Substrate selectivity of an isolated enoyl reductase catalytic domain from an iterative highly reducing fungal polyketide synthase reveals key components of programming

A cis-acting enoyl reductase (ER) catalytic domain was isolated from a fungal highly reducing iterative polyketide synthase (HR-iPKS) for the first time and studied in vitro. The ER from the squalestatin tetraketide synthase forms a discrete dimeric protein in solution. The ER shows broad substrate selectivity, reducing enoyl species including both natural and unnatural substrates. Pantetheine-bound substrate thiolesters reacted much faster than the corresponding SNAC thiolesters. The unnatural substrates included Z-olefins, 2-ethyl olefins and pentaketides. Methylation of the substrate modifies the activity of the ER such that the 2,4-dimethyl oct-2-enoyl substrate fits into the active site but cannot be reduced. A new NMR-based assay was developed for the direct observation of the stereochemical preferences at the 4′ position of the NADPH cofactor and the C-2 and C-3 positions of the substrates. The assay reveals that the fungal iPKS ER-catalysed reaction is stereochemically identical to that of the vertebrate FAS (vFAS) at the cofactor 4′ position and the substrate 3-position, but the high stereoselectivity displayed by intact SQTKS is lost such that reprotonation at the 2-position is unselective by the isolated ER. A 3D model of ER was consistent with these observations and showed that the ER may sequester its final substrate to prevent further chain extension. The results support a developing model for programming by HR-iPKS in which competition for substrates between restrictive and permissive catalytic domains chaperones the growing polyketide to completion, while allowing for errors and evolution

From Ideas to Practice, Pilots to Strategy: Practical Solutions and Actionable Insights on How to Do Impact Investing

This report is the second publication in the World Economic Forum's Mainstreaming Impact Investing Initiative. The report takes a deeper look at why and how asset owners began to include impact investing in their portfolios and continue to do so today, and how they overcame operational and cultural constraints affecting capital flow. Given that impact investing expertise is spread among dozens if not hundreds of practitioners and academics, the report is a curation of some -- but certainly not all -- of those leading voices. The 15 articles are meant to provide investors, intermediaries and policy-makers with actionable insights on how to incorporate impact investing into their work.The report's goals are to show how mainstream investors and intermediaries have overcome the challenges in the impact investment sector, and to democratize the insights and expertise for anyone and everyone interested in the field. Divided into four main sections, the report contains lessons learned from practitioner's experience, and showcases best practices, organizational structures and innovative instruments that asset owners, asset managers, financial institutions and impact investors have successfully implemented

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Toric Construction of Global F-Theory GUTs

We systematically construct a large number of compact Calabi-Yau fourfolds which are suitable for F-theory model building. These elliptically fibered Calabi-Yaus are complete intersections of two hypersurfaces in a six dimensional ambient space. We first construct three-dimensional base manifolds that are hypersurfaces in a toric ambient space. We search for divisors which can support an F-theory GUT. The fourfolds are obtained as elliptic fibrations over these base manifolds. We find that elementary conditions which are motivated by F-theory GUTs lead to strong constraints on the geometry, which significantly reduce the number of suitable models. The complete database of models is available at http://hep.itp.tuwien.ac.at/f-theory/. We work out several examples in more detail.Comment: 35 pages, references adde

Nietzsche, Dionysus, and the Ontology of Music

This essay examines Nietzsche’s musical ontology and situates it within the naturalist and anti-metaphysical framework evident throughout his corpus. Nietzsche often associated this position with the figure of Dionysus, which plays a leading role in The Birth of Tragedy, his most sustained consideration of music and musical ontology. The essay returns to The Birth of Tragedy in an effort to recover Nietzsche’s musical ontology and its relationship with ontology more generally. Heeding Nietzsche’s own remarks, I read this text in light of his mature philosophy. My analysis draws on the work of the late twentieth-century Nietzschean, Gilles Deleuze, whose distinction between “the virtual” and “the actual” enables us to see what is really at issue in The Birth of Tragedy

Experimental investigations and modeling of S(IV)-species in the absorption of SO2 in seawater-like electrolyte solutions

