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// Matthias M. Gaida 1 , Christine Mayer 2 , Ulrike Dapunt 3 , Sabine Stegmaier 4 , Peter Schirmacher 1 , Guido H. Wabnitz 4 and G. Maria Hansch 4 1 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany 2 Department for Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany 3 Department for Orthopedics, University Hospital Heidelberg, Heidelberg, Germany 4 Institute of Immunology, University Heidelberg, Heidelberg, Germany Correspondence to: Matthias M. Gaida, email: // Keywords : pancreatic cancer, bitter receptor, microbiome, ABCB1 Received : October 10, 2015 Accepted : January 24, 2016 Published : February 05, 2016 Abstract T2R38 belongs to the family of bitter receptors and was initially detected in cells of the oral cavity. We now describe expression of T2R38 in tumor cells in patients with pancreatic cancer and in tumor-derived cell lines. T2R38 is localized predominantly intracellular in association with lipid droplets, particularly with the lipid droplet membrane. The receptor can be activated by the bona fide ligand for T2R38, phenylthiourea (PTU), and by N-acetyl-dodecanoyl homoserine (AHL-12), a quorum sensing molecule of Pseudomonas aeruginosa , the latter is the only known natural ligand for T2R38. In response to PTU or AHL-12, key transcription factors are activated including phosphorylation of the MAP kinases p38 and ERK1/2, and upregulation of NFATc1. Moreover, we found increased expression of the multi-drug resistance protein 1 (also known as ABCB1), a transmembrane transporter molecule, participating in shuttling of a plethora of drugs, such as chemotherapeutics or antibiotics. In conclusion, our data indicate a new, additional function of the taste receptor T2R38 beyond sensing “bitter”. Moreover, because T2R38 can be stimulated by a bacteria-derived signaling molecule the receptor could link microbiota and cancer.

Abdominal aortic aneurysm (AAA) is heavily infiltrated with leukocytes, expressing the DNA sensor absent in melanoma 2 (AIM2) and other inflammasome components. Using multicolour flow cytometry, we here compared the expression of the inflammasome components AIM2, NLRP3, and ASC in different peripheral immune cells derived from AAA patients with those from non-AAA patients in a case–control study. In parallel, peripheral blood mononuclear cells (PBMC) of AAA patients and controls were stimulated in vitro with poly-dA:dT or lipopolysaccharide (LPS) to analyze inflammasome activation. AIM2 expression was significantly increased in peripheral granulocytes (P = 0.026), monocytes (P = 0.007), B lymphocytes (P

Silicon crystalline samples were exposed to intense single pulses of XUV radiation ( λ =13.5 nm) what lead to melting and ablation of the surface material. The deformation field around craters along the whole thickness of silicon wafers was observed by means of the synchrotron transmission section topography using the beam perpendicular to the surface of the sample. The geometrical shape and depth extension around craters was evaluated based on numerous, dense series of section topographs spaced by 10 µm. In the topographs we observed the direct image connected with the boundary of the crater associated with some deformation of the Kato fringes. The evaluated depth extension, different for individual craters, was in the range of 30–100 µm. The depth values were confirmed also by evaluations based on the Bragg case section topographs. It was possible to reproduce the contrast of the craters in transmission section topographs by numerical simulation based on integration of the Takagi–Taupin equations. The damage of the crystal defects connected with craters was approximated as droplet-like inclusions.

An important problem in the experiments performed with the intense fourth generation X-ray sources is the damages of the examined samples caused by the high energy impact. The effect introduced by the beam from the FLASH source in crystalline silicon samples was studied through synchrotron white beam projection and section topography, enabling the evaluation of the strain field associated with the damages. The topographs indicated the existence of deformed field of cylindrical symmetry providing the dark contrast. It was also shown that some of the Bragg-case section images of spots in silicon correspond well to the simulated images of rod-like inclusions.

