Finding the right molecule - knowledge-driven enzyme discovery

Activity based screening of microbial strain or expression libraries from metagenomic sampling is still the strongest approach for discovery of unknown enzyme functionalities. However, the abundance of genomic and/or protein sequences suggests easy access to new, uncharacterized enzymes of known function, having the required physical properties for industrial use simply by extracting the right sequence from databases, ordering the gene and express it for application. This sequence based enzyme discovery is unfortunately hampered by two key factors: The functional classification is not of a quality that guarantees a correct functional prediction (see e.g. Furnham N et al., 2009, Walsh, JR et al., 2016) As of today it is almost impossible to unambiguously predict physical parameters of enzyme function based on amino acid sequence alone As a consequence numerous tools have to be employed to come at least to a correct functional prediction (Alderson, RG, 2012) using the available resources, which the scientific community has developed. Resources for sequence based enzyme discovery span from (meta-)genomic databases, a plethora of genome data, amino acid sequence databases (Schomburg and Schomburg, 2010), via the RCSB protein structure database (Rose PW et al., 2017) to enzyme property databases like BRENDA (Chang, A et al. 2015). A huge set of bioinformatics tools enables access to this databases, evaluation and classification of search results (e.g. Kuiper, RK et al. 2010). A streamlined enzyme discovery process is most likely achieved by setting it up as a multidisciplinary effort. Alderson et al. remark that biologists and chemists have different view, interests and interpretation of enzyme data and functionality. That professional bias in looking at molecules offers a chance to develop methods for speeding up the search for new enzymes. In the presentation, we will discuss, using examples, the exploitation of various databases and bioinformatics tools to enhance sequence based enzyme discovery processes. We will also look at the applicability of these technologies for protein engineering projects, which have evolved into an integral part of enzyme discovery and development. Literature: Alderson RG et al. (2012) Curr Top Med Chem. 2012 Sep 1; 12(17): 1911–1923 Chang A et al. (2015), Nucleic Acids Res. 2015 43 (D1): D439-46 Furnham N et al. (2009), Nature Chemical Biology 5, 521 - 525 Kuipers RK et al. (2010), Proteins. 2010 Jul;78(9):2101-13. Rose PW et al. (2017), Nucleic Acids Res 2017, 45 (D1): D271-D281. Schomburg D and Schomburg I (2010), Methods Mol Biol. 2010;609:113-28 Walsh JR et al. (2016), BMC Syst Biol. 2016; 10: 12

Virtual restoration of the sound of the Hispanic Rite

The virtual acoustic reality techniques are powerful tools for the recovery of acoustical heritage of historic buildings. Through the acoustic modeling and auralization techniques it´s possible to reconstruct the sound of disappeared buildings or the ones with significant modifications over the years, knowing the original geometry and the acoustic characteristics of their surfaces. This paper shows the results of a research project whose goal is the virtual recovery of the sound of the Hispanic Rite, the rite celebrated by Christians of the Iberian Peninsula before the imposition of the Roman Rite in the mid-eleventh century. For this purpose, acoustic models of a series of Pre-Romanesque churches were made. These acoustic models represent the churches in their original state, following the reconstruction hypothesis proposed by leading researchers in medieval liturgical archeology. Multichannel anechoic recordings of several pieces of the music of the Hispanic Rite have been carried out using a spherical array composed of 31 microphones. Finally, static and dynamic auralizations have been developed, involving the different liturgical configurations which were usual in this rite