Ziel dieser Arbeit war es, die Absorptionskapazität von Meerwassersole als Waschmittel in der Rauchgasentschwefelung zu untersuchen. Dazu wurden Versuche in unterschiedlichen Elektrolytlösungen durchgeführt, um Parameter des Pitzer-Modells zu bestimmen. Mit dem angepassten thermodynamischen Modell kann die Absorptionsfähigkeit verschiedener Elektrolytlösungen, im speziellen Meerwasser und Meerwassersole, vorhergesagt werden. Anhand der Gleichgewichtsdaten aus Absorptionsmessungen in binären Salzsystemen bei 25 °C wurde der Einfluss der verschiedenen Salze auf die Absorptionskapazität herausgearbeitet. Anschließend an die Versuche in den binären Systemen wurden ausgewählte Wechselwirkungsparameter des Pitzer-Modells angepasst, um die thermodynamische Beschreibung der Absorptionskapazität zu verbessern. Die in den binären Systemen angepassten Parameter wurden zu einem Modell zusammengefasst, mit dem die SO2-Absorptionsversuche in den komplexen Systemen Meerwasser und Meerwassersole bei 25 °C beschrieben wurden. Dabei wurde deutlich, dass die binären Parameter alleine die komplexen Systeme nicht beschreiben konnten. Es wurden daher ausgewählte ternäre Wechselwirkungsparameter angepasst, um eine thermodynamische Beschreibung des Absorptionsgleichgewichts in allen untersuchen Elektrolytlösungen zu erzielen. Da sich in industriellen Absorptionsprozessen zumeist Kühlgrenztemperaturen von 40 - 60 °C einstellen, wurde die Güte des thermodynamischen Modells auch in diesem Temperaturbereich untersucht. Dazu wurden sowohl die binären als auch die komplexen Systeme bei 50 °C vermessen und mit dem angepassten Modell beschrieben. Des Weiteren konnte in dieser Arbeit mittels UV-spektroskopischen Untersuchungen ein Einblick in die Speziesverteilung der Schwefel-(IV)-Spezies in der Flüssigphase gewonnen werden. Weitere Untersuchungen der aufgenommenen Extinktionsspektren ermöglichten eine Ermittlung der Extinktionskoeffizienten aller gelösten Schwefel-(IV)-Spezies in der Flüssigphase. Abschließend wurden Auswertemethoden entwickelt, mit denen die Spezieskonzentrationen in der Flüssigphase UV-spektroskopisch bestimmt werden können, ohne dabei auf eine thermodynamische Berechnung zurückgreifen zu müssen. Mit diesen Verfahren können beispielsweise Oxidations- oder Absorptionskinetiken deutlich genauer untersucht werden.In this work the absorption capacity of seawater brine is systematically investigated and discussed for the use in flue gas purification processes. Therefore, experiments were performed in various electrolyte solutions to optimize parameters of the pitzer model. With the adjusted thermodynamic model the absorption capacity of different electrolyte solutions, in particular seawater and brined, can be predicted. Based on equilibrium data of absorption experiments in binary salt systems at 298 K, the influence of different salts on the absorption capacity had been determined. Following to the experiments in binary-systems, selected parameters of the pitzer model were adjusted to improve the thermodynamic description of the absorption capacity. These parameters were combined into a model to describe the absorption experiments in the complex seawater and brine systems at 25 °C. It became evident that the use of optimized binary parameters only does not provide a sufficiently accurate description of the complex systems. Therefore, selected ternary interaction parameters were adjusted to achieve a more accurate thermodynamic description of the absorption equilibrium in all investigated electrolyte solutions. Industrial absorption processes run at temperatures of 313 – 333 K, so the quality of the thermodynamic model was also tested in this temperature range. The binary and complex systems were measured at 323 K and described with the fitted model. Furthermore, an insight into the distribution of the sulfur (IV) species in the liquid phase could be obtained in this work by uv spectroscopic measurements. Investigations of the recorded absorbance spectra allowed a determination of the extinction coefficients of all dissolved sulfur (IV) species. Finally, evaluation methods have been developed with which the species concentrations can be determined in the liquid phase by uv spectroscopy without needing to resort to a thermodynamic calculation

Measurement of Leading Proton and Neutron Production in Deep Inelastic Scattering at HERA