We investigated tolerability and efficacy of ezetimibe treatment (10 mg/d) in 25 heart allograft recipients already on stable statin therapy. Total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglycerides (TG), immunosuppressant drug levels, laboratory and clinical parameters were assessed before, four months and one yr after initiation of ezetimibe treatment. Mean equivalent statin dose was 53.5 +/- 12.3 mg of pravastatin, remaining unchanged throughout the study period. Ezetimibe was generally well tolerated, only two patients (8%) discontinued ezetimibe due to stomach pain or headache. Mean TC decreased from 231.8 +/- 6.4 mg/dL before therapy to 202.2 +/- 8.8 mg/dL after four months and 192.9 +/- 7.0 mg/dL after one yr (p < 0.001). Mean LDL-C decreased from 143.1 +/- 5.4 mg/dL to 121.4 +/- 7.9 mg/dL (month 4; p < 0.05) and 107.1 +/- 5.6 mg/dL (one yr; p < 0.001). TG decreased from 182 +/- 14.3 mg/dL to 173.3 +/- 17.5 mg/dL after one yr (p < 0.05), whereas HDL-C was unchanged. Initial LDL-C and cardiac diagnosis before transplantation were identified as predictors of absolute LDL-C reduction. Immunosuppressant drug doses and blood concentrations were unchanged as well as other laboratory and clinical parameters. Ezetimibe appears safe and effective for further reduction of TC and LDL-C in heart allograft recipients already on stable statin therapy. Extent of pre-treatment LDL-C and cardiac disorder prior to transplantation appear to correlate with the efficacy of ezetimibe therapy.

We review development of multimillijoule X-ray lasers and of applications of these new laboratory sources carried out recently at the PALS facility. A backbone of this development is the neon-like zinc laser providing saturated output at 21.2 nm, with up to 10 mJ of energy per pulse. This represents currently the most energetic soft X-ray laboratory source. Recent improvements in its operation include better control of the beam shape, and more complete understanding of the prepulse pumping. The laser at 21.2 nm has been employed for a number of application experiments reviewed in this paper. They include transmission measurements of intense soft X-ray radiation, studies of fundamental processes of soft X-ray ablation, ablation micropatterning, feasibility study of soft X-ray Thomson scattering from dense plasmas, visualization of nanometric transient perturbation of optical surfaces, measurements of ablation rates of foils heated by IR pulses, and studies of 2D plasma hydrodynamics in the regime of sequen...

Summary Objectives : The study of neurovascular coupling greatly benefits from combined measurements of neuronal and vascular signals. Two-step signal processing is developed to extract parameters describing the coupling. Methods : Using a magnetometer in an extremely well shielded room a broadband magnetoencephalogram was simultaneously measured with time-resolved nearinfrared spectroscopy during a motor activity paradigm. The raw MEG and NIRS data were denoised separately using independent component analysis. Results : After averaging the resulting signals showed motor activity-related changes. The temporal correspondence between MEG and NIRS was assessed plotting a combined trajectory and calculating a crosscorrelation. Compared to the MEG signal, at movement onset the NIRS signal showed an onsetdelay in the range of seconds. Conclusions : Multi-variate signal pre-processing followed by temporal delay estimates demonstrated the extraction of neurovascular coupling parameters.

In this article, we describe the experimental station and procedures for investigating the interaction of short-wavelength free-electron lasers (FELs) pulses with solids. With the advent of these sources, a unique combination of radiation properties (including wavelength range from tens of nanometers down to sub-Angstroms, femtosecond pulse duration, and high pulse energy reaching milli-Joules level) creates new research possibilities for the systematic studies of radiation-induced structural changes in solids. However, the properties of the intense FEL radiation generate, apart from the new experimental opportunities, extreme demands on the experimental set-up (mostly in terms of radiation hardness of detectors and their saturation levels). Thus, radiation-induced phase transitions in solids, beyond the fundamental scientific interest, are of importance for the design of FEL beamlines and instruments which interact with the direct beam. In this report, we focus on the instrumentation and experimental techniques used in the recent studies performed at the FLASH facility in Hamburg.

