MUMAL: multivariate analysis in shotgun proteomics using machine learning techniques.

BACKGROUND: The shotgun strategy (liquid chromatography coupled with tandem mass spectrometry) is widely applied for identification of proteins in complex mixtures. This method gives rise to thousands of spectra in a single run, which are interpreted by computational tools. Such tools normally use a protein database from which peptide sequences are extracted for matching with experimentally derived mass spectral data. After the database search, the correctness of obtained peptide-spectrum matches (PSMs) needs to be evaluated also by algorithms, as a manual curation of these huge datasets would be impractical. The target-decoy database strategy is largely used to perform spectrum evaluation. Nonetheless, this method has been applied without considering sensitivity, i.e., only error estimation is taken into account. A recently proposed method termed MUDE treats the target-decoy analysis as an optimization problem, where sensitivity is maximized. This method demonstrates a significant increase in the retrieved number of PSMs for a fixed error rate. However, the MUDE model is constructed in such a way that linear decision boundaries are established to separate correct from incorrect PSMs. Besides, the described heuristic for solving the optimization problem has to be executed many times to achieve a significant augmentation in sensitivity. RESULTS: Here, we propose a new method, termed MUMAL, for PSM assessment that is based on machine learning techniques. Our method can establish nonlinear decision boundaries, leading to a higher chance to retrieve more true positives. Furthermore, we need few iterations to achieve high sensitivities, strikingly shortening the running time of the whole process. Experiments show that our method achieves a considerably higher number of PSMs compared with standard tools such as MUDE, PeptideProphet, and typical target-decoy approaches. CONCLUSION: Our approach not only enhances the computational performance, and thus the turn around time of MS-based experiments in proteomics, but also improves the information content with benefits of a higher proteome coverage. This improvement, for instance, increases the chance to identify important drug targets or biomarkers for drug development or molecular diagnostics

Extension of thermonuclear functions through the pathway model including Maxwell-Boltzmann and Tsallis distributions

The Maxwell-Boltzmannian approach to nuclear reaction rate theory is extended to cover Tsallis statistics (Tsallis, 1988) and more general cases of distribution functions. An analytical study of respective thermonuclear functions is being conducted with the help of statistical techniques. The pathway model, recently introduced by Mathai (2005), is utilized for thermonuclear functions and closed-form representations are obtained in terms of H-functions and G-functions. Maxwell-Boltzmannian thermonuclear functions become particular cases of the extended thermonuclear functions. A brief review on the development of the theory of analytic representations of nuclear reaction rates is given.Comment: 16 pages, LaTe

Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer

Altres ajuts: This work was supported in part by La Marató de TV3 (20131530, TPuig), financial support was from the University of Girona (MPCUdG2016/036), and the University of Girona and La Caixa Foundation awarded S. Palomeras with a predoctoral grant.Background: Acquired resistance to trastuzumab is a major clinical problem in the treatment of HER2-positive (HER2+) breast cancer patients. The selection of trastuzumab-resistant patients is a great challenge of precision oncology. The aim of this study was to identify novel epigenetic biomarkers associated to trastuzumab resistance in HER2+ BC patients. Methods: We performed a genome-wide DNA methylation (450K array) and a transcriptomic analysis (RNA-Seq) comparing trastuzumab-sensitive (SK) and trastuzumab-resistant (SKTR) HER2+ human breast cancer cell models. The methylation and expression levels of candidate genes were validated by bisulfite pyrosequencing and qRT-PCR, respectively. Functional assays were conducted in the SK and SKTR models by gene silencing and overexpression. Methylation analysis in 24 HER2+ human BC samples with complete response or non-response to trastuzumab-based treatment was conducted by bisulfite pyrosequencing. Results: Epigenomic and transcriptomic analysis revealed the consistent hypermethylation and downregulation of TGFBI, CXCL2, and SLC38A1 genes in association with trastuzumab resistance. The DNA methylation and expression levels of these genes were validated in both sensitive and resistant models analyzed. Of the genes, TGFBI presented the highest hypermethylation-associated silencing both at the transcriptional and protein level. Ectopic expression of TGFBI in the SKTR model suggest an increased sensitivity to trastuzumab treatment. In primary tumors, TGFBI hypermethylation was significantly associated with trastuzumab resistance in HER2+ breast cancer patients. Conclusions: Our results suggest for the first time an association between the epigenetic silencing of TGFBI by DNA methylation and trastuzumab resistance in HER2+ cell models. These results provide the basis for further clinical studies to validate the hypermethylation of TGFBI promoter as a biomarker of trastuzumab resistance in HER2+ breast cancer patients

