A Chiral, Dendralenic C–H Acid

We report the synthesis of a chiral dendralenic C–H acid, which contains three unsubstituted binaphthyl moieties. This motif and an achiral variant can be made from their corresponding bis(sulfone) precursors in one step. Despite the presence of the enantiopure binaphthyl backbone, the newly designed chiral C–H acid showed only poor enantioselectivity in a Mukaiyama aldol reaction. First attempts toward the synthesis of 3,3′-hexasubstituted binaphthyl-based dendralenic acids are also reported

A Chiral Sulfoxide-Based C–H Acid

We report the design and synthesis of a strong, chiral, enantiopure sulfoxide-based C–H acid. Single crystal X-ray analysis confirms the proposed structure and its absolute configuration. The new motif shows a high acidity and activity in Brønsted and Lewis acid catalyzed transformations. So far,only little to no enantioselectivities were achieved

1,1,3,3-Tetratriflylpropene (TTP): A Strong, Allylic C–H Acid for Brønsted and Lewis Acid Catalysis

Tetratrifylpropene (TTP) has been developed as a highly acidic, allylic C–H acid for Brønsted and Lewis acid catalysis. It can readily be obtained in two steps and consistently shows exceptional catalytic activities for Mukaiyama aldol, Hosomi–Sakurai, and Friedel–Crafts acylation reactions. X-ray analyses of TTP and its salts confirm its designed, allylic structure, in which the negative charge is delocalized over four triflyl groups. NMR experiments, acidity measurements, and theoretical investigations provide further insights to rationalize the remarkable reactivity of TTP

Characterization of a naturally-occurring p27 mutation predisposing to multiple endocrine tumors

<p>Abstract</p> <p>Background</p> <p>p27Kip1 (p27) is an important negative regulator of the cell cycle and a putative tumor suppressor. The finding that a spontaneous germline frameshift mutation in <it>Cdkn1b </it>(encoding p27) causes the MENX multiple endocrine neoplasia syndrome in the rat provided the first evidence that <it>Cdkn1b </it>is a tumor susceptibility gene for endocrine tumors. Noteworthy, germline p27 mutations were also identified in human patients presenting with endocrine tumors. At present, it is not clear which features of p27 are crucial for this tissue-specific tumor predisposition in both rats and humans. It was shown that the MENX-associated <it>Cdkn1b </it>mutation causes reduced expression of the encoded protein, but the molecular mechanisms are unknown. To better understand the role of p27 in tumor predisposition and to characterize the MENX animal model at the molecular level, a prerequisite for future preclinical studies, we set out to assess the functional properties of the MENX-associated p27 mutant protein (named p27fs177) <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p><it>In vitro</it>, p27fs177 retains some properties of the wild-type p27 (p27wt) protein: it localizes to the nucleus; it interacts with cyclin-dependent kinases and, to lower extent, with cyclins. In contrast to p27wt, p27fs177 is highly unstable and rapidly degraded in every phase of the cell-cycle, including quiescence. It is in part degraded by Skp2-dependent proteasomal proteolysis, similarly to p27wt. Photobleaching studies showed reduced motility of p27fs177 in the nucleus compared to p27wt, suggesting that in this compartment p27fs177 is part of a multi-protein complex, likely together with the degradation machinery. Studies of primary rat newborn fibroblasts (RNF) established from normal and MENX-affected littermates confirmed the rapid degradation of p27fs177 <it>in vivo </it>which can be rescued by Bortezomib (proteasome inhibitor drug). Overexpression of the negative regulators microRNA-221/222 plays no role in regulating the amount of p27fs177 in RNFs and rat tissues.</p> <p>Conclusion</p> <p>Our findings show that reduced p27 levels, not newly acquired properties, trigger tumor formation in rats, similarly to what has been observed in mice. The molecular characteristics of p27fs177 establish MENX as a useful preclinical model to evaluate compounds that inhibit p27 degradation for their efficacy against endocrine tumors.</p

