Algorithmen im Wirkstoffdesign

Die Bestimmung der Ähnlichkeit von molekularen Strukturen und das Clustern solcher Strukturen gemäß Ähnlichkeit sind zwei zentrale Fragen im Wirkstoffdesign. Die Arbeit beschreibt im ersten Teil zwei neue Verfahren zum Vergleich von Molekülen auf 3-dimensionale Ähnlichkeit. Der erste Algorithmus benutzt als Eingabe nur die Koordinaten der Atome der zu vergleichenden Moleküle. Wir können zeigen, daß eine rein geometrische Zielfunktion in der Lage ist, Wirkungsähnlichkeit von Substanzen vorherzusagen, und daß der Algorithmus geeignet ist, Ähnlichkeiten zu finden, die mit bisherigen, einfacheren Methoden nicht gefunden werden konnten. Das zweite Verfahren nutzt zusätzlich noch die Bindungsstruktur der Eingabemoleküle. Es ist flexibel, d.h. alle Konformere der Moleküle werden simultan behandelt. Wir erhalten ein sehr schnelles Verfahren, das bei geeigneter Parametereinstellung auch beweisbar optimale Lösungen liefert. Für praktisch relevante Anwendungen erreichen wir erstmals Laufzeiten, die selbst das Durchsuchen großer Datenbanken ermöglichen. Im zweiten Teil beschreiben wir zwei Methoden, eine Menge von molekularen Strukturen so zu organisieren, daß die Suche nach geometrisch ähnlichen deutlich schneller durchgeführt werden kann als durch lineare Suche. Nach Analyse der Daten mit graphentheoretischen Methoden finden hierarchische Verfahren und repräsentantenbasierte Ansätze ihre Anwendung. Schließlich geben wir einen neuen Algorithmus zum Biclustern von Daten an, einem Problem, das bei der Analyse von Genexpressionsdaten eine wichtige Rolle spielt. Mit graphentheoretischen Methoden konstruieren wir zunächst deterministisch Obermengen von Lösungen, die danach heuristisch ausgedünnt werden. Wir können zeigen, daß dieser neue Ansatz bisherige, vergleichbare z.T. deutlich überbietet. Seine prinzipielle Einfachheit läßt anwendungsbezogene Modifikationen leicht zu.Two important questions in drug design are the following: "How to compute the similarity of two molecules?" and "How to cluster molecules by similarity?" In the first part we describe two different approaches to compare molecules for 3D-similarity. The first algorithm just uses the 3D coordinates of the atoms as input. We show that this algorithm is able to detect similar activity or similar adverse reaction, even with a simple purely geometry based scoring function. Compared to previous simpler approaches more interesting hits are found. The connectivity structures of the molecular graphs are used by the second algorithm as additional input. This fully flexible approach -- conformers of the molecules are treated simultaneously -- may even find provably optimal solutions. Parameter settings for practically relevant instances allow running times that make it possible to even search large databases. The second part describes two methods to search a database of molecular structures. After analyzing the data with graph theoretical methods two algorithms for two different ranges of similarity are designed. Scanning the database for structures similar to a given query can be accelerated considerably. We use hierarchical methods and dominating set techniques. Finally we propose a new biclustering algorithm. Biclustering problems recently appeared mainly in the context of analysing gene expression data. Again graph theoretical methods are our main tools. In our model biclusters correspond to dense subgraphs of certain bipartite graphs. In a first phase the algorithm deterministically finds supersets of solution candidates. Thinning out these sets by heuristical methods leads to solutions. This new algorithm outperforms former comparable methods and its simple structure make it easy to customize it for practical applications

Co-generation of Ammonia and H2 from H2O Vapor and N2 Using a Membrane Electrode Assembly

The direct electrochemical synthesis of NH3 from nitrogen and water vapor without the use of a fossil carbon source is highly desired. This synthesis is a viable option to store energy and produce fertilizer precursors. Here, a new Pt-free membrane electrode assembly is presented. An electrochemical membrane reactor demonstrates the feasibility of co-generating NH3 and H2 directly from nitrogen and water vapor at ambient conditions. An unprecedented high NH3-specific current efficiency of up to 27.5% using Ti as cathodic catalyst is reported. The co-generation can be tuned by the balance of process parameters. © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinhei

A TESTING BATTERY ON BALANCE AND PERFORMANCE SYMMETRY FOR TEAM SPORTS – AN EXAMPLE FROM ICE HOCKEY

The purpose of this study was to develop and apply an injury and performance screening programme for team sports and exemplify this for ice hockey. A set of four tests including landing, jumping and turning was employed and performance and balance related symmetry was extracted from force plate data and velocity measures in a test group of 28 elite ice hockey players. In this team, certain exercises showed a reflection of individual injury history while players showed a high symmetry for single leg landing task. This may be an effect of the specific training this group of athletes had undergone prior to the tests. Currently, we are assessing other teams who followed different training programs and apply these tests as a longitudinal screening tool. While final results are still outstanding, the potential of this approach was discussed

The Kondo Box: A Magnetic Impurity in an Ultrasmall Metallic Grain

We study the Kondo effect generated by a single magnetic impurity embedded in an ultrasmall metallic grain, to be called a ``Kondo box''. We find that the Kondo resonance is strongly affected when the mean level spacing in the grain becomes larger than the Kondo temperature, in a way that depends on the parity of the number of electrons on the grain. We show that the single-electron tunneling conductance through such a grain features Kondo-induced Fano-type resonances of measurable size, with an anomalous dependence on temperature and level spacing.Comment: 4 Latex pages, 4 figures, submitted to Phys. Rev. Let

Warsaw Argumentation Week (Waw 2018) Organised by the Polish School of Argumentation and Our Colleagues from Germany and the UK, 6th-16th September 2018

In September 2018, the ArgDiaP association, along with colleagues from Germany and the UK, organised one of the longest and most interdisciplinary series of events ever dedicated to argumentation - Warsaw Argumentation Week, WAW 2018. The eleven-day ‘week’ featured a five day graduate school on computational and linguistic perspectives on argumentation (3rd SSA school); five workshops: on systems and algorithms for formal argumentation (2nd SAFA), argumentation in relation to society (1st ArgSoc), philosophical approaches to argumentation (1st ArgPhil), legal argumentation (2ndMET-ARG) and argumentation in rhetoric (1st MET-RhET); and two conferences: on computational models of argumentation (7th COMMA conference) and on argumentation and corpus linguistics (16th ArgDiaP conference). WAW hosted twelve tutorials and eight invited talks as well as welcoming over 130 participants. All the conferences and workshops publish pre- or post-proceedings in the top journals and book series in the field

Molecular analysis of the early interaction between the grapevine flower and Botrytis cinerea reveals that prompt activation of specific host pathways leads to fungus quiescence

Grape quality and yield can be impaired by bunch rot, caused by the necrotrophic fungus Botrytis cinerea. Infection often occurs at flowering, and the pathogen stays quiescent until fruit maturity. Here, we report a molecular analysis of the early interaction between B. cinerea and Vitis vinifera flowers, using a controlled infection system, confocal microscopy and integrated transcriptomic and metabolic analysis of the host and the pathogen. Flowers from fruiting cuttings of the cultivar Pinot Noir were infected with green fluorescent protein (GFP)-labelled B. cinerea and studied at 24 and 96 hours post-inoculation (h.p.i.). We observed that penetration of the epidermis by B. cinerea coincided with increased expression of genes encoding cell-wall-degrading enzymes, phytotoxins and proteases. Grapevine responded with a rapid defence reaction involving 1193 genes associated with the accumulation of antimicrobial proteins, polyphenols, reactive oxygen species and cell wall reinforcement. At 96 h.p.i., the reaction appears largely diminished both in the host and in the pathogen. Our data indicate that the defence responses of the grapevine flower collectively are able to restrict invasive fungal growth into the underlying tissues, thereby forcing the fungus to enter quiescence until the conditions become more favourable to resume pathogenic development

Deconvolving the pre-Himalayan Indian margin – tales of crustal growth and destruction