We present results of damage studies performed at the Free-Electron LASer in Hamburg (FLASH) on amorphous carbon (a-C). The experiment was performed in the total external reflection geometry representing the working configuration of X-ray mirrors. The 177 eV photon laser beam was focused on a 40 nm thin layer of a-C coated on a silicon substrate. Single-shot damages were produced at two different grazing angles (4.3 degrees and 7.7 degrees) below the critical angle (0(c)=8 degrees) calculated for this photon energy. The corresponding damage fluence thresholds were determined to be 43.7 and 74 mJ/cm(2). No evidence of delamination or mechanical damages (cracks) under grazing angles on the 40 nm thin sample was observed. The results are compared with the results of the previous experiment done on thicker layers (900 nm) of a-C with the same experimental conditions [1]. (C) 2010 Elsevier B.V. All rights reserved.

We investigated the damage mechanism of MoN/SiN multilayer XUV optics under two extreme conditions: thermal annealing and irradiation with single shot intense XUV pulses from the free-electron laser facility in Hamburg - FLASH. The damage was studied "post-mortem" by means of X-ray diffraction, interference-polarizing optical microscopy, atomic force microscopy, and scanning transmission electron microscopy. Although the timescale of the damage processes and the damage threshold temperatures were different (in the case of annealing it was the dissociation temperature of Mo2N and in the case of XUV irradiation it was the melting temperature of MoN) the main damage mechanism is very similar: molecular dissociation and the formation of N-2, leading to bubbles inside the multilayer structure. (C) 2010 Optical Society of America

As liver fibrosis is the result of persistent necroinflammation in the liver, pro-inflammatory cytokines secreted in response to cell injury have a central role in the pathogenesis of liver fibrosis. We aimed to investigate the association of cytokine gene polymorphism and liver fibrosis among Chinese patients with chronic hepatitis B.Polymorphisms at interleukin-10 (IL-10-627, -1117), interleukin-1-beta (IL-1beta-511, -31, -3964), interleukin-1 receptor antagonist (IL-1RN), and tumor necrosis factor-alpha (TNF-alpha-308, -238) among Chinese chronic hepatitis B patients were determined. Severe liver fibrosis was defined as Ishak fibrosis score = 4 (of 6).Fifty-nine of 273 (22%) patients had severe fibrosis. The distribution of genotypes for IL-10-627 was CC (11%), CA (41%), and AA (48%). The CC genotype at IL-10-627 was protective against severe fibrosis (odds ratio (OR) 0.11; 95% CI 0.014-0.82; P = 0.032). After adjusted for baseline variables, the adjusted OR of CC genotypes at IL-10-627 for severe fibrosis was 0.063 (95% CI 0.06-0.64; P = 0.063). Other gene polymorphisms at IL-1beta, IL-1RN, TNF-alpha, and IL-10 had no significant association with severe fibrosis. Weak linkage disequilibrium was observed between IL-10-627 and IL-10-1117 with linkage disequilibrium coefficient of 0.12 (P < 0.001). The distribution of haplotypes of IL-10-1117 and IL-10-627 was A-A (69%), A-C (26%), and G-C (5%). High and intermediate IL-10 production (A-C and G-C) haplotypes were protective against severe fibrosis (OR 0.62; 95% CI 0.39-0.99; P = 0.046).High production genotype and haplotypes of IL-10 were associated with less severe liver fibrosis in chronic hepatitis B in Chinese.

We present a new technique for the characterization of non-Gaussian laser beams which cannot be described by an analytical formula. As a generalization of the beam spot area we apply and refine the definition of so called effective area (A(eff)) [1] in order to avoid using the full-width at half maximum (FWHM) parameter which is inappropriate for non-Gaussian beams. Furthermore, we demonstrate a practical utilization of our technique for a femtosecond soft X-ray free-electron laser. The ablative imprints in poly(methyl methacrylate) - PMMA and amorphous carbon (a-C) are used to characterize the spatial beam profile and to determine the effective area. Two procedures of the effective area determination are presented in this work. An F-scan method, newly developed in this paper, appears to be a good candidate for the spatial beam diagnostics applicable to lasers of various kinds. (C) 2010 Optical Society of America

A linear accelerator based source of coherent radiation, FLASH (Free-electron LASer in Hamburg) provides ultra-intense femtosecond radiation pulses at wavelengths from the extreme ultraviolet (XUV; lambda< 100nm) to the soft X-ray (SXR; lambda

Single shot radiation damage of bulk silicon induced by ultrashort XUV pulses was studied. The sample was chosen because it is broadly used in XUV optics and detectors where radiation damage is a key issue. It was irradiated at FLASH facility in Hamburg, which provides intense femtosecond pulses at 32.5 nm wavelength. The permanent structural modifications of the surfaces exposed to single shots were characterized by means of phase contrast optical microscopy and atomic force microscopy. Mechanisms of different, intensity dependent stages of the surface damage are described.