DFB Quantum Cascade Laser Arrays

DFB quantum cascade laser (DFB-QCL) arrays operating between 8.7 and 9.4 mum are investigated for their performance characteristics-single-mode selection of the DFB grating, and variability in threshold, slope efficiency, and output power of different lasers in the array. Single-mode selection refers to the ability to choose a desired mode/frequency of laser emission with a DFB grating. We apply a theoretical framework developed for general DFB gratings to analyze DFB-QCL arrays. We calculate how the performance characteristics of DFB-QCLs are affected by the coupling strength kappaL of the grating, and the relative position of the mirror facets at the ends of the laser cavity with respect to the grating. We discuss how single-mode selection can be improved by design. Several DFB-QCL arrays are fabricated and their performance examined. We achieve desired improvements in single-mode selection, and we observe the predicted variability in the threshold, slope efficiency, and output power of the DFB-QCLs. As a demonstration of potential applications, the DFB-QCL arrays are used to perform infrared absorption spectroscopy with fluids.Engineering and Applied Science

Epilepsie und dissoziative Anfälle: Kommunikative Besonderheiten und ihre Implikationen für Diagnostik und Therapie

In unserem narrativen Review beschreiben wir die Besonderheiten der Interaktion von Patient:innen mit dissoziativen Anfällen. Wir zeigen, welches Potenzial in der Kenntnis dieser Besonderheiten liegt sowohl für die Differenzialdiagnose von epileptischen und dissoziativen Anfällen als auch für den klinischen Gebrauch. Patient:innen mit epileptischen Anfällen wollen das Gespräch mit der Ärztin/dem Arzt nutzen, um möglichst viel von dem nachvollziehbar zu machen, was mit ihnen im Anfall passiert und wie sie versuchen mit den Anfällen sinnvoll umzugehen. Wir berichten davon, wie sich nach unserer Erfahrung die Kommunikation unterscheidet, wenn wir mit Patient:innen mit dissoziativen Anfällen sprechen: Sie berichten eher ohne Details und ohne das subjektive Erleben des Anfalls zu schildern. In ihren Beschreibungen wird meist deutlich, wie stark sie dem Geschehen ausgeliefert sind. Sie sind eher irritiert von den Nachfragen zum Erleben im Anfall und lenken das Gespräch in andere Richtungen. Damit die Gespräche mit Patient:innen, die von dissoziativen Anfällen betroffen sind, nicht ins Leere laufen, ist es wichtig, diese kommunikativen Besonderheiten zu kennen und Einsicht in ihre Bedeutung für Diagnose und Therapie zu haben. Wir machen konkrete Vorschläge, wie Gesprächsführende mit der eigenen Irritation und mit den Aussagen der Patient:innen so umgehen, dass beide Seiten zu einem tieferen Verständnis der Situation kommen. So kann schon das Erstgespräch den Beginn der therapeutischen Arbeit einleiten. Wenn Kinder und Jugendliche zur Abklärung von Anfallsereignissen vorgestellt werden, so treten die Unterschiede in der Darstellung meist noch deutlicher zutage, da sie weniger Erzählroutine haben und eine meist deutlich kürzere Krankengeschichte

Re-interpreting conventional interval estimates taking into account bias and extra-variation

BACKGROUND: The study design with the smallest bias for causal inference is a perfect randomized clinical trial. Since this design is often not feasible in epidemiologic studies, an important challenge is to model bias properly and take random and systematic variation properly into account. A value for a target parameter might be said to be "incompatible" with the data (under the model used) if the parameter's confidence interval excludes it. However, this "incompatibility" may be due to bias and/or extra-variation. DISCUSSION: We propose the following way of re-interpreting conventional results. Given a specified focal value for a target parameter (typically the null value, but possibly a non-null value like that representing a twofold risk), the difference between the focal value and the nearest boundary of the confidence interval for the parameter is calculated. This represents the maximum correction of the interval boundary, for bias and extra-variation, that would still leave the focal value outside the interval, so that the focal value remained "incompatible" with the data. We describe a short example application concerning a meta analysis of air versus pure oxygen resuscitation treatment in newborn infants. Some general guidelines are provided for how to assess the probability that the appropriate correction for a particular study would be greater than this maximum (e.g. using knowledge of the general effects of bias and extra-variation from published bias-adjusted results). SUMMARY: Although this approach does not yet provide a method, because the latter probability can not be objectively assessed, this paper aims to stimulate the re-interpretation of conventional confidence intervals, and more and better studies of the effects of different biases

