel antigens will be frustrated by their lack of similarity to antigens of known provenance. To overcome the limitations of alignment-dependent methods, we propose a new alignment-free approach for antigen prediction, which is based on auto cross covariance (ACC) transformation of protein sequences into uniform vectors of principal amino acid properties. RESULTS: Bacterial, viral and tumour protein datasets were used to derive models for prediction of whole protein antigenicity. Every set consisted of 100 known antigens and 100 non-antigens. The derived models were tested by internal leave-one-out cross-validation and external validation using test sets. An additional five training sets for each class of antigens were used to test the stability of the discrimination between antigens and non-antigens. The models performed well in both validations showing prediction accuracy of 70% to 89%. The models were implemented in a server, which we call VaxiJen. CONCLUSION: VaxiJen is the first server for alignment-independent prediction of protective antigens. It was developed to allow antigen classification solely based on the physicochemical properties of proteins without recourse to sequence alignment. The server can be used on its own or in combination with alignment-based prediction methods. It is freely-available online at the URL:

Estimating the costs of air pollution to the National Health Service and social care : An assessment and forecast up to 2035

BACKGROUND: Air pollution damages health by promoting the onset of some non-communicable diseases (NCDs), putting additional strain on the National Health Service (NHS) and social care. This study quantifies the total health and related NHS and social care cost burden due to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) in England. METHOD AND FINDINGS: Air pollutant concentration surfaces from land use regression models and cost data from hospital admissions data and a literature review were fed into a microsimulation model, that was run from 2015 to 2035. Different scenarios were modelled: (1) baseline 'no change' scenario; (2) individuals' pollutant exposure is reduced to natural (non-anthropogenic) levels to compute the disease cases attributable to PM2.5 and NO2; (3) PM2.5 and NO2 concentrations reduced by 1 μg/m3; and (4) NO2 annual European Union limit values reached (40 μg/m3). For the 18 years after baseline, the total cumulative cost to the NHS and social care is estimated at £5.37 billion for PM2.5 and NO2 combined, rising to £18.57 billion when costs for diseases for which there is less robust evidence are included. These costs are due to the cumulative incidence of air-pollution-related NCDs, such as 348,878 coronary heart disease cases estimated to be attributable to PM2.5 and 573,363 diabetes cases estimated to be attributable to NO2 by 2035. Findings from modelling studies are limited by the conceptual model, assumptions, and the availability and quality of input data. CONCLUSIONS: Approximately 2.5 million cases of NCDs attributable to air pollution are predicted by 2035 if PM2.5 and NO2 stay at current levels, making air pollution an important public health priority. In future work, the modelling framework should be updated to include multi-pollutant exposure-response functions, as well as to disaggregate results by socioeconomic status

Implementation of outpatient schema therapy for borderline personality disorder: study design

ABSTRACT: BACKGROUND: Schema Therapy (ST) is an integrative psychotherapy based upon a cognitive schema model which aims at identifying and changing dysfunctional schemas and modes through cognitive, experiential and behavioral pathways. It is specifically developed for patients with personality disorders. Its effectiveness and efficiency have been demonstrated in a few randomized controlled trials, but ST has not been evaluated in regular mental healthcare settings. This paper describes the study protocol of a multisite randomized 2-group design, aimed at evaluating the implementation of outpatient schema therapy for patients with borderline personality disorder (BPD) in regular mental healthcare and at determining the added value of therapist telephone availability outside office hours in case of crisis. METHODS/DESIGN: Patient outcome measures will be assessed with a semi-structured interview and self-report measures on BPD, therapeutic alliance, quality of life, costs and general psychopathology at baseline, 6, 12, 18 and 36 months. Intention-to-treat analyses will be executed with survival analysis for dichotomous variables, and one-sample t-tests and ANCOVAs for continuous variables with baseline as covariate and condition as between group factor. All tests will be two-tailed with a significance level of 5%. DISCUSSION: The study will provide an answer to the question whether ST can be effectively implemented and whether phone support by the therapist has an additional value. TRIAL REGISTRATION: The Dutch Cochrane Center, NTR (TC = 1781

RECO level \sqrt{s}_{min} and subsystem \sqrt{s}_{min}: improved global inclusive variables for measuring the new physics mass scale in missing energy events at hadron colliders

The variable \sqrt{s}_{min} was originally proposed in arXiv:0812.1042 as a model-independent, global and fully inclusive measure of the new physics mass scale in missing energy events at hadron colliders. In the original incarnation of \sqrt{s}_{min}, however, the connection to the new physics mass scale was blurred by the effects of the underlying event, most notably initial state radiation and multiple parton interactions. In this paper we advertize two improved variants of the \sqrt{s}_{min} variable, which overcome this problem. First we show that by evaluating the \sqrt{s}_{min} variable at the RECO level, in terms of the reconstructed objects in the event, the effects from the underlying event are significantly diminished and the nice correlation between the peak in the \sqrt{s}_{min}^{(reco)} distribution and the new physics mass scale is restored. Secondly, the underlying event problem can be avoided altogether when the \sqrt{s}_{min} concept is applied to a subsystem of the event which does not involve any QCD jets. We supply an analytic formula for the resulting subsystem \sqrt{s}_{min}^{(sub)} variable and show that its peak exhibits the usual correlation with the mass scale of the particles produced in the subsystem. Finally, we contrast \sqrt{s}_{min} to other popular inclusive variables such as H_T, M_{Tgen} and M_{TTgen}. We illustrate our discussion with several examples from supersymmetry, and with dilepton events from top quark pair production.Comment: 41 pages, 26 figure