Irradiation experiments were conducted at Prague Asterix Laser System (PALS) with the Ne-like zinc soft x-ray laser (SXRL) at 21.2 nm (58.5 eV) delivering up to 4 mJ (~4 x 10 14 photons), 100-ps pulses in a narrowly collimated beam. The SXRL beam was focused using a 1 inch diameter off-axis parabolic mirror (f = 253 mm at 14 degrees) with a Mo:Si multilayer coating (R = 30% at 21 nm) placed 2825 mm from the SXRL. The diameter of the SXRL beam incident on the mirror was about 11 mm. Ablation experiments with a gradually attenuated beam were performed to determine the single-shot damage threshold of various materials. In this case, the sample was positioned at the tightest focus of the SXRL whose pulse energy was attenuated by aluminum filters of various thickness to adjust the fluence. Both the focal spot area and single-shot damage threshold were determined from the plot of damaged surface areas as a function of a pulse energy logarithm to dete. For PMMA, the focal spot area and the ablation threshold inferred from the data are S foc = (1172±230) μm 2 and F th = (1.25±0.4) J/cm 2 , respectively. Inorganic materials have thresholds significantly higher than organic polymers, e.g., amorphous and monocrystalline silicon gave values 2.5 J/cm 2 and 4.2 J/cm 2 , respectively. For prospective SASE FEL optical elements, the SiC coating is of great interest. Its damage threshold is of 20 J/cm 2 , i.e., slightly lower than that of monocrystalline silicon. The thresholds determined with the 100-ps pulses from plasma-based, quasi-steady state SXRL are significantly higher than the thresholds obtained for 20-fs pulses provided by the SXR freeelectron laser in Hamburg. There is a difference in PMMA thresholds of two orders of magnitude for these two sources.

We present results of damage studies conducted at the Free Electron LASer in Hamburg (FLASH) facility with 13.5 nm (91.8 eV) and 7 nm (177.1 eV) radiations. The laser beam was focused on a sample of 890-nm-thick amorphous carbon coated on a silicon wafer mimicking a x-ray mirror. The fluence threshold for graphitization was determined for different grazing angles above and below the critical angle. The observed angular dependence of Fth is explained by the variation in absorption depth and reflectivity. Moreover, the absorbed local dose needed for the phase transition leading to graphitization is shown to vary with the radiation wavelength.

Cardiac troponins provide excellent risk stratification in unstable angina (UA), but no reliable markers are available in troponin-negative patients. Beta2-integrin mediated T cell recruitment plays a pivotal role in coronary atherosclerotic plaque rupture. The present study investigates beta2-integrin activation on T cell subsets as a risk marker in UA. Functional activation (affinity/avidity) of beta2-integrins on T cells was measured using a flow cytometry-based whole blood assay in 87 patients with UA. Beta2-integrin activation was significantly higher in patients with severe coronary artery disease (sC) and myocardial infarction (MI) compared to patients with no/minimal coronary atherosclerosis (no/mC), irrespective of troponin status. Adjusted for cardiovascular risk factors, medication, left ventricular function, MI at enrollment and high sensitivity C-reactive protein (hsCRP), beta2-integrin activation was independently associated with incidence of revascularization, hospitalization and all major cardiovascular events during 9 months of follow-up after index investigation. The highest prognostic value of beta2-integrin activation was seen in troponin-and hsCRP-negative patients. Quantitative assessment of T cell beta2-integrin activation allows to identify high risk patients with UA and sC without established MI; furthermore, it is associated with incidence of future cardiovascular events independent of conventional risk factors (troponin, hsCRP).