Auralización del canto mozárabe en una iglesia pre-románica

Las tecnologías de realidad acústica virtual ofrecen una herramienta muy apropiada para la reconstrucción del patrimonio inmaterial del sonido de los recintos históricos. Este trabajo es parte de un proyecto de investigación cuyo objetivo es la restauración virtual del sonido del Antiguo Rito Hispánico y que consiste en la auralización del Canto Mozárabe en una serie de iglesias pre-Románicas de la península ibérica. En este caso se presentan los resultados más relevantes de las auralizaciones realizadas para la iglesia de Santa María de Melque. Para ello se ha elaborado un modelo acústico virtual de la iglesia en las condiciones que, según la documentación arqueológica, tenía el recinto original, se han realizado grabaciones anecoicas de una serie de piezas del repertorio primitivo del Canto Mozárabe y se han efectuado las auralizaciones correspondientes a diferentes configuraciones litúrgicas del Antiguo Rito Hispánico. ABSTRACT Acoustic Virtual Reality technology offers a highly appropriate tool for the reconstruction of the acoustic intangible heritage of the sound of historical enclosures. This work is part of a research project whose aim is the virtual restoration of the sound of the Old Hispanic Rite, auralizing the Mozarabic Chant in Pre-Romanesque churches of the Iberian Peninsula. This paper shows the most relevant results of the auralization of Santa María de Melque church. For that purpose, an acoustic virtual model has been created according to archaeological documentation of the original building conditions, anechoic recordings of several Early Mozarabic Chant musical pieces have been recorded and auralization corresponding to Old Hispanic liturgical Rite multiple settings has been completed

Coherent photo-thermal noise cancellation in a dual-wavelength optical cavity for narrow-linewidth laser frequency stabilisation

Optical resonators are used for the realisation of ultra-stable frequency lasers. The use of high reflectivity multi-band coatings allows the frequency locking of several lasers of different wavelengths to a single cavity. While the noise processes for single wavelength cavities are well known, the correlation caused by multi-stack coatings has as yet not been analysed experimentally. In our work, we stabilise the frequency of a $729\,$nm and a $1069\,$nm laser to one mirror pair and determine the residual-amplitude modulation (RAM) and photo-thermal noise (PTN). We find correlations in PTN between the two lasers and observe coherent cancellation of PTN for the $1069\,$nm coating. We show that the fractional frequency instability of the $729\,$nm laser is limited by RAM at $1\times10^{-14}$. The instability of the $1069\,$nm laser is at $3\times10^{-15}$ close to the thermal noise limit of $1.5\times10^{-15}$.Comment: 17 pages, 5 figure

In-vivo somatostatin-receptor expression in small cell lung cancer as a prognostic image biomarker and therapeutic target

Background: Given the dismal prognosis of small cell lung cancer (SCLC), novel therapeutic targets are urgently needed. We aimed to evaluate whether SSTR expression, as assessed by positron emission tomography (PET), can be applied as a prognostic image biomarker and determined subjects eligible for peptide receptor radionuclide therapy (PRRT). Methods: A total of 67 patients (26 females; age, 41–80 years) with advanced SCLC underwent SSTR-directed PET/computed tomography (somatostatin receptor imaging, SRI). SRI-avid tumor burden was quantified by maximum standardized uptake values (SUVmax) and tumor-to-liver ratios (T/L) of the most intense SCLC lesion. Scan findings were correlated with progression-free (PFS) and overall survival (OS). In addition, subjects eligible for SSTR-directed radioligand therapy were identified, and treatment outcome and toxicity profile were recorded. Results: On a patient basis, 36/67 (53.7%) subjects presented with mainly SSTR-positive SCLC lesions (>50% lesions positive); in 10/67 patients (14.9%), all lesions were positive. The median SUVmax was found to be 8.5, while the median T/L was 1.12. SRI-uptake was not associated with PFS or OS, respectively (SUVmax vs. PFS, ρ = 0.13 with p = 0.30 and vs. OS, ρ = 0.00 with p = 0.97; T/L vs. PFS, ρ = 0.07 with p = 0.58 and vs. OS, ρ = −0.05 with p = 0.70). PRRT was performed in 14 patients. One patient succumbed to treatment-independent infectious complications immediately after PRRT. In the remaining 13 subjects, disease control was achieved in 5/13 (38.5%) with a single patient achieving a partial response (stable disease in the remainder). In the sub-group of responding patients, PFS and OS were 357 days and 480 days, respectively. Conclusions: SSTR expression as detected by SRI is not predictive of outcome in patients with advanced SCLC. However, it might serve as a therapeutic target in selected patient

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

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

Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured