Genome-wide analysis of core promoter elements from conserved human and mouse orthologous pairs

BACKGROUND: The canonical core promoter elements consist of the TATA box, initiator (Inr), downstream core promoter element (DPE), TFIIB recognition element (BRE) and the newly-discovered motif 10 element (MTE). The motifs for these core promoter elements are highly degenerate, which tends to lead to a high false discovery rate when attempting to detect them in promoter sequences. RESULTS: In this study, we have performed the first analysis of these core promoter elements in orthologous mouse and human promoters with experimentally-supported transcription start sites. We have identified these various elements using a combination of positional weight matrices (PWMs) and the degree of conservation of orthologous mouse and human sequences – a procedure that significantly reduces the false positive rate of motif discovery. Our analysis of 9,010 orthologous mouse-human promoter pairs revealed two combinations of three-way synergistic effects, TATA-Inr-MTE and BRE-Inr-MTE. The former has previously been putatively identified in human, but the latter represents a novel synergistic relationship. CONCLUSION: Our results demonstrate that DNA sequence conservation can greatly improve the identification of functional core promoter elements in the human genome. The data also underscores the importance of synergistic occurrence of two or more core promoter elements. Furthermore, the sequence data and results presented here can help build better computational models for predicting the transcription start sites in the promoter regions, which remains one of the most challenging problems

Chemical abundances of Seyfert 2 AGNs – III. Reducing the oxygen abundance discrepancy

We investigate the discrepancy between oxygen abundance estimations for narrow-line regions (NLRs) of Active Galactic Nuclei (AGNs) type Seyfert 2 derived by using direct estimations of the electron temperature (Te-method) and those derived by using photoionization models. In view of this, observational emission-line ratios in the optical range (3000 < \lambda(\AA) < 7000) of Seyfert 2 nuclei compiled from the literature were reproduced by detailed photoionization models built with the Cloudy code. We find that the derived discrepancies are mainly due to the inappropriate use of the relations between temperatures of the low (t2) and high (t3) ionization gas zones derived for H II regions in AGN chemical abundance studies. Using a photoionization model grid, we derived a new expression for t2 as a function of t3 valid for Seyfert 2 nuclei. The use of this new expression in the AGN estimation of the O/H abundances based on Te-method produces O/H abundances slightly lower (about 0.2 dex) than those derived from detailed photoionization models. We also find that the new formalism for the Te-method reduces by about 0.4 dex the O/H discrepancies between the abundances obtained from strong emission-line calibrations and those derived from direct estimations.ERC STF

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer’s disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system’s integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions

Molecular Responses of Mussel Mytilus galloprovincialis Associated to Accumulation and Depuration of Marine Biotoxins Okadaic Acid and Dinophysistoxin-1 Revealed by Shotgun Proteomics

The molecular pathways behind the toxicity of diarrheic shellfish toxins (DSTs) in bivalves have been scarcely studied. Thus, a shotgun proteomics approach was applied in this work to understand bivalves’ molecular responses to the dinoflagellate Prorocentrum lima (1.0 × 106 cells/L). Protein expression along with toxins levels were analyzed in the gills and digestive gland of the mussel Mytilus galloprovincialis during and after exposure to this toxic strain. Results revealed an accumulation of OA and DTX1 only in the digestive gland with maximum amounts attained at the end of uptake phase (day 5; 2819.2 ± 522.2 µg OA/kg and 1107.1 ± 267.9 µg DTX1/kg). At the end of the depuration phase (day 20), 16% and 47% of total OA and DTX1 concentrations remained in the digestive gland tissues, respectively. The shotgun proteomic analyses yielded 3051 proteins in both organs. A total of 56 and 54 differentially expressed proteins (DEPs) were revealed in the digestive gland and gills, respectively. Both organs presented the same response dynamics along the experiment, although with tissue-specific features. The early response (3 days uptake) was characterized by a high number of DEPs, being more marked in gills, in relation to the latter time points (5 days uptake and depuration). Functional enrichment analysis revealed the up-regulation of carboxylic (GO:0046943) and organic acid transmembrane transporter activity (GO:0005342) pathways after 3 days uptake for digestive gland. Matching to these pathways are a group of proteins related to transmembrane transport and response to toxic substances and xenobiotics, namely P-glycoprotein (ABCB11), Sodium-dependent proline transporter (SLC6A7), and Sideroflexin-1 (SFXN1). According to Clusters of Orthologous Groups (GOs) categories, most of the DEPs found for digestive gland in all time-points were related with “cellular processes and signaling” and involving signal transduction mechanisms, cytoskeleton and post-translational modification, protein turnover, chaperone functions. In gills, the early uptake phase was marked by a balance between DEPs related with “cellular processes and signaling” and “metabolism.” Depuration is clearly marked by processes related with “metabolism,” mainly involving secondary metabolites biosynthesis, transport, and catabolism. Proteomic data are available via ProteomeXchange with identifier PXD022293.This work was funded by Portuguese Science Foundation (Fundação para a Ciência e a Tecnologia, FCT) and under the Projects MOREBIVALVES (PTDC/ASP-PES/31762/2017) and by the Strategic Funding UIDB/04423/2020 and UIDP/04423/2020 through national funds provided by FCT and European Regional Development Fund (ERDF), in the framework of the program PT2020. This work had also support from the Portuguese Mass Spectrometry Network, integrated in the National Roadmap of Research Infrastructures of Strategic Relevance (ROTEIRO/0028/2013 and LISBOA-01-0145-FEDER-022125)

Introducing a new breed of wine yeast: interspecific hybridisation between a commercial Saccharomyces cerevisiae wine yeast and Saccharomyces mikatae

Interspecific hybrids are commonplace in agriculture and horticulture; bread wheat and grapefruit are but two examples. The benefits derived from interspecific hybridisation include the potential of generating advantageous transgressive phenotypes. This paper describes the generation of a new breed of wine yeast by interspecific hybridisation between a commercial Saccharomyces cerevisiae wine yeast strain and Saccharomyces mikatae, a species hitherto not associated with industrial fermentation environs. While commercially available wine yeast strains provide consistent and reliable fermentations, wines produced using single inocula are thought to lack the sensory complexity and rounded palate structure obtained from spontaneous fermentations. In contrast, interspecific yeast hybrids have the potential to deliver increased complexity to wine sensory properties and alternative wine styles through the formation of novel, and wider ranging, yeast volatile fermentation metabolite profiles, whilst maintaining the robustness of the wine yeast parent. Screening of newly generated hybrids from a cross between a S. cerevisiae wine yeast and S. mikatae (closely-related but ecologically distant members of the Saccharomyces sensu stricto clade), has identified progeny with robust fermentation properties and winemaking potential. Chemical analysis showed that, relative to the S. cerevisiae wine yeast parent, hybrids produced wines with different concentrations of volatile metabolites that are known to contribute to wine flavour and aroma, including flavour compounds associated with non-Saccharomyces species. The new S. cerevisiae x S. mikatae hybrids have the potential to produce complex wines akin to products of spontaneous fermentation while giving winemakers the safeguard of an inoculated ferment.Jennifer R. Bellon, Frank Schmid, Dimitra L. Capone, Barbara L. Dunn, Paul J. Chamber

Virtual screening for inhibitors of the human TSLP:TSLPR interaction

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Ra), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP: TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP: alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP: TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-ofprinciple for use of fragments in the inhibition of TSLP: TSLPR complexation

A general piecewise multi-state survival model: Application to breast cancer

Multi-state models are considered in the field of survival analysis for modelling illnesses that evolve through several stages over time. Multi-state models can be developed by applying several techniques, such as non-parametric, semi-parametric and stochastic processes, particularly Markov processes. When the development of an illness is being analysed, its progression is tracked periodically. Medical reviews take place at discrete times, and a panel data analysis can be formed. In this paper, a discrete-time piecewise non-homogeneous Markov process is constructed for modelling and analysing a multi-state illness with a general number of states. The model is built, and relevant measures, such as survival function, transition probabilities, mean total times spent in a group of states and the conditional probability of state change, are determined. A likelihood function is built to estimate the parameters and the general number of cut-points included in the model. Time-dependent covariates are introduced, the results are obtained in a matrix algebraic form and the algorithms are shown. The model is applied to analyse the behaviour of breast cancer. A study of the relapse and survival times of 300 breast cancer patients who have undergone mastectomy is developed. The results of this paper are implemented computationally with MATLAB and R.Ministerio de Economía y Competitividad FQM-307European Regional Development Fund (ERDF) MTM2017-88708-PUniversity of Milano-Bicocca 2014-ATE-022