Deep--inelastic scattering events with a leading baryon have been detected by the H1 experiment at HERA using a forward proton spectrometer and a forward neutron calorimeter. Semi--inclusive cross sections have been measured in the kinematic region 2 <= Q^2 <= 50 GeV^2, 6.10^-5 <= x <= 6.10^-3 and baryon p_T <= MeV, for events with a final state proton with energy 580 <= E' <= 740 GeV, or a neutron with energy E' >= 160 GeV. The measurements are used to test production models and factorization hypotheses. A Regge model of leading baryon production which consists of pion, pomeron and secondary reggeon exchanges gives an acceptable description of both semi-inclusive cross sections in the region 0.7 <= E'/E_p <= 0.9, where E_p is the proton beam energy. The leading neutron data are used to estimate for the first time the structure function of the pion at small Bjorken--x.Comment: 30 pages, 9 figures, 2 tables, submitted to Eur. Phys.

Multi-Jet Event Rates in Deep Inelastic Scattering and Determination of the Strong Coupling Constant

Jet event rates in deep inelastic ep scattering at HERA are investigated applying the modified JADE jet algorithm. The analysis uses data taken with the H1 detector in 1994 and 1995. The data are corrected for detector and hadronization effects and then compared with perturbative QCD predictions using next-to-leading order calculations. The strong coupling constant alpha_S(M_Z^2) is determined evaluating the jet event rates. Values of alpha_S(Q^2) are extracted in four different bins of the negative squared momentum transfer~\qq in the range from 40 GeV2 to 4000 GeV2. A combined fit of the renormalization group equation to these several alpha_S(Q^2) values results in alpha_S(M_Z^2) = 0.117+-0.003(stat)+0.009-0.013(syst)+0.006(jet algorithm).Comment: 17 pages, 4 figures, 3 tables, this version to appear in Eur. Phys. J.; it replaces first posted hep-ex/9807019 which had incorrect figure 4

Multiplicity Structure of the Hadronic Final State in Diffractive Deep-Inelastic Scattering at HERA

The multiplicity structure of the hadronic system X produced in deep-inelastic processes at HERA of the type ep -> eXY, where Y is a hadronic system with mass M_Y< 1.6 GeV and where the squared momentum transfer at the pY vertex, t, is limited to |t|<1 GeV^2, is studied as a function of the invariant mass M_X of the system X. Results are presented on multiplicity distributions and multiplicity moments, rapidity spectra and forward-backward correlations in the centre-of-mass system of X. The data are compared to results in e+e- annihilation, fixed-target lepton-nucleon collisions, hadro-produced diffractive final states and to non-diffractive hadron-hadron collisions. The comparison suggests a production mechanism of virtual photon dissociation which involves a mixture of partonic states and a significant gluon content. The data are well described by a model, based on a QCD-Regge analysis of the diffractive structure function, which assumes a large hard gluonic component of the colourless exchange at low Q^2. A model with soft colour interactions is also successful.Comment: 22 pages, 4 figures, submitted to Eur. Phys. J., error in first submission - omitted bibliograph

Crumbling Crystals: On the Dissolution Mechanism of NaCl in Water

Life on Earth depends upon the dissolution of ionic salts in water, particularly NaCl. However, an atomistic scale understanding of the process remains elusive. Simulations lend themselves conveniently to studying dissolution since they provide the spatio-temporal resolution that can be difficult to obtain experimentally. Nevertheless, the complexity of various inter- and intra-molecular interactions require careful treatment and long time scale simulations, both of which are typically hindered by computational expense. Here, we use advances in machine learning potential methodology to resolve for the first time at an ab initio level of theory the dissolution mechanism of NaCl in water. The picture that emerges is that of a steady ion-wise unwrapping of the crystal preceding its rapid disintegration, reminiscent of crumbling. The onset of crumbling can be explained by a strong increase in the ratio of the surface to volume of the crystal. Overall, dissolution is comprised of a series of highly dynamical microscopic sub-processes, resulting in an inherently stochastic mechanism. These atomistic level insights now pave the way for a general understanding of dissolution mechanisms in other crystals, and the methodology is primed for more complex systems of recent interest such as water/salt interfaces under flow and salt crystals under confinement