Proton beam quality enhancement by spectral phase control of a PW-class laser system.

We report on experimental investigations of proton acceleration from solid foils irradiated with PW-class laser-pulses, where highest proton cut-off energies were achieved for temporal pulse parameters that varied significantly from those of an ideally Fourier transform limited (FTL) pulse. Controlled spectral phase modulation of the driver laser by means of an acousto-optic programmable dispersive filter enabled us to manipulate the temporal shape of the last picoseconds around the main pulse and to study the effect on proton acceleration from thin foil targets. The results show that applying positive third order dispersion values to short pulses is favourable for proton acceleration and can lead to maximum energies of 70 MeV in target normal direction at 18 J laser energy for thin plastic foils, significantly enhancing the maximum energy compared to ideally compressed FTL pulses. The paper further proves the robustness and applicability of this enhancement effect for the use of different target materials and thicknesses as well as laser energy and temporal intensity contrast settings. We demonstrate that application relevant proton beam quality was reliably achieved over many months of operation with appropriate control of spectral phase and temporal contrast conditions using a state-of-the-art high-repetition rate PW laser system.

Demonstration of a beam loaded nanocoulomb-class laser wakefield accelerator.

Laser-plasma wakefield accelerators have seen tremendous progress, now capable of producing quasi-monoenergetic electron beams in the GeV energy range with few-femtoseconds bunch duration. Scaling these accelerators to the nanocoulomb range would yield hundreds of kiloamperes peak current and stimulate the next generation of radiation sources covering high-field THz, high-brightness X-ray and γ-ray sources, compact free-electron lasers and laboratory-size beam-driven plasma accelerators. However, accelerators generating such currents operate in the beam loading regime where the accelerating field is strongly modified by the self-fields of the injected bunch, potentially deteriorating key beam parameters. Here we demonstrate that, if appropriately controlled, the beam loading effect can be employed to improve the accelerator's performance. Self-truncated ionization injection enables loading of unprecedented charges of ∼0.5 nC within a mono-energetic peak. As the energy balance is reached, we show that the accelerator operates at the theoretically predicted optimal loading condition and the final energy spread is minimized.Higher beam quality and stability are desired in laser-plasma accelerators for their applications in compact light sources. Here the authors demonstrate in laser plasma wakefield electron acceleration that the beam loading effect can be employed to improve beam quality by controlling the beam charge.

Zonation of hepatic fatty acid metabolism - The diversity of its regulation and the benefit of modeling.

A pronounced heterogeneity between hepatocytes in subcellular structure and enzyme activities was discovered more than 50years ago and initiated the idea of metabolic zonation. In the last decades zonation patterns of liver metabolism were extensively investigated for carbohydrate, nitrogen and lipid metabolism. The present review focuses on zonation patterns of the latter. We review recent findings regarding the zonation of fatty acid uptake and oxidation, ketogenesis, triglyceride synthesis and secretion, de novo lipogenesis, as well as bile acid and cholesterol metabolism. In doing so, we expose knowledge gaps and discuss contradictory experimental results, for example on the zonation pattern of fatty acid oxidation and de novo lipogenesis. Thus, possible rewarding directions of further research are identified. Furthermore, recent findings about the regulation of metabolic zonation are summarized, especially regarding the role of hormones, nerve innervation, morphogens, gender differences and the influence of the circadian clock. In the last part of the review, a short collection of models considering hepatic lipid metabolism is provided. We conclude that modeling, despite its proven benefit for understanding of hepatic carbohydrate and ammonia metabolisms, has so far been largely disregarded in the study of lipid metabolism; therefore some possible fields of modeling interest are presented.

[The ecology of ticks, tick-borne diseases and biological tick control in Baden-Württemberg]. / Ökologie von Zecken als Überträger von Krankheitserregern in Baden-Württemberg und biologische Zeckenbekämpfung.

