Constraints on dark matter annihilation from M87

As the largest mass concentrations in the local Universe, nearby clusters of galaxies and their central galaxies are prime targets in searching for indirect signatures of dark matter annihilation (DMA). We seek to constrain the dark matter annihilation emission component from multi-frequency observations of the central galaxy of the Virgo cluster. The annihilation emission component is modeled by the prompt and inverse-Compton gamma rays from the hadronization of annihilation products from generic weakly interacting dark matter particles. This component is fitted to the excess of the observed data above the spectral energy distribution (SED) of the jet in M87, described with a best-fit synchrotron-self-Compton (SSC) spectrum. While this result is not sufficiently significant to claim a detection, we emphasize that a dark matter “double hump signature” can be used to unambiguously discriminate the dark matter emission component from the variable jet-related emission of M87 in future, more extended observation campaigns.     

Multi-dimensional,mechanical stimulation of cartilage implants

In biomedical engineering, it is a common practice to replace injured cartilage by implants, which are seeded with human cartilage cells. Before implanting, the implants are cultivated and usually stimulated electrically or mechanically in a bioreactor to initiate cell multiplication and oriented cell growth. A new experimental set-up is developed leading to the possibility of stimulating such implants in a multi-dimensional, physiologically consistent way. In cooperation with the University Medical Centre Aachen, a human knee simulator is developed. Cell-seeded implants are placed in a recreated human environment and stimulated with several load cycles of reproduced walking. After the cultivation period, the implanted material is removed and biologically and mechanically evaluated. The quality of the implanted material as well as the influence of the body-conformable load on the material is studied. To understand the correlation between tissue remodelling and mechanical load history, the load and movement scenario is also numerically investigated. For this reason, the experiment is transferred to a geometrically realistic FE model of a human knee. As a first approach, an elastic material model is used. The aim is to have a predictive FE model with an optimal trade-off between accuracy and efficiency using an appropriate material formulation. The results will be compared to experimental data. (© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Development and validation of two LC-MS/MS methods for the detection and quantification of amphetamines, designer amphetamines, benzoylecgonine, benzodiazepines, opiates, and opioids in urine using turbulent flow chromatography

In the context of driving ability diagnostics in Germany, administrative cutoffs for various drugs and pharmaceuticals in urine have been established. Two liquid chromatography–tandem mass spectrometry methods for simultaneous detection and quantification of amphetamines, designer amphetamines, benzoylecgonine, benzodiazepines, opiates, and opioids in urine were developed and validated. A 500-μL aliquot of urine was diluted and fortified with an internal standard solution. After enzymatic cleavage, online extraction was performed by an ion-exchange/reversed-phase turbulent flow column. Separation was achieved by using a reversed-phase column and gradient elution. For detection, a Thermo Fisher TSQ Quantum Ultra Accurate Mass tandem mass spectrometer with positive electrospray ionization was used, and the analytes were measured in multiple-reaction monitoring mode detecting two transitions per precursor ion. The total run time for both methods was about 15 min. Validation was performed according to the guidelines of the Society of Toxicological and Forensic Chemistry. The results of matrix effect determination were between 78 % and 116 %. The limits of detection and quantification for all drugs, except zopiclone, were less than10?ng/mL and less than 25 ng/mL, respectively. Calibration curves ranged from 25 to 200 ng/mL for amphetamines, designer amphetamines, and benzoylecgonine, from 25 to 250 ng/mL for benzodiazepines, from 12.5 to 100 ng/mL for morphine, codeine, and dihydrocodeine, and from 5 to 50 ng/mL for buprenorphine and norbuprenorphine. Intraday and interday precision values were lower than 15 %, and bias values within?±?15 % were achieved. Turbulent flow chromatography needs no laborious sample preparation, so the workup is less time-consuming compared with gas chromatography–mass spectrometry methods. The methods are suitable for quantification of multiple analytes at the cutoff concentrations required for driving ability diagnostics in Germany.     

Determination of pharmaceuticals, iodinated contrast media and musk fragrances in sludge by LC/tandem MS and GC/MS

Analytical methods have been developed that allow for the determination of antiphlogistics, lipid regulators, the antiepileptic carbamazepine, cytostatic agents, the psychiatric drug diazepam and iodinated contrast media (ICM) as well as two major polycyclic musk fragrances HHCB (galaxolide) and AHTN (tonalide) in activated and digested sludge. The procedures consist of ultrasonic solvent extraction (USE) using methanol/acetone or pressurized liquid extraction (PLE) using 100% methanol. Clean-up was performed with C18ec material and silica gel followed by LC tandem MS (electrospray or atmospheric pressure chemical ionization) detection for pharmaceuticals and iodinated contrast media as well as GC/MS in the SIM mode for musk fragrances. Absolute recoveries from spiked activated sludge in general ranged from 88+/-4 to 119+/-20% for ICM and were 78+/-15 and 87+/-10% for the AHTN and HHCB, respectively. For the pharmaceuticals, absolute recoveries in activated sludge ranged between 43 and 78%. Subsequently, compensation of losses was carried out by using surrogate standards (acidic pharmaceuticals: fenoprop, neutral pharmaceuticals: dihydro-carbamazepine, musk fragrances: AHTN-D3). With one exception the recoveries were also adequate in digested sludge ranging from 43% to 120%.     