Kothe dual of Banach lattices generated by vector measures

We study the Kothe dual spaces of Banach function lattices generated by abstract methods having roots in the theory of interpolation spaces. We apply these results to Banach spaces of integrable functions with respect to Banach space valued countably additive vector measures. As an application we derive a description of the Banach dual of a large class of these spaces, including Orlicz spaces of integrable functions with respect to vector measuresThe first author was supported by the Foundation for Polish Science (FNP). The second author was supported by the Ministerio de Economia y Competitividad (Spain) under Grant #MTM2012-36740-C02-02.Mastylo, M.; Sánchez Pérez, EA. (2014). Kothe dual of Banach lattices generated by vector measures. Monatshefte fur Mathematik. 173(4):541-557. https://doi.org/10.1007/s00605-013-0560-8S5415571734Aronszajn, N., Gagliardo, E.: Interpolation spaces and interpolation methods. Ann. Mat. Pura. Appl. 68, 51–118 (1965)Bartle, R.G., Dunford, N., Schwartz, J.: Weak compactness and vector measures. Canad. J. Math. 7, 289–305 (1955)Brudnyi, Yu.A., Krugljak, N.Ya.: Interpolation functors and interpolation spaces $$I$$ I . North-Holland, Amsterdam (1991)Curbera, G.P.: Operators into $$L^1$$ L 1 of a vector measure and applications to Banach lattices. Math. Ann. 293, 317–330 (1992)Curbera, G.P., Ricker, W.J.: The Fatou property in $$p$$ p -convex Banach lattices. J. Math. Anal. Appl. 328, 287–294 (2007)Delgado, O.: Banach function subspaces of $$L^1$$ L 1 of a vector measure and related Orlicz spaces. Indag. Math. 15(4), 485–495 (2004)Diestel, J., Jr., Uhl, J.J.: Vector measures, Amer. Math. Soc. Surveys 15, Providence, R.I. (1977)Fernández, A., Mayoral, F., Naranjo, F., Sánchez-Pérez, E.A.: Spaces of $$p$$ p -integrable functions with respect to a vector measure. Positivity 10, 1–16 (2006)Ferrando, I., Rodríguez, J.: The weak topology on $$L_p$$ L p of a vector measure. Topol. Appl. 155, 1439–1444 (2008)Ferrando, I., Sánchez Pérez, E.A.: Tensor product representation of the (pre)dual of the $$L_p$$ L p -space of a vector measure. J. Aust. Math. Soc. 87, 211–225 (2009)Galaz-Fontes, F.: The dual space of $$L^p$$ L p of a vector measure. Positivity 14(4), 715–729 (2010)Kamińska, A.: Indices, convexity and concavity in Musielak-Orlicz spaces, dedicated to Julian Musielak. Funct. Approx. Comment. Math. 26, 67–84 (1998)Kantorovich, L.V., Akilov, G.P.: Functional analysis, 2nd edn. Pergamon Press, New York (1982)Krein, S.G., Petunin, Yu.I., Semenov, E.M.: Interpolation of linear operators. In: Translations of mathematical monographs, 54. American Mathematical Society, Providence, R.I., (1982)Lewis, D.R.: Integration with respect to vector measures. Pacific. J. Math. 33, 157–165 (1970)Lewis, D.R.: On integrability and summability in vector spaces. Ill. J. Math. 16, 583–599 (1973)Lindenstrauss, J., Tzafriri, L.: Classical Banach spaces II. Springer, Berlin (1979)Lozanovskii, G.Ya.: On some Banach lattices, (Russian). Sibirsk. Mat. Z. 10, 419–430 (1969)Musielak, J.: Orlicz spaces and modular spaces. In: Lecture Notes in Math. 1034, Springer-Verlag, Berlin (1983)Okada, S.: The dual space of $$L^1(\mu )$$ L 1 ( μ ) of a vector measure $$\mu$$ μ . J. Math. Anal. Appl. 177, 583–599 (1993)Okada, S., Ricker, W.J., Sánchez Pérez, E.A.: Optimal domain and integral extension of operators acting in function spaces, operator theory. Adv. Appl., vol. 180, Birkhäuser, Basel (2008)Rao, M.M., Zen, Z.D.: Applications of Orlicz spaces. Marcel Dekker, Inc., New York (2002)Rivera, M.J.: Orlicz spaces of integrable functions with respect to vector-valued measures. Rocky Mt. J. Math. 38(2), 619–637 (2008)Sánchez Pérez, E.A.: Compactness arguments for spaces of $$p$$ p -integrable functions with respect to a vector measure and factorization of operators through Lebesgue-Bochner spaces. Ill. J. Math. 45(3), 907–923 (2001)Sánchez Pérez, E.A.: Vector measure duality and tensor product representation of $$L_p$$ L p spaces of vector measures. Proc. Amer. Math. Soc. 132, 3319–3326 (2004)Zaanen, A.C.: Integration. North Holland, Amsterdam (1967

Experimental estimation of the dimension of classical and quantum systems

An overwhelming majority of experiments in classical and quantum physics make a priori assumptions about the dimension of the system under consideration. However, would it be possible to assess the dimension of a completely unknown system only from the results of measurements performed on it, without any extra assumption? The concept of a dimension witness answers this question, as it allows one to bound the dimension of an unknown classical or quantum system in a device-independent manner, that is, only from the statistics of measurements performed on it. Here, we report on the experimental demonstration of dimension witnesses in a prepare and measure scenario. We use pairs of photons entangled in both polarization and orbital angular momentum to generate ensembles of classical and quantum states of dimensions up to 4. We then use a dimension witness to certify their dimensionality as well as their quantum nature. Our results open new avenues for the device-independent estimation of unknown quantum systems and for applications in quantum information science.Comment: See also similar, independent and jointly submitted work of J. Ahrens et al., quant-ph/1111.127