Ticks and tick-borne diseases are of great significance for the health of humans and animals. However, the factors influencing their distribution and dynamics are inadequately known. In a project financed by the Baden-Württemberg Ministry of the Environment, Climate and Energy Industry, as part of the program BWPLUS, interdisciplinary specialists work together to determine the influence of weather, (micro)climate, habitat, land use, human activities, and the population dynamics of host animals on the distribution and abundance of ticks and the diseases that they transmit in Baden-Württemberg. The project comprises four modules: the large-scale distribution of ticks in Baden-Württemberg (module 1), detailed studies of host-tick-pathogen interaction in relation to the microclimate (module 2), and the spatial occurrence of important tick-borne pathogens (module 3). The fourth module involves the comprehensive analysis and synthesis of all data in order to determine the relative importance of the factors studied and to develop a risk model. Recently, intensive investigations into tick control have been undertaken using various entomopathogenic fungi and nematodes as well as a parasitoid wasp. Our aim was to determine whether these natural enemies could be used to effectively reduce the number of free-living ticks.

Structural changes of deposited casein micelles induced by membrane filtration.

Casein micelles undergo shape changes when subjected to frontal filtration forces. Grazing incidence small angle X-ray scattering (GISAXS) and atomic force microscopy (AFM) allow a quantification of such structural changes on filtration cakes deposited on smooth silicon micro-sieves. A trans-membrane pressure of deltap = 400 mbar across the micro-sieve leads to an immediate film formation after deposition of casein solution. We observe significant changes in the GISAXS pattern depending on how many layers are stacked on top of each other. Compared to a deposit formed by one layer, GISAXS on a deposit formed by three layers of casein micelles leads to less scattering in the vertical and more scattering in the horizontal direction. Simulations show that the experimental results can be interpreted by a structural transformation from an originally spherical micelle shape to an ellipsoidal-deformed shape. The results are supported by AFM measurements showing a reduced lateral size of casein micelles deposited on top of a membrane pore. The observed shape changes could be due to filtration forces acting on densely packed deposits confining the micelles into ellipsoidal shapes.

[Smoke-free by ramadan: experience with a low-threshold prevention offer on smoking cessation for persons with migration background]. / Rauchfrei zu Ramadan. Erfahrungen mit einem niederschwelligen Präventionsangebot zur Raucherentwöhnung bei Personen mit Migrationshintergrund.

BACKGROUND: Persons with migration background exhibit higher smoking rates in comparison to the general population.These smokers often cannot be reached by prevention measures at the family doctor's office. METHODS: In summer 2011 the health campaign "Smoke-free by Ramadan" was launched in 11 German cities. Measures included the training of doctors on smoking cessation methods, general bilingual information flyers, and in some cases lectures on smoking, specifically for imams. A number of local events, especially for individuals with Turkish migration background were initiated. For these health events a specially equipped health bus of the BKK-vor-Ort was used, in which visitors were offered following elements: systematic data collection about age, sex and smoking behavior, a test to determine of the severity of nicotine dependence (Fagerström test, FTNA), as well as spirometric lung function test. Smokers were generally motivated to stop smoking. Data were anonymously collected and analysed in a documentation and communication sheet in Turkish language, and test results were handed over to participants on a printed information sheet. RESULTS: Data of 1012 people collected on 8 health days were analysed (70% men, mean age 46.5 years). The percentage of smokers was 41.5% (men) or 30% (women). Of 294 male smokers, according to FTNA 43.6% had low, 24.8% had moderate, and 31.6% strong nicotine dependence; in the 91 female smokers the corresponding rates were 54.9%, 30.8% and 14.3%. The distribution pattern of the dependency levels was statistically significantly different between genders (p = 0.006). Reduced lung function (FEV, < 80%) occurred in smokers more often than in nonsmokers (30% versus 21%). CONCLUSIONS: These results reinforce the importance of low-threshold prevention measures. By screening, here shown by the example of individuals with Turkish migration background, a significant number of smokers was identified who had in addition to strong nicotine addiction also significantly impaired lung function. As the odds for successful cessation without support are below 5%, evidence-based smoking cessation was advised to all smokers.

[Smoking cessation in pneumological routine care]. / Tabakentwöhnung in der pneumologischen Routineversorgung.