X-ray free-electron lasers generate ultrashort and very intense x-ray radiation in the wavelength domain reaching from the VUV (100 nm and shorter) all the way to the hard x-ray domain (typically 0.1 nm). FEL radiation features extreme brilliance, ultrashort pulse duration, and high peak power. Superconducting accelerators provide furthermore the possibility to accelerate a large number of electron bunches during a single radio-frequency pulse. Likewise the total number of x-ray pulses available for the experiments is increased leading to a significantly higher average brilliance. FEL light sources, and those based on super-conducting accelerator technology, are therefore considered to provide a new quality of short wavelength radiation if compared to existing x-ray sources. The high intensity and the high repetition rate lead to new requirements for x-ray optics in terms of peak and average power. Values for peak and average power are presented in relation to the proposed realization of the photon beamlines at the European XFEL facility.

An advanced time integrated method has been developed for soft X-ray pulsed laser beam characterization. A technique based on poly (methyl methacrylate) - PMMA laser induced ablation has been used for beam investigations of soft X-ray laser sources like FLASH (Free-electron LASer in Hamburg; formerly known as VUV FEL and/or TTF2 FEL) and plasma-based Ne-like Zn laser performed at PALS (Prague Asterix Laser System). For the interaction experiments reported here, the FLASH system provided ultra-short pulses (~10-fs) of 21.7-nm radiation. The PMMA ablation was also induced by plasma-based Ne-like Zn soft X-ray laser pumped by NIR beams at the PALS facility. This quasi-steady-state (QSS) soft X-ray laser provides 100-ps pulses of 21.2-nm radiation, i.e. at a wavelength very close to that of FLASH but with about 5,000 times longer pulses. In both cases, the PMMA samples were irradiated by a single shot with a focused beam under normal incidence conditions. Characteristics of ablated craters obtained with AFM (Atomic Force Microscope) and Nomarski microscopes were utilized for profile reconstruction and diameter determination of the focused laser beams ablating the PMMA surface.

The first soft X-ray free-electron laser has recently been put into operation at DESY in Hamburg. Tunable soft X-ray coherent radiation can be generated at the FLASH (Free-electron LASer in Hamburg; formerly known as VUV FEL or TTF2 FEL). In the interaction experiments reported here, the laser system provided ~ 25-fs, ~ 10-μ J pulses of 32-nm radiation. We irradiated thin (500 nm) layers of poly (methyl methacrylate) – PMMA deposited on a silicon substrate by single, focused FLASH pulses. The pulse energy was adjusted using a gas attenuator.

We report on the generation of a focused X-ray laser beam with high energy density. The output of the 21.2 nm X-ray laser at PALS containing energy of 4 mJ was focused down to 20 x 40 μm2 elliptical spot. Samples of various solids were irradiated by the focused X-ray laser beam at various fluences. Feasibility of single-shot projection ablation lithography has been explored. First measurement of the XUV opacity of volumetrically heated thin foil by the focused X-ray laser has been performed.

We discuss the expected dependence of the probability transitions for 2-photon and 3-photon absorption in Helium gas on the spatial and temporal structure of the exciting radiation pulses. Regarding spatial structure, we assumed a Gaussian radial intensity distribution; we find, as expected, that the 2-photon and 3-photon processes become negligible at distances D away from the focus, where D is of the order of the beam waist FWHM. Regarding temporal structure, we compared transition probabilities for square, Gaussian and cosine squared temporal profiles; we find that for the same FWHM, Gaussian and cosine squared pulses give essentially the same transition probabilities, but the square pulses are about twice as efficient. We finally studied the effect of sharp versus smooth rise and fall edges in the light pulse; we find negligible correlation with the shape of the pulse edges, and strong correlation with the pulse FWHM, i.e., with pulse total energy, as might be expected.

Compared to cw techniques, contrast in optical mammography may be improved by frequency or time domain approaches.