Multi-Particle Collision Dynamics -- a Particle-Based Mesoscale Simulation Approach to the Hydrodynamics of Complex Fluids

In this review, we describe and analyze a mesoscale simulation method for fluid flow, which was introduced by Malevanets and Kapral in 1999, and is now called multi-particle collision dynamics (MPC) or stochastic rotation dynamics (SRD). The method consists of alternating streaming and collision steps in an ensemble of point particles. The multi-particle collisions are performed by grouping particles in collision cells, and mass, momentum, and energy are locally conserved. This simulation technique captures both full hydrodynamic interactions and thermal fluctuations. The first part of the review begins with a description of several widely used MPC algorithms and then discusses important features of the original SRD algorithm and frequently used variations. Two complementary approaches for deriving the hydrodynamic equations and evaluating the transport coefficients are reviewed. It is then shown how MPC algorithms can be generalized to model non-ideal fluids, and binary mixtures with a consolute point. The importance of angular-momentum conservation for systems like phase-separated liquids with different viscosities is discussed. The second part of the review describes a number of recent applications of MPC algorithms to study colloid and polymer dynamics, the behavior of vesicles and cells in hydrodynamic flows, and the dynamics of viscoelastic fluids

Lattice Boltzmann simulations of soft matter systems

This article concerns numerical simulations of the dynamics of particles immersed in a continuum solvent. As prototypical systems, we consider colloidal dispersions of spherical particles and solutions of uncharged polymers. After a brief explanation of the concept of hydrodynamic interactions, we give a general overview over the various simulation methods that have been developed to cope with the resulting computational problems. We then focus on the approach we have developed, which couples a system of particles to a lattice Boltzmann model representing the solvent degrees of freedom. The standard D3Q19 lattice Boltzmann model is derived and explained in depth, followed by a detailed discussion of complementary methods for the coupling of solvent and solute. Colloidal dispersions are best described in terms of extended particles with appropriate boundary conditions at the surfaces, while particles with internal degrees of freedom are easier to simulate as an arrangement of mass points with frictional coupling to the solvent. In both cases, particular care has been taken to simulate thermal fluctuations in a consistent way. The usefulness of this methodology is illustrated by studies from our own research, where the dynamics of colloidal and polymeric systems has been investigated in both equilibrium and nonequilibrium situations.Comment: Review article, submitted to Advances in Polymer Science. 16 figures, 76 page

A supervised adverse drug reaction signalling framework imitating Bradford Hill’s causality considerations

Big longitudinal observational medical data potentially hold a wealth of information and have been recognised as potential sources for gaining new drug safety knowledge. Unfortunately there are many complexities and underlying issues when analysing longitudinal observational data. Due to these complexities, existing methods for large-scale detection of negative side effects using observational data all tend to have issues distinguishing between association and causality. New methods that can better discriminate causal and non-causal relationships need to be developed to fully utilise the data. In this paper we propose using a set of causality considerations developed by the epidemiologist Bradford Hill as a basis for engineering features that enable the application of supervised learning for the problem of detecting negative side effects. The Bradford Hill considerations look at various perspectives of a drug and outcome relationship to determine whether it shows causal traits. We taught a classifier to find patterns within these perspectives and it learned to discriminate between association and causality. The novelty of this research is the combination of supervised learning and Bradford Hill’s causality considerations to automate the Bradford Hill’s causality assessment. We evaluated the framework on a drug safety gold standard known as the observational medical outcomes partnership’s non-specified association reference set. The methodology obtained excellent discrimination ability with area under the curves ranging between 0.792 and 0.940 (existing method optimal: 0.73) and a mean average precision of 0.640 (existing method optimal: 0.141). The proposed features can be calculated efficiently and be readily updated, making the framework suitable for big observational data