Scattered high-energy synchrotron radiation at the KARA visible-light diagnostic beamline.

To characterize an electron beam, visible synchrotron light is often used and dedicated beamlines at synchrotron sources are becoming a more common feature as instruments and methods for the diagnostics are, along with the accelerators, further developed. At KARA (Karlsruhe Research Accelerator), such a beamline exists and is based on a typical infrared/visible-light configuration. From experience at such beamlines no significant radiation was expected (dose rates larger than 0.5 µSv h-1). This was found not to be the case and a higher dose was measured which fortunately could be shielded to an acceptable level with 0.3 mm of aluminium foil or 2.0 mm of Pyrex glass. The presence of this radiation led to further investigation by both experiment and calculation. A custom setup using a silicon drift detector for energy-dispersive spectroscopy (Ketek GmbH) and attenuation experiments showed the radiation to be predominantly copper K-shell fluorescence and is confirmed by calculation. The measurement of secondary radiation from scattering of synchrotron and other radiation, and its calculation, is important for radiation protection, and, although a lot of experience exists and methods for radiation protection are well established, changes in machine, beamlines and experiments mean a constant appraisal is needed.

Opportunities and challenges of applying advanced X-ray spectroscopy to actinide and lanthanide N-donor ligand systems.

N-donor ligands such as n-Pr-BTP [2,6-bis(5,6-dipropyl-1,2,4-triazin-3-yl)pyridine] preferentially bind trivalent actinides (An3+) over trivalent lanthanides (Ln3+) in liquid-liquid separation. However, the chemical and physical processes responsible for this selectivity are not yet well understood. Here, an explorative comparative X-ray spectroscopy and computational (L3-edge) study for the An/Ln L3-edge and the N K-edge of [An/Ln(n-Pr-BTP)3](NO3)3, [Ln(n-Pr-BTP)3](CF3SO3)3 and [Ln(n-Pr-BTP)3](ClO4)3 complexes is presented. High-resolution X-ray absorption near-edge structure (HR-XANES) L3-edge data reveal additional features in the pre- and post-edge range of the spectra that are investigated using the quantum chemical codes FEFF and FDMNES. X-ray Raman spectroscopy studies demonstrate the applicability of this novel technique for investigations of liquid samples of partitioning systems at the N K-edge.

X-SPEC: a 70†eV to 15†keV undulator beamline for X-ray and electron spectroscopies.

X-SPEC is a high-flux spectroscopy beamline at the KIT (Karlsruhe Institute of Technology) Synchrotron for electron and X-ray spectroscopy featuring a wide photon energy range. The beamline is equipped with a permanent magnet undulator with two magnetic structures of different period lengths, a focusing variable-line-space plane-grating monochromator, a double-crystal monochromator and three Kirkpatrick-Baez mirror pairs. By selectively moving these elements in or out of the beam, X-SPEC is capable of covering an energy range from 70 eV up to 15 keV. The flux of the beamline is maximized by optimizing the magnetic design of the undulator, minimizing the number of optical elements and optimizing their parameters. The beam can be focused into two experimental stations while maintaining the same spot position throughout the entire energy range. The first experimental station is optimized for measuring solid samples under ultra-high-vacuum conditions, while the second experimental station allows in situ and operando studies under ambient conditions. Measurement techniques include X-ray absorption spectroscopy (XAS), extended X-ray absorption fine structure (EXAFS), photoelectron spectroscopy (PES) and hard X-ray PES (HAXPES), as well as X-ray emission spectroscopy (XES) and resonant inelastic X-ray scattering (RIXS).

On-surface condensation of low-dimensional benzotriazole-copper assemblies.