FEW: A workflow tool for free energy calculations of ligand binding

In the later stages of drug design projects, accurately predicting relative binding affinities of chemically similar compounds to a biomolecular target is of utmost importance for making decisions based on the ranking of such compounds. So far, the extensive application of binding free energy approaches has been hampered by the complex and time‐consuming setup of such calculations. We introduce the free energy workflow (FEW) tool that facilitates setup and execution of binding free energy calculations with the AMBER suite for multiple ligands. FEW allows performing free energy calculations according to the implicit solvent molecular mechanics (MM‐PB(GB)SA), the linear interaction energy, and the thermodynamic integration approaches. We describe the tool's architecture and functionality and demonstrate in a show case study on Factor Xa inhibitors that the time needed for the preparation and analysis of free energy calculations is considerably reduced with FEW compared to a fully manual procedure. © 2013 Wiley Periodicals, Inc.     

Study of the Drying Behavior of Poly(vinyl alcohol) Aqueous Solution

This paper deals with the drying behavior of poly(vinyl alcohol) aqueous solution containing an active substance and placed into a Petri box. The objective is to reduce the drying time while respecting some constraints. To succeed, it is important to understand complex mechanisms governing heat and mass transfers. During the drying, the product thickness shrinks and its properties evolve. Drying kinetics in convective and infrared radiation are presented.     

Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE‐1 and GSK‐3β Inhibitors

Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer′s disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6‐amino‐4‐phenyl‐3,4‐dihydro‐1,3,5‐triazin‐2(1H)‐ones as the first class of molecules able to simultaneously modulate BACE‐1 and GSK‐3β. Notably, one triazinone showed well‐balanced in vitro potencies against the two enzymes (IC₅₀ of (18.03±0.01) μM and (14.67±0.78) μM for BACE‐1 and GSK‐3β, respectively). In cell‐based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD‐modifying potential.     

The dynamics of spatiotemporal modulations

The modulational instability of traveling waves is often thought to be a crucial point in the mechanism of transition to space-time disorder and turbulence. The aim of this paper is to study the effect of spatiotemporal modulations on some dynamics u(0)(x,t), which may occur as an instability process when a control parameter varies, for instance. We analyze the properties of the modulated dynamics of the form g(1)(x)g(2)(t)u(0)(x,t) compared to those of the reference dynamics u(0)(x,t), using operator theory. We show that, if the reference dynamics is invariant under some space-time symmetry in the sense of Ref. [J. Nonlinear Sci. 2, 183 (1992)], the modulation has the effect of either deforming this symmetry or breaking it, depending on whether the corresponding operator remains unitary or not. We also demonstrate that the smallest Euclidean space containing the modulated dynamics has a dimension smaller than or equal to the smallest Euclidean space containing u(0)(x,t). The previous results are then applied to the case of modulated uniformly traveling waves. While the spatiotemporal translation invariance of the wave never persists in the presence of a modulation, the existence of a spatiotemporal symmetry depends on the resonance of the Fourier sidebands due to the modulation. In case of nonresonance, a spatiotemporal symmetry exists and is explicitly determined. In this situation, the modulated wave and the carrier wave have the same spectrum (up to a normalization factor), the same entropy, and the spatial (resp., temporal) two-point correlation is deformed only by the spatial (resp., temporal) modulation. (c) 1995 American Institute of Physics.     

Spatiotemporal and statistical symmetries

The notion of symmetries, either statistical or deterministic, can be useful for the characterization of complex systems and their bifurcations. In this paper, we investigate the connection between the (microscopic) spatiotemporal symmetries of a space-time functionu(x, t), on the one hand, and the (macroscopic) symmetries of statistical quantities such as the spatial (resp. temporal) two-point correlations and the spatial (resp. temporal) average, on the other hand. We show, how, under certain conditions, these symmetries are related to the symmetries of the orbits described byu(x, t) in the characteristic (phase) spaces. We also determine the largest group of spatiotemporal symmetries (in the sense introduced in our earlier work) satisfied by a given space-time functionu(x, t) and indicate how to extract the subgroups of point symmetries, namely those directly implemented on the space and time variables. Conversely, we determine all the functions invariant by a given space-time symmetry group. Finally, we illustrate all the previous points with specific examples.