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There is wide evidence for gender differences in competitive behavior and performance under pressure from experimental economics and single-sex professional sports. We analyze these differences in a sport with direct gender competition. Our unique data consist of over 500,000 observations from around 11,000 German ninepin bowling games of which around 15% are from mixed-gender leagues. Men perform better against women on average, but this is fully explained by differences in ability. Our results are robust to instrumenting for opposite gender using the sex composition of the opponent team. Gender differences in tight situations do not seem to play a role.

We present implicit visualization of 2D vector field topology, and show its utility for validating and guiding approaches for periodic orbit extraction. Instead of following the traditional approach by explicit extraction of the topological skeleton, we investigate its implicit visualization by approaches that label the regions that are separated by the skeleton. While such approaches perform well for gradient fields, they fail, in particular, to visualize periodic orbits. This motivates us to complement the label-based approach with a closely related distance-based metric. We show that our approach is able to reveal periodic orbits, also in configurations in which the state-of-the-art techniques for periodic orbit extraction fail, and demonstrate their utility for interactive extraction of all periodic orbits of a 2D vector field.

Simulations of cosmic evolution are a means to explain the formation of the universe as we see it today. The resulting data of such simulations comprise numerous physical quantities, which turns their analysis into a complex task. Here, we analyze such high-dimensional and time-varying particle data using various visualization techniques from the fields of particle visualization, flow visualization, volume visualization, and information visualization. Our approach employs specialized filters to extract and highlight the development of so-called active galactic nuclei and filament structures formed by the particles. Additionally, we calculate X-ray emission of the evolving structures in a pre-processing step to complement visual analysis. Our approach is integrated into a single visual analytics framework to allow for analysis of star formation at interactive frame rates. Finally, we lay out the methodological aspects of our work that led to success at the 2019 IEEE SciVis Contest.

The analysis of large multiphase flow simulation data poses an interesting and complex research question, which can be addressed with interactive visualization techniques, as well as semi-automated analysis processes. In this project, the focus lies on the investigation of forces governing droplet evolution. Therefore, our proposed methods visualize and allow the analysis of droplet deformation and breakup, droplet behavior and evolution, and droplet-internal flow. By deriving quantities for interface stretching and bending, we visualize and analyze the influence of surface tension force on breakup dynamics, and forces induced by Marangoni convection. Using machine learning to train a simple model for the prediction of physical droplet properties, we provide a visual analysis framework that can be used to analyze large simulation data. Computing droplet-local velocity fields where every droplet is observed separately in its own frame of reference, we create local, interpretable visualizations of flow within droplets, allowing for the investigation of the influence of flow dynamics on droplet evolution.

We present a data-driven visual analysis approach for the in-depth exploration of large numbers of droplets. Understanding droplet dynamics in sprays is of interest across many scientific fields for both simulation scientists and engineers. In this paper, we analyze large-scale direct numerical simulation datasets of the two-phase flow of non-Newtonian jets. Our interactive visual analysis approach comprises various dedicated exploration modalities that are supplemented by directly linking to ParaView. This hybrid setup supports a detailed investigation of droplets, both in the spatial domain and in terms of physical quantities. Considering a large variety of extracted physical quantities for each droplet enables investigating different aspects of interest in our data. To get an overview of different types of characteristic behaviors, we cluster massive numbers of droplets to analyze different types of occurring behaviors via domain-specific pre-aggregation, as well as different methods and parameters. Extraordinary temporal patterns are of high interest, especially to investigate edge cases and detect potential simulation issues. For this, we use a neural network-based approach to predict the development of these physical quantities and identify irregularly advected droplets., Projekt DEAL

The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.

The IEEE SciVis 2019 Contest targets the visual analysis of structure formation in the cosmic evolution of the universe from when the universe was five million years old up to now. In our submission, we analyze high-dimensional data to get an overview, then investigate the impact of Active Galactic Nuclei (AGNs) using various visualization techniques, for instance, an adapted filament filtering method for detailed analysis and particle flow in the vicinity of filaments. Based on feedback from domain scientists on these initial visualizations, we also analyzed X-ray emissions and star formation areas. The conversion of star-forming gas to stars and the resulting increasing molecular weight of the particles could be observed.

This paper analyses how both own appearance and the beauty composition of other candidates influence the chances of being selected for a job interview. Based on our lab experiment with randomised CVs, we confirm the role of appearance on job recruitment. Importantly, we show that appearance of other applicants with the same gender has significant incremental effects on top of the existing beauty premium. This “wingman effect” is more pronounced in high skilled occupations and mainly among male recruiters. We provide evidence that the “wingman effect” is not driven by system one decision making and predominantly affects choices at the margin.

Bislang mussen sich Patienten zur Vorbeugung von Thrombosen nach Operationen taglich Heparin spritzen oder mussen zur Schlaganfallprophylaxe bei Vorhofflimmern Vitamin-K-Antagonisten vom Cumarintyp einnehmen, die eine geringe therapeutische Breite haben und deren Dosierung regelmasig uberwacht werden muss. Um den Therapiestandard bei thromboembolischen Erkrankungen, wie tiefen Venenthrombosen, Lungenembolien und Hirnschlag bei Vorhofflimmern, zu verbessern, wurde in der letzten Dekade intensiv an neuen, oral wirksamen Thrombin- und Faktor-Xa-Inhibitoren geforscht. Einige dieser Verbindungen sind bereits auf dem Markt oder befinden sich in fortgeschrittener klinischer Entwicklung; sie konnten den Antikoagulantienmarkt revolutionieren.

The anticoagulant rivaroxaban is the first approved direct inhibitor of the serine protease factor Xa. This article presents the history of rivaroxaban's development, from its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development. The activated serine protease factor Xa is a promising target for new anticoagulants. After studies on naturally occurring factor Xa inhibitors indicated that such agents could be effective and safe, research focused on small-molecule direct inhibitors of factor Xa that might address the major clinical need for improved oral anticoagulants. In 2008, rivaroxaban (Xarelto; Bayer HealthCare) became the first such compound to be approved for clinical use. This article presents the history of rivaroxaban's development, from the structure–activity relationship studies that led to its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development.

Rivaroxaban is a direct inhibitor of factor Xa, a coagulation factor at a critical juncture in the blood coagulation pathway leading to thrombin generation and clot formation. It is selective for human factor Xa, for which it has >10 000-fold greater selectivity than for other biologically relevant serine proteases (half-maximal inhibitory concentration [IC 50 ], >20 μmol/L). Rivaroxaban inhibits factor Xa in a concentration-dependent manner (inhibitory constant [K i ], 0.4 nmol/L) and binds rapidly (kinetic association rate constant [k on ], 1.7×10 7 mol/L −1 s −1 ) and reversibly (kinetic dissociation rate constant [k off ], 5×10 −3 s −1 ). By inhibiting prothrombinase complex-bound (IC 50 , 2.1 nmol/L) and clot-associated factor Xa (IC 50 , 75 nmol/L), rivaroxaban reduces the thrombin burst during the propagation phase. In animal models of venous and arterial thrombosis, rivaroxaban showed dose-dependent antithrombotic activity. In healthy individuals, rivaroxaban was found to have predictable pharmacokinetics and pharmacodynamics across a 5- to 80-mg total daily dose range, inhibiting factor Xa activity and prolonging plasma clotting time. In phase III clinical trials, rivaroxaban regimens reduced rates of venous thromboembolism in patients after total hip or knee arthroplasty compared with enoxaparin regimens, without significant differences in rates of major bleeding, showing that rivaroxaban has a favorable benefit-to-risk profile.

Several clinical candidates have now emerged as a result of an intense search for orally available, antithrombotic factor Xa inhibitors. This review highlights the discovery of XareltoTM (Rivaroxaban) starting from an initial tetrahydrophthalimide screening hit. The major breakthrough was the finding that a chlorothiophene moiety can undergo an interaction in the S1 binding site thus leading to high potency combined with favorable oral bioavailability. The binding mode of this P1 moiety is discussed, and further non-basic S1 binders of this new type are reviewed.

Despite recent progress in antithrombotic therapy, there is still an unmet medical need for safe and orally available anticoagulants. The coagulation enzyme Factor Xa (FXa) is a particularly promising target, and recent efforts in this field have focused on the identification of small-molecule inhibitors with good oral bioavailability. We identified oxazolidinone derivatives as a new class of potent FXa inhibitors. Lead optimization led to the discovery of BAY 59-7939 (5), a highly potent and selective, direct FXa inhibitor with excellent in vivo antithrombotic activity. The X-ray crystal structure of 5 in complex with human FXa clarified the binding mode and the stringent requirements for high affinity. The interaction of the neutral ligand chlorothiophene in the S1 subsite allows for the combination of good oral bioavailability and high potency for nonbasic 5. Compound 5 is currently under clinical development for the prevention and treatment of thromboembolic diseases.

(E/Z)-2-(1-Allyloxycyclopropyl)-3-methoxyacrylonitrile (4-All) was designed and prepared in five steps (58% overall yield) from ethyl cyclopropylidenacetate as a valuable precursor to various 1-heteroarylcyclopropanols. Its condensation with amidines, guanidine, hydrazine, and methyl thioglycolate and subsequent removal of the allyl protecting group yields 1-heteroarylcyclopropanols such as 1-OH (36% over 2 steps), a very potent NO-independent stimulator of soluble guanylate cyclase. Direct cleavage of the allyl ether protecting group [by palladium-catalyzed substitution with lithium p-toluenesulfinate in AcOH or treatment with c-HexMgBr/Ti(OiPr)4] gives highly functionalized, sterically congested 1-heteroarylcyclopropanols 29, 30, and 34 with intact amino and ester groups.

The pyrazolopyridine stimulators of soluble guanylate cyclase BAY 41-2272 and 41-8543 were oxidised in rats and dogs at their 5-pyrimidinyl-cyclopropyl and -morpholino residue. These metabolites activate the soluble guanylate cyclase, induce vasoelaxation and thereby may contribute to the in vivo activity of BAY 41-2272 and BAY 41-8543.

BAY 41-8543 is a novel, highly specific and so far the most potent NO-independent stimulator of sGC. Here we report the effects of BAY 41-8543 on the isolated enzyme, endothelial cells, platelets, isolated vessels and Langendorff heart preparation. BAY 41-8543 stimulates the recombinant sGC concentration-dependently from 0.0001 microM to 100 microM up to 92-fold. In combination, BAY 41-8543 and NO have synergistic effects over a wide range of concentrations. Similar results are shown in implying that BAY 41-8543 stimulates the sGC directly and furthermore makes the enzyme more sensitive to its endogenous activator NO. In vitro, BAY 41-8543 is a potent relaxing agent of aortas, saphenous arteries, coronary arteries and veins with IC(50)-values in the nM range. In the rat heart Langendorff preparation, BAY 41-8543 potently reduces coronary perfusion pressure from 10(-9) to 10(-6) g ml(-1) without any effect on left ventricular pressure and heart rate. BAY 41-8543 is effective even under nitrate tolerance conditions proved by the same vasorelaxing effect on aortic rings taken either from normal or nitrate-tolerant rats. BAY 41-8543 is a potent inhibitor of collagen-mediated aggregation in washed human platelets (IC(50)=0.09 microM). In plasma, BAY 41-8543 inhibits collagen-mediated aggregation better than ADP-induced aggregation, but has no effect on the thrombin pathway. BAY 41-8543 is also a potent direct stimulator of the cyclic GMP/PKG/VASP pathway in platelets and synergizes with NO over a wide range of concentrations. These results suggest that BAY 41-8543 is on the one hand an invaluable tool for studying sGC signaling in vitro and on the other hand its unique profile may offer a novel approach for treating cardiovascular diseases.

SARs around a novel type of guanylate cyclase stimulator which act by a mechanism different from classical NO-donors are described. Several pyrazolopyridinylpyrimidines are shown to relax aortic rings and revealed a long-lasting blood pressure lowering effect in rats after oral application.

Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to cGMP2-4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the alpha1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases.

Enantiopure 4-aryl-1,4-dihydropyridines (DHPs) were oxidised with 2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate 1 to axially chiral 4-arylpyridines with excellent yields and high enantiomeric excesses. The results can be rationalised via a hydride abstraction of 1 at C-(4) of the DHP from the less sterically shielded ap -conformer.

The fate of recombinant DNA (rDNA) from genetically modified starter organisms in thermally treated fermented sausages (Kochsalami) was monitored by a polymerase chain reaction (PCR)-based estimation of the concentration of the rDNA. We defined an rDNA titre as the smallest volume of the DNA solution which still results in a detectable amplicon on PCR. In sausages a degradation of the rDNA was observed during storage. However, this did not proceed so far that rDNA was no longer detectable after 9 weeks of incubation. It was observed that the rDNA is strongly protected against the activity of DNase I in the meat matrix. To include the aspect of release of rDNA from genetically modified starter organisms into the meat matrix, Kochsalami-type sausage was produced with the aid of recombinant strains of Lactobacillus curvatus as starter organisms. It was shown that only a minute part of the rDNA contained in the starter organisms can be recovered from the meat matrix by extraction as "free" DNA. To recover the total rDNA, cell wall lytic enzymes were necessary. No significant effect on the detectability of the rDNA was observed on variation of the ecological factors prevailing during the production and storage of the sausages, such as the temperature of thermal treatment, pH and fat content. The concomitant presence of Staphylococcus aureus (>106 cfu/g) producing heat-stable nuclease did not affect the detection of the rDNA.

A heterologous internal standard, termed "mimic", was developed for the polymerase chain reaction (PCR)-based detection of Campylobacter jejuni and Campylobacter coli in food. Mimic was designed to contain a heterologous DNA fragment of plasmid pUC18, flanked by a primer binding site, identical to the bacterial target DNA. Application of mimic in the PCR permitted its co-amplification together with the bacterial DNA with similar efficiency. As the length of the amplified products differed, they were easily detectable by agarose gel electrophoresis. The presence or absence of the mimic PCR product was indicative of the efficacy of the PCR. The use of approximately 60 mimic molecules per reaction was optimal for determining the reliability of the diagnostic PCR assays without decreasing the detection limit. This system for the detection of the two species of Campylobacter was successfully applied in routine food surveillance.

The official PCR-based method for the detection of recombinant DNA from glyphosate-tolerant soya beans (GTS), laid down in the collection of methods according to Sect. 35 of the German Food Law, was investigated for applicability. As a model, wheat bread was produced with a 1% addition of baking aid consisting of 45% GTS flour. DNA extraction of samples drawn at various stages of the production process revealed that during the process a degradation of DNA took place, resulting in fragment sizes in bread of

We report X-ray crystal structures and NMR solution data of the unusual antiperiplanar conformation of 1,4-dihydro-5-cyano-2,6-dimethyl-4-biaryl-3-pyridine carboxylic acid esters with 3′-(4′-(1″- or 2″-naphthyl)pyridyl)- and 2′-(9″-anthracenyl) phenyl-residues as the biaryl moiety. This class might serve as a biological tool to identify which DHP-rotamer is responsible for the interaction with the biological receptor.

With samples of p-aramid fibers embedded in a DGEBA-based epoxy (T g = 110 °C), a series of experiments were conducted by the microbond method to determine the effect of testing rate and temperature on the fiber/matrix interfacial shear strength (IFSS). Microbond tests were conducted over three orders of magnitude of testing rate (0.1–100 mm min −1 ) and a range of temperatures (21–130 °C). While the general trend observed is that the IFSS decreased with increasing testing rate, the effect was more pronounced below T g than near or above T g , where the IFSS seemed to be insensitive to testing rate. We have analyzed these data by using an exponential breakdown model proposed by Zhurkov, enabling the determination of an activation energy for the failure process.

The ecto-nucleoside triphosphate diphosphohydrolase CD39 represents a promising antithrombotic therapeutic. It degrades adenosine 5'-diphosphate (ADP), a main platelet activating/recruiting agent. We hypothesized that delayed enrichment of CD39 on developing thrombi will allow for a low and safe systemic concentration and thus avoid bleeding. We use a single-chain antibody (scFv, specific for activated GPIIb/IIIa) for targeting CD39. This should allow delayed enrichment on growing thrombi but not on the initial sealing layer of platelets, which do not yet express activated GPIIb/IIIa. CD39 was recombinantly fused to an activated GPIIb/IIIa-specific scFv (targ-CD39) and a nonfunctional scFv (non-targ-CD39). Targ-CD39 was more effective at preventing ADP-induced platelet activation than non-targ-CD39. In a mouse carotid artery thrombosis model, non-targ-CD39, although protective against vessel occlusion, was associated with significant bleeding on tail transection. In contrast, targ-CD39 concentrated at the thrombus site; hence, a dose ∼10 times less of CD39 prevented vessel occlusion to a similar extent as high-dose non-targ-CD39, without prolonged bleeding time. An equimolar dose of non-targ-CD39 at this low concentration was ineffective at preventing vessel occlusion. Thus, delayed targeting of CD39 via scFv to activated platelets provides strong antithrombotic potency and yet prevents bleeding and thereby promotes CD39 toward clinical use.

The vasodilatory properties of nitric oxide (NO) have been utilized in pharmacotherapy for more than 130 years. Still today, NO-donor drugs are important in the management of cardiovascular diseases. However, inhaled NO or drugs releasing NO and organic nitrates are associated with noteworthy therapeutic shortcomings, including resistance to NO in some disease states, the development of tolerance during long-term treatment, and nonspecific effects, such as post-translational modification of proteins. The beneficial actions of NO are mediated by stimulation of soluble guanylate cyclase (sGC), a heme-containing enzyme which produces the intracellular signaling molecule cyclic guanosine monophosphate (cGMP). Recently, two classes of compounds have been discovered that amplify the function of sGC in a NO-independent manner, the so-called sGC stimulators and sGC activators. The most advanced drug, the sGC stimulator riociguat, has successfully undergone Phase III clinical trials for different forms of pulmonary hypertension.

Novel guanylate cyclase stimulators are disclosed. Design, synthesis, SAR, and pharmacological profile of the compounds are discussed.

To prevent thromboses after surgery, patients have until now had to inject themselves daily with heparin. For stroke prophylaxis in atrial fibrillation, patients take vitamin K antagonists of the coumarin type, which have a narrow therapeutic window and whose dosage must be regularly monitored. In order to improve the standard of therapy in thromboembolic diseases such as deep-vein thrombosis, pulmonary embolism, and stroke in atrial fibrillation, intensive research has been carried out over the last decade in the search for new, orally active thrombin and factor Xa inhibitors. A number of these compounds are already on the market or are in advanced clinical development; they could revolutionize the anticoagulant market.

2-(1,3-Dioxan-2-yl)-3-methyl-4- and 2-chloro-3,4-dimethyl-5-pivaloylaminopyridines were prepared and converted to 1,6- and 1,7-naphthyridines via regioselective lithiation of the ortho-methyl group, reaction with 2,2-diethoxyacetophenone and subsequent acid-catalyzed cyclization.

2-(1,3-Dioxan-2-yl)-3-methyl-4- and 2-chloro-3,4-dimethyl-5-pivaloylaminopyridines were prepared and converted to 1,6- and 1,7-naphthyridines via regioselective lithiation of the ortho-methyl group, reaction with 2,2-diethoxyacetophenone and subsequent acid-catalyzed cyclization.

To prevent thromboses after surgery, patients have until now had to inject themselves daily with heparin. For stroke prophylaxis in atrial fibrillation, patients take vitamin K antagonists of the coumarin type, which have a narrow therapeutic window and whose dosage must be regularly monitored. In order to improve the standard of therapy in thromboembolic diseases such as deep-vein thrombosis, pulmonary embolism, and stroke in atrial fibrillation, intensive research has been carried out over the last decade in the search for new, orally active thrombin and factor Xa inhibitors. A number of these compounds are already on the market or are in advanced clinical development; they could revolutionize the anticoagulant market.

We report X-ray crystal structures and NMR solution data of the unusual antiperiplanar conformation of 1,4-dihydro-5-cyano-2,6-dimethyl-4-biaryl-3-pyridine carboxylic acid esters with 3′-(4′-(1″- or 2″-naphthyl)pyridyl)- and 2′-(9″-anthracenyl) phenyl-residues as the biaryl moiety. This class might serve as a biological tool to identify which DHP-rotamer is responsible for the interaction with the biological receptor.

Enzyme-Catalyzed Reactions, 14. — Stereoselective Synthesis of Thiosugars from Achiral Starting Compounds by Enzymes A novel synthesis for thiosugars starting from achiral compounds by using enzymes as catalysts is described. 5-Thio-D-threo-2-pentulofuranose (4), for example, is prepared either by the RAMA (rabbit muscle aldolase)-catalyzed reaction of mercaptoacetaldehyde (1b) with dihydroxyacetonephosphate (2) or by the yeast transketolase-catalyzed reaction of 2-hydroxy-3-mercaptopanal (R/S)-6 with lithium 3-hydroxypyruvate (9). 6-Thio-D-arabino-2-hexulopyranose (8a) and 6-thio-L-xylo-2-hexulopyranose (8b) are obtained by the RAMA-catalyzed reaction of racemic (R/S)-6 with 2.

Several clinical candidates have now emerged as a result of an intense search for orally available, antithrombotic factor Xa inhibitors. This review highlights the discovery of XareltoTM (Rivaroxaban) starting from an initial tetrahydrophthalimide screening hit. The major breakthrough was the finding that a chlorothiophene moiety can undergo an interaction in the S1 binding site thus leading to high potency combined with favorable oral bioavailability. The binding mode of this P1 moiety is discussed, and further non-basic S1 binders of this new type are reviewed.

The title compounds 1, 2, and 3 are highly effective glycosidase inhibitors. They were synthesized from achiral starting compounds by enzyme-catalyzed CC coupling of dihydroxyacetone phosphate (1, 2) or hydroxypyruvate (3) with racemic 3-azido-2-hydroxypropanal via fructose, sorbose and xylulose derivatives and their subsequent enantioselective catalytic hydrogenation.