The reactivity of benzotriazole with copper on a gold surface has been studied by a combination of surface sensitive methods with support from DFT (density functional theory) calculations. For some time benzotriazole has been known to enhance the corrosion resistance of copper at the monolayer level, although the exact mechanism is still a matter of discussion and disagreement in the literature. A single crystal Au(111) surface allows evaluation of the interaction of weakly physisorbed, intact benzotriazole molecules with copper atoms dosed to sub-monolayer amounts. These interactions have been characterised, in the temperature range ca. 300-650 K, by scanning tunnelling microscopy, high resolution electron energy loss spectroscopy and synchrotron-based X-ray photoemission spectroscopy and near-edge X-ray absorption fine structure studies. Supporting DFT calculations considered the stability of isolated, gas-phase, benzotriazole/Cu species and their corresponding spectroscopic signature at the N K absorption edge. In agreement with previous investigations, benzotriazole physisorbs on a clean Au(111) surface at room temperature forming a hydrogen-bonded network of flat-lying BTAH molecules, relatively weakly bonded to the underlying gold surface. However, in the presence of co-adsorbed copper atoms, proton removal from the molecules leads to species better described as BTA- interacting directly with Cu atoms. In these situations the molecules adopt a more upright orientation and Cu(BTA)2 and -[Cu(BTA)]n- species are formed, depending on temperature and coverage of the adsorbed species. These species are stable to relatively high temperatures, 550-600 K.

Is High-Intensity Functional Training (HIFT)/CrossFit Safe for Military Fitness Training?

High-intensity functional training (HIFT) is a promising fitness paradigm that gained popularity among military populations. Rather than biasing workouts toward maximizing fitness domains such as aerobic endurance, HIFT workouts are designed to promote general physical preparedness. HIFT programs have proliferated as a result of concerns about the relevance of traditional physical training (PT), which historically focused on aerobic condition via running. Other concerns about traditional PT include: (1) the relevance of service fitness tests given current combat demands, (2) the perception that military PT is geared toward passing service fitness tests, and (3) that training for combat requires more than just aerobic endurance. Despite its' popularity in the military, concerns have been raised about HIFT's injury potential, leading to some approaches being labeled as "extreme conditioning programs" by several military and civilian experts. Given HIFT programs' popularity in the military and concerns about injury, a review of data on HIFT injury potential is needed to inform military policy. The purpose of this review is to: (1) provide an overview of scientific methods used to appropriately compare injury rates among fitness activities and (2) evaluate scientific data regarding HIFT injury risk compared to traditional military PT and other accepted fitness activities.

In vivo and in situ synchrotron radiation-based µ-XRF reveals elemental distributions during the early attachment phase of barnacle larvae and juvenile barnacles.

Barnacles are able to establish stable surface contacts and adhere underwater. While the composition of adult barnacle cement has been intensively studied, far less is known about the composition of the cement of the settlement-stage cypris larva. The main challenge in studying the adhesives used by these larvae is the small quantity of material available for analysis, being on the order of nanograms. In this work, we applied, for the first time, synchrotron radiation-based µ-X-ray fluorescence analysis (SR-µ-XRF) for in vivo and in situ analysis of young barnacles and barnacle cyprids. To obtain biologically relevant information relating to the body tissues, adhesives, and shell of the organisms, an in situ sample environment was developed to allow direct microprobe investigation of hydrated specimens without pretreatment of the samples. In 8-day-old juvenile barnacles (Balanus improvisus), the junctions between the six plates forming the shell wall showed elevated concentrations of calcium, potassium, bromine, strontium, and manganese. Confocal measurements allowed elemental characterization of the adhesive interface of recently attached cyprids (Balanus amphitrite), and substantiated the accumulation of bromine both at the point of initial attachment as well as within the cyprid carapace. In situ measurements of the cyprid cement established the presence of bromine, chlorine, iodine, sulfur, copper, iron, zinc, selenium, and nickel for both species. The previously unrecognized presence of bromine, iron, and selenium in the cyprid permanent adhesive will hopefully inspire further biochemical investigations of the function of these substances.

Labile or stable: can homoleptic and heteroleptic PyrPHOS-copper complexes be processed from solution?

Luminescent Cu(I) complexes are interesting candidates as dopants in organic light-emitting diodes (OLEDs). However, open questions remain regarding the stability of such complexes in solution and therefore their suitability for solution processing. Since the emission behavior of Cu(I) emitters often drastically differs between bulk and thin film samples, it cannot be excluded that changes such as partial decomposition or formation of alternative emitting compounds upon processing are responsible. In this study, we present three particularly interesting candidates of the recently established copper-halide-(diphenylphosphino)pyridine derivatives (PyrPHOS) family that do not show such changes. We compare single crystals, amorphous bulk samples, and neat thin films in order to verify whether the material remains stable upon processing. Solid-state nuclear magnetic resonance (MAS (31)P NMR) was used to investigate the electronic environment of the phosphorus atoms, and X-ray absorption spectroscopy at the Cu K edge provides insight into the local electronic and geometrical environment of the copper(I) metal centers of the samples. Our results suggest that--unlike other copper(I) complexes--the copper-halide-PyrPHOS clusters are significantly more stable upon processing and retain their initial structure upon quick precipitation as well as thin film processing.