Large Scale Pressure Fluctuations and Sunyaev-Zel'dovich Effect

The Sunyaev-Zel'dovich (SZ) effect associated with pressure fluctuations of the large scale structure gas distribution will be probed with current and upcoming wide-field small angular scale cosmic microwave background experiments. We study the generation of pressure fluctuations by baryons which are present in virialized dark matter halos and by baryons present in small overdensities. For collapsed halos, assuming the gas distribution is in hydrostatic equilibrium with matter density distribution, we predict the pressure power spectrum and bispectrum associated with the large scale structure gas distribution by extending the dark matter halo approach which describes the density field in terms of correlations between and within halos. The projected pressure power spectrum allows a determination of the resulting SZ power spectrum due to virialized structures. The unshocked photoionized baryons present in smaller overdensities trace the Jeans-scale smoothed dark matter distribution. They provide a lower limit to the SZ effect due to large scale structure in the absence of massive collapsed halos. We extend our calculations to discuss higher order statistics, such as bispectrum and skewness in SZ data. The SZ-weak lensing cross-correlation is suggested as a probe of correlations between dark matter and baryon density fields, while the probability distribution functions of peak statistics of SZ halos in wide field CMB data can be used as a probe of cosmology and non-Gaussian evolution of large scale structure pressure fluctuations.Comment: 16 pages, 9 figures; Revised with expanded discussions. Phys. Rev. D. (in press

Electrochemical behavior of Ti/Al2O3 interfaces produced by diffusion bonding

In the field of biomedical applications a special interest exists regarding the study of the physicochemical and mechanical behaviour of materials, with special focus on the electrochemical degradation of metal/ceramic interfaces. In fact, etal/ceramic interfaces may be present in several biomedical devices, ranging from external or implantable sensors, to dental implants. Diffusion bonding represents an important technique since, in opposition to other production technologies, such as active metal brazing, avoid the possible liberation of certain chemical components harmful to health. The aim of this work is to study the electrochemical degradation of the interface formed between commercially pure Ti and Al2O3 produced by diffusion bonding, in contact with a physiological solution. The present approach included the evaluation of the contribution of individual and pairs of interfacial layers on the global degradation processes. For this propose d.c. electrochemical techniques were used to monitor the open-circuit potential, and to perform potentiodynamic polarization and galvanic corrosion evaluation. Also, electrochemical impedance spectroscopy was used as a complementary technique of the corrosion behaviour of the interface. Chemical composition and morphology of samples and corrosion products were evaluated by SEM and EDS analysis. According to experimental results, two principal reaction layers were formed in the interface: TiAl and Ti3Al. The TiAl layer appears to be the responsible for the strong increase in corrosion rate of the interface.Fundação para a Ciência e Tecnologia -POCTI/CTM/33384/2000; SFRH/BPD/ 5518/2001

Non-Perturbative QCD Treatment of High-Energy Hadron-Hadron Scattering

Total cross-sections and logarithmic slopes of the elastic scattering cross-sections for different hadronic processes are calculated in the framework of the model of the stochastic vacuum. The relevant parameters of this model, a correlation length and the gluon condensate, are determined from scattering data, and found to be in very good agreement with values coming from completely different sources of information. A parameter-free relation is given between total cross-sections and slope parameters, which is shown to be remarkably valid up to the highest energies for which data exist.Comment: 60 pages, Heidelberg preprin

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02