We exposed bulk SiC and films of SiC and B4C to single 25 fs long free-electron-laser pulses with wavelengths between 13.5 and 32 nm. The materials are candidates for x-ray free-electron laser optics. We found that the threshold for surface-damage of the bulk SiC samples exceeds the fluence required for thermal melting at all wavelengths. The damage threshold of the film sample shows a strong wavelength dependence. For wavelengths of 13.5 and 21.7 nm, the damage threshold is equal to or exceeds the melting threshold, whereas at 32 nm the damage threshold falls below the melting threshold.

FLASH, the Free-electron LASer in Hamburg, is a worldwide unique source for extremely bright ultra-short laser-like pulses tunable in a wide spectral range in the extreme ultraviolet and soft x-ray region (Ackermann et?al 2007 Nat. Photonics 1 336?42). To fully exploit the features of this new generation of light sources, a user facility with efficient radiation transport to the experimental area and novel online photon diagnostics capable of characterizing the unique parameters of the FLASH radiation has been built. It serves a broad user community active in many scientific fields ranging from atomic and molecular physics to plasma and solid state physics as well as chemistry and biology. A special focus is placed on the exploitation of the ultra-short FLASH pulses using pump?probe techniques. Thus, the facility is equipped with optical and THz sources synchronized to FLASH. This paper gives a detailed overview of the FLASH user facility.

International audience; We report the first observation of single-shot soft x-ray laser induced desorption occurring below the ablation threshold in a thin layer of poly (methyl methacrylate) - PMMA. Irradiated by the focused beam from the Free-electron LASer in Hamburg (FLASH) at 21.7nm, the samples have been investigated by atomic-force microscope (AFM) enabling the visualization of mild surface modifications caused by the desorption. A model describing non-thermal desorption and ablation has been developed and used to analyze single-shot imprints in PMMA. An intermediate regime of materials removal has been found, confirming model predictions. We also report below-threshold multiple-shot desorption of PMMA induced by high-order harmonics (HOH) at 32nm. Short-time exposure imprints provide sufficient information about transverse beam profile in HOH's tight focus whereas long-time exposed PMMA exhibits radiation-initiated surface ardening making the beam profile measurement infeasible.

We have developed a laser-pulse mammograph capable of recording optical mammograms within approximately 3 min by measuring time-resolved transmittance at each of typically 1500 scan positions, 2.5 mm apart. As a first application two patients who have tumors were investigated successfully. From measured distributions of times of flight of photons corrected for edge effects we derived (1) characteristic quantities, such as photon counts in selected time windows, to generate optical mammograms; (2) effective transport scattering and absorption coefficients of breast tissue at each scan position, assuming the breast to be homogeneous; and (3) optical properties of a selected tumor by applying the theory of diffraction of photon density waves by spherical inhomogeneity. Mammograms recorded at different lateral offsets between source and detector fiber were used to estimate the depth of inhomogeneities.

The conversion of flash-evaporated merocyanine layers results in an equilibrium of two or more molecular units with the same terminal spectrum as in the case of slow evaporation. Different molecular units could be detected via their time-resolved spectra and their kinetics which are influenced by the layer thickness d . Comparison with the fluorescence behaviour in ethanol and in polyvinylbutyral layers reveals that at small thicknesses ( d d , and thickness-dependent spectral sensitization efficiency was observed in contact with evaporated AgBr.

Fluorescence spectroscopy is advantageously applied in order to measure excited state lifetime and reorientation of the transition moment after excitation (see, e. g., [1], [2]). Applying ultrashort light pulses the time resolution is limited in most cases by the signal detection system. MAHR et al. [3] proposed a method in which an excite-and-probe scheme is combined with fluorescence observation. The dependence of the integrated fluorescence signal on the relative delay between two successive exciting light pulses is measured. That dependence arises under the condition that the second pulse views a ground state population depleted by the first pulse. The time resolution is only limited by the pulse duration and hence values in the sub-psrange can be achieved. The method proposed in [3] represents a modification of that given in [4] where the fluorescence from a higher singlet level has been measured after a two step excitation S0 → S1 → Sx, in which one of the exciting pulse trains has been middulated.

The method proposed by Mahr et al. is considered with respect to the influence of orientational relaxation on the measured signal.