X-ray absorption near edge structure spectroscopy to resolve the in vivo chemistry of the redox-active indazolium trans-[Tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019).

Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (1, KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (2, KP1339) are promising redox-active anticancer drug candidates that were investigated with X-ray absorption near edge structure spectroscopy. The analysis was based on the concept of the coordination charge and ruthenium model compounds representing possible coordinations and oxidation states in vivo. 1 was investigated in citrate saline buffer (pH 3.5) and in carbonate buffer (pH 7.4) at 37 °C for different time intervals. Interaction studies on 1 with glutathione in saline buffer and apo-transferrin in carbonate buffer were undertaken, and the coordination of 1 and 2 in tumor tissues was studied too. The most likely coordinations and oxidation states of the compound under the above mentioned conditions were assigned. Microprobe X-ray fluorescence of tumor thin sections showed the strong penetration of ruthenium into the tumor tissue, with the highest concentrations near blood vessels and in the edge regions of the tissue samples.

A desktop X-ray monochromator for synchrotron radiation based on refraction in mosaic prism lenses.

Focusing planar refractive mosaic lenses based on triangular prism microstructures have been used as an alternative approach for wide-bandpass monochromatization of high-energy X-rays. The strong energy dependence of the refractive index of the lens material leads to an analogous energy dependence of the focal length of the lens. The refractive mosaic lens, in comparison with the refractive lens of continuous parabolic profile, is characterized by a higher aperture because of reduced passive material. In combination with a well defined pinhole aperture in the focal plane, the transmittance of photons of an appropriate energy can be relatively high and photons of deviating energy can be efficiently suppressed. The photon energy can be tuned by translating the pinhole along the optical axis, and the bandwidth changed by selecting appropriate pinhole aperture and beam stop. This method of monochromatization was realised at the ANKA FLUO beamline using a mosaic lens together with a 20 µm pinhole and beam stop. An energy resolution of 2.0% at 16 keV has been achieved.

An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: the discovery of N-{(1S)-1-(3-fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]propyl}acetamide (PF-232798).

Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.

Design and synthesis of piperazinylpyrimidinones as novel selective 5-HT(2C) agonists.

This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.

SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.

NNZ-2566: a Gly-Pro-Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke.

The N-terminal cleavage product of human insulin-like growth factor-1 (IGF-1) in the brain is the tripeptide molecule Glypromate (Gly-Pro-Glu). Glypromate has demonstrated neuroprotective effects in numerous in vitro and in vivo models of brain injury and is in clinical trials for the prevention of cognitive impairment following cardiac surgery. NNZ-2566 is a structural analogue of Glypromate, resulting from alpha-methylation of the proline moiety, which has improved the elimination half-life and oral bioavailability over the parent peptide. In vivo, NNZ-2566 reduces injury size in rats subjected to focal stroke. An intravenous infusion of NNZ-2566 of 4 h duration (3-10 mg/kg/h), initiated 3 h after endothelin-induced middle-cerebral artery constriction, significantly reduced infarct area as assessed on day 5. Neuroprotective efficacy in the MCAO model was also observed following oral administration of the drug (30-60 mg/kg), when formulated as a microemulsion. In vitro, NNZ-2566 significantly attenuates apoptotic cell death in primary striatal cultures, suggesting attenuation of apoptosis is one mechanism of action underlying its neuroprotective effects. NNZ-2566 is currently in clinical trials for the treatment of cognitive deficits following traumatic brain injury, and these data further support the development of the drug as a neuroprotective agent for acute brain injury.

Inhaled adenosine A(2A) receptor agonists for the treatment of chronic obstructive pulmonary disease.

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.

Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route.

This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.