The metamorphic core of the Himalaya is composed of Indian cratonic rocks with two distinct crustal affinities that are defined by radiogenic isotopic geochemistry and detrital zircon age spectra. One is derived predominantly from the Paleoproterozoic and Archean rocks of the Indian cratonic interior and is either represented as metamorphosed sedimentary rocks of the Lesser Himalayan Sequence (LHS) or as slices of the distal cratonic margin. The other is the Greater Himalayan Sequence (GHS) whose provenance is less clear and has an enigmatic affinity. Here we present new detrital zircon Hf analyses from LHS and GHS samples spanning over 1000 kilometers along the orogen that respectively show a striking similarity in age spectra and Hf isotope ratios. Within the GHS, the zircon age populations at 2800–2500 Ma, 1800 Ma, 1000 Ma and 500 Ma can be ascribed to various Gondwanan source regions; however, a pervasive and dominant Tonian age population (∼860–800 Ma) with a variably enriched radiogenic Hf isotope signature (εHf = 10 to -20) has not been identified from Gondwana or peripheral accreted terranes. We suggest this detrital zircon age population was derived from a crustal province that was subsequently removed by tectonic erosion. Substantial geologic evidence exists from previous studies across the Himalaya supporting the Cambro-Ordovician Kurgiakh Orogeny. We propose the tectonic removal of Tonian lithosphere occurred prior to or during this Cambro-Ordovician episode of orogenesis in a similar scenario as is seen in the modern Andean and Indonesian orogenies, wherein tectonic processes have removed significant portions of the continental lithosphere in a relatively short amount of time. This model described herein of the pre-Himalayan northern margin of Greater India highlights the paucity of the geologic record associated with the growth of continental crust. Although the continental crust is the archive of Earth history, it is vital to recognize the ways in which preservation bias and destruction of continental crust informs geologic models

Kondo effect in coupled quantum dots: a Non-crossing approximation study

The out-of-equilibrium transport properties of a double quantum dot system in the Kondo regime are studied theoretically by means of a two-impurity Anderson Hamiltonian with inter-impurity hopping. The Hamiltonian, formulated in slave-boson language, is solved by means of a generalization of the non-crossing approximation (NCA) to the present problem. We provide benchmark calculations of the predictions of the NCA for the linear and nonlinear transport properties of coupled quantum dots in the Kondo regime. We give a series of predictions that can be observed experimentally in linear and nonlinear transport measurements through coupled quantum dots. Importantly, it is demonstrated that measurements of the differential conductance ${\cal G}=dI/dV$, for the appropriate values of voltages and inter-dot tunneling couplings, can give a direct observation of the coherent superposition between the many-body Kondo states of each dot. This coherence can be also detected in the linear transport through the system: the curve linear conductance vs temperature is non-monotonic, with a maximum at a temperature $T^*$ characterizing quantum coherence between both Kondo states.Comment: 20 pages, 17 figure

Daratumumab in first-line treatment of patients with light chain amyloidosis and Mayo stage IIIb improves treatment response and overall survival

Treatment of patients with Mayo stage IIIb light chain (AL) amyloidosis is still challenging, and the prognosis remains very poor. Mayo stage IIIb patients were excluded from the pivotal trial leading to the approval of daratumumab in combination with bortezomib-cyclophosphamide-dexamethasone. This retrospective, multicenter study evaluates the addition of daratumumab to first-line therapy in patients with newly diagnosed stage IIIb AL amyloidosis. In total, data from 119 consecutive patients were analyzed, 27 patients received an upfront treatment including daratumumab, 63 a bortezomibbased regimen without daratumumab, eight received therapies other than daratumumab or bortezomib and 21 pretreated patients or deceased prior to treatment were excluded. In the daratumumab group, median overall survival was not reached after a median follow-up time of 14.5 months, while it was significantly worse in the bortezomib- and the otherwise treated group (6.6 and 2.2 months, respectively) (P=0.002). Overall hematologic response rate at 2 and 6 months was better in the daratumumab group compared to the bortezomib group (59% vs. 37%, P=0.12, 67% vs. 41%, P=0.04, respectively). Landmark survival analyses revealed a significantly improved overall survival in patients with partial hematologic response or better, compared to non-responders. Cardiac response at 6 months was 46%, 21%, 0% in the daratumumab-, bortezomib- and otherwise treated groups, respectively (P=0.04). A landmark survival analysis revealed markedly improved overall survival in patients with cardiac very good partial response vs. cardiac non-responders (P=0.002). This study demonstrates for the first time the superiority of an upfront treatment with daratumumab over standard-of-care in stage IIIb AL amyloidosis