Truly On-The-Fly LTL Model Checking

We propose a novel algorithm for automata-based LTL model checking that interleaves the construction of the generalized B\"{u}chi automaton for the negation of the formula and the emptiness check. Our algorithm first converts the LTL formula into a linear weak alternating automaton; configurations of the alternating automaton correspond to the locations of a generalized B\"{u}chi automaton, and a variant of Tarjan's algorithm is used to decide the existence of an accepting run of the product of the transition system and the automaton. Because we avoid an explicit construction of the B\"{u}chi automaton, our approach can yield significant improvements in runtime and memory, for large LTL formulas. The algorithm has been implemented within the SPIN model checker, and we present experimental results for some benchmark examples

Substrate Pre-Folding and Water Molecule Organization Matters for Terpene Cyclase Catalyzed Conversion of Unnatural Substrates

Terpene cyclase enzymes have recently been challenged with terpene substrate derivatives to generate additional chemical complexity beyond to what is currently found in nature. Herein, molecular dynamics and biocatalysis are used to shed light on the flexibility and inherent limitation of a triterpene cyclase in converting unnatural substrates. Our studies suggest that populating binding modes which allows for concerted reaction pathways is a key element towards an expanded substrate scope and new chemistries displayed by terpene cyclases. Additionally, we show that the spatial organization of water, which is influenced by both the substrate architecture as well as the active site geometry, controls the product selectivity. This highlights that activity and selectivity displayed by terpene cyclases acting on unnatural substrates is particularly difficult to predict, since they depend on various parameters

Immunhistochemische und molekularbiologische Charakterisierung von nichtkleinzelligen Lungentumoren unter besonderer Berücksichtigung von Adenokarzinomen

Vor dem Hintergrund einer sich ändernden Klassifikation wurden Lungenkarzinome einer Zweitbegutachtung und einer Biopsiesimulation zugeführt, wobei sich Aktualisierungen ergaben. Immunhistochemisch zeigten sich keine eineindeutigen Befunde, die Kombination von Antikörpern aber einen deutlichen Trend. Dies unterstützte die Auffassung von großzelligen Karzinomen als entdifferenzierte, v.a. Adenokarzinome. Die therapeutisch relevante EGFR-Testung mittels IHC und FISH blieb ohne klaren Favoriten, die entsprechende ALK-Testung zeigte die FISH als Methode der Wahl, die IHC als Screening

Anti-Markovnikov alkene oxidation by metal-oxo–mediated enzyme catalysis

Catalytic anti-Markovnikov oxidation of alkene feedstocks could simplify synthetic routes to many important molecules and solve a long-standing challenge in chemistry. Here we report the engineering of a cytochrome P450 enzyme by directed evolution to catalyze metal-oxo–mediated anti-Markovnikov oxidation of styrenes with high efficiency. The enzyme uses dioxygen as the terminal oxidant and achieves selectivity for anti-Markovnikov oxidation over the kinetically favored alkene epoxidation by trapping high-energy intermediates and catalyzing an oxo transfer, including an enantioselective 1,2-hydride migration. The anti-Markovnikov oxygenase can be combined with other catalysts in synthetic metabolic pathways to access a variety of challenging anti-Markovnikov functionalization reactions

Chiral Alcohols from Alkenes and Water: Directed Evolution of a Styrene Hydratase

Enantioselective synthesis of chiral alcohols through asymmetric addition of water across an unactivated alkene is a highly sought-after transformation and a big challenge in catalysis. Herein we report the identification and directed evolution of a fatty acid hydratase from Marinitoga hydrogenitolerans for the highly enantioselective hydration of styrenes to yield chiral 1-arylethanols. While directed evolution for styrene hydration was performed in the presence of heptanoic acid to mimic fatty acid binding, the engineered enzyme displayed remarkable asymmetric styrene hydration activity in the absence of the small molecule activator. The evolved styrene hydratase provided access to chiral alcohols from simple alkenes and water with high enantioselectivity (>99 : 1 e.r.) and could be applied on a preparative scale

Substrate Pre-Folding and Water Molecule Organization Matters for Terpene Cyclase Catalyzed Conversion of Unnatural Substrates

Terpene cyclase enzymes have recently been challenged with terpene substrate derivatives to generate additional chemical complexity beyond to what is currently found in nature. Herein, molecular dynamics and biocatalysis are used to shed light on the flexibility and inherent limitation of a triterpene cyclase in converting unnatural substrates. Our studies suggest that populating binding modes which allows for concerted reaction pathways is a key element towards an expanded substrate scope and new chemistries displayed by terpene cyclases. Additionally, we show that the spatial organization of water, which is influenced by both the substrate architecture as well as the active site geometry, controls the product selectivity. This highlights that activity and selectivity displayed by terpene cyclases acting on unnatural substrates is particularly difficult to predict, since they depend on various parameters

Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake

Adenovirus type 2 (Ad2) binds the coxsackie B virus Ad receptor and is endocytosed upon activation of the αv integrin coreceptors. Here, we demonstrate that expression of dominant negative clathrin hub, eps15, or K44A-dynamin (dyn) inhibited Ad2 uptake into epithelial cells, indicating clathrin-dependent viral endocytosis. Surprisingly, Ad strongly stimulated the endocytic uptake of fluid phase tracers, coincident with virus internalization but without affecting receptor-mediated transferrin uptake. A large amount of the stimulated endocytic activity was macropinocytosis. Macropinocytosis depended on αv integrins, PKC, F-actin, and the amiloride-sensitive Na+/H+ exchanger, which are all required for Ad escape from endosomes and infection. Macropinocytosis stimulation was not a consequence of viral escape, since it occurred in K44A-dyn–expressing cells. Surprisingly, 30–50% of the endosomal contents were released into the cytosol of control and also K44A-dyn–expressing cells, and the number of fluid phase–positive endosomes dropped below the levels of noninfected cells, indicating macropinosomal lysis. The release of macropinosomal contents was Ad dose dependent, but the presence of Ad particles on macropinosomal membranes was not sufficient for contents release. We conclude that Ad signaling from the cell surface controls the induction of macropinosome formation and leakage, and this correlates with viral exit to the cytosol and infection

Measurements of scattering observables for the pdpd break-up reaction

High-precision measurements of the scattering observables such as cross sections and analyzing powers for the proton-deuteron elastic and break-up reactions have been performed at KVI in the last two decades and elsewhere to investigate various aspects of the three-nucleon force (3NF) effects simultaneously. In 2006 an experiment was performed to study these effects in $\vec{p}+d$ break-up reaction at 135 MeV with the detection system, Big Instrument for Nuclear polarization Analysis, BINA. BINA covers almost the entire kinematical phase space of the break-up reaction. The results are interpreted with the help of state-of-the-art Faddeev calculations and are partly presented in this contribution.Comment: Proceedings of 19th International IUPAP Conference on Few-Body Problems in Physics, Bonn University, 31.08 - 05.09.2009, Bonn, GERMAN

Measurement of Strange Quark Contributions to the Nucleon's Form Factors at Q^2=0.230 (GeV/c)^2

We report on a measurement of the parity-violating asymmetry in the scattering of longitudinally polarized electrons on unpolarized protons at a $Q^2$ of 0.230 (GeV/c)^2 and a scattering angle of \theta_e = 30^o - 40^o. Using a large acceptance fast PbF_2 calorimeter with a solid angle of \Delta\Omega = 0.62 sr the A4 experiment is the first parity violation experiment to count individual scattering events. The measured asymmetry is A_{phys} =(-5.44 +- 0.54_{stat} +- 0.27_{\rm sys}) 10^{-6}. The Standard Model expectation assuming no strangeness contributions to the vector form factors is $A_0=(-6.30 +- 0.43) 10^{-6}$. The difference is a direct measurement of the strangeness contribution to the vector form factors of the proton. The extracted value is G^s_E + 0.225 G^s_M = 0.039 +- 0.034 or F^s_1 + 0.130 F^s_2 = 0.032 +- 0.028.Comment: 5 pages, 3 figures, submitted to Phys. Rev. Letters on Dec 11, 200

Renal sympathetic denervation restores aortic distensibility in patients with resistant hypertension: data from a multi-center trial

Renal sympathetic denervation (RDN) is under investigation as a treatment option in patients with resistant hypertension (RH). Determinants of arterial compliance may, however, help to predict the BP response to therapy. Aortic distensibility (AD) is a well-established parameter of aortic stiffness and can reliably be obtained by CMR. This analysis sought to investigate the effects of RDN on AD and to assess the predictive value of pre-treatment AD for BP changes. We analyzed data of 65 patients with RH included in a multicenter trial. RDN was performed in all participants. A standardized CMR protocol was utilized at baseline and at 6-month follow-up. AD was determined as the change in cross-sectional aortic area per unit change in BP. Office BP decreased significantly from 173/92 ± 24/16 mmHg at baseline to 151/85 ± 24/17 mmHg (p < 0.001) 6 months after RDN. Maximum aortic areas increased from 604.7 ± 157.7 to 621.1 ± 157.3 mm2 (p = 0.011). AD improved significantly by 33% from 1.52 ± 0.82 to 2.02 ± 0.93 × 10-3 mmHg-1 (p < 0.001). Increase of AD at follow-up was significantly more pronounced in younger patients (p = 0.005) and responders to RDN (p = 0.002). Patients with high-baseline AD were significantly younger (61.4 ± 10.1 vs. 67.1 ± 8.4 years, p = 0.022). However, there was no significant correlation of baseline AD to response to RDN. AD is improved after RDN across all age groups. Importantly, these improvements appear to be unrelated to observed BP changes, suggesting that RDN may have direct effects on the central vasculature