Continuous cigarette smoking clearly influences the course and prognosis of diseases like COPD/emphysema and asthma bronchiale in an adverse manner. However smoking cessation as a therapy measure is not a common part of general health-care in Germany as reimbursement of the central component of psychosocial support (behavioural therapy - BT) is allowed only to a minor degree and of pharmacotherapy support (nicotine replacement, varenicline, bupropione) is completely excluded by the legislator. This prospective "real-life" study with 198 participants shows, that with the abolition of the reimbursement barrier for cognitive behavioural therapy in the setting of a pneumological practice/clinic a high long-term abstinence of 45.4 % (point prevalence after 12 months) can be achieved. Apart from the reimbursement of BT, predominant success factors were the implementation of the measure in the practice/clinic, where patients are under long-term treatment and the application of a two-stage motivational model for the participation. Reimbursement of smoking cessation pharmacotherapy was not possible in this study. Thus, pharmacotherapy was applied to fewer than necessary patients and was predominantly too short and in a too low dosage.

Structural characterization of casein micelles: shape changes during film formation.

The objective of this study was to determine the effect of size-fractionation by centrifugation on the film structure of casein micelles. Fractionated casein micelles in solution were asymmetrically distributed with a small distribution width as measured by dynamic light scattering. Films prepared from the size-fractionated samples showed a smooth surface in optical microscopy images and a homogeneous microstructure in atomic force micrographs. The nano- and microstructure of casein films was probed by micro-beam grazing incidence small angle x-ray scattering (µGISAXS). Compared to the solution measurements, the sizes determined in the film were larger and broadly distributed. The measured GISAXS patterns clearly deviate from those simulated for a sphere and suggest a deformation of the casein micelles in the film.

Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is constitutively released from human hepatocytes.

Circulating NAMPT (PBEF/visfatin) has pleiotropic functions and is secreted from adipocytes. Since it is doubtful whether serum levels can be explained by secretion from adipocytes alone, we asked whether hepatocytes are also able to liberate NAMPT. Using HepG2 cells and primary rat and human hepatocytes, release of NAMPT into the cell culture supernatant was found to occur constitutively in a time-dependent manner. In primary human hepatocytes, secretion within 24h was far higher than the cellular content, but was neither influenced by inhibitors of secretion nor by glucose, insulin or TNFalpha. As determined by size exclusion chromatography, HepG2 lysates and supernatants primarily contained the dimeric form of NAMPT which exhibited similar in vitro specific enzymatic activity. In primary human hepatocytes, secreted NAMPT was less active. Our results demonstrate that human hepatocytes are a potential source of circulating NAMPT.

Hydration behavior of casein micelles in thin film geometry: a GISANS study?

The water content of casein micelle films in water vapor atmosphere is investigated using time-resolved grazing incidence small-angle neutron scattering (GISANS). Initial dry casein films are prepared with a spin-coating method. At 30 degrees C, the formation of a water-equilibrated casein protein film is reached after 11 min with a total content of 0.36 g of water/g of protein. With increasing water vapor temperature up to 70 degrees C, an increase in the water content is found. With GISANS, lateral structures on the nanometer scale are resolved during the swelling experiment at different temperatures and modeled using two types of spheres: micelles and mini-micelles. Upon water uptake, molecular assemblies in the size range of 15 nm (mini-micelles) are attributed to the formation of a high-contrast D2O outer shell on the small objects that already exist in the protein film. For large objects (>100 nm), the mean size increases at high D2O vapor temperature because of possible aggregation between hydrated micelles. These results are discussed and compared with various proposed models for casein micelle structures.

High-pressure potato starch granule gelatinization: synchrotron radiation micro-SAXS/WAXS using a diamond anvil cell.

Potato starch granules have been examined by synchrotron radiation small- and wide-angle scattering in a diamond anvil cell (DAC) up to 750 MPa. Use of a 1 microm synchrotron radiation beam allowed the mapping of individual granules at several pressure levels. The data collected at 183 MPa show an increase in the a axis and lamellar period from the edge to the center of the granule, probably due to a gradient in water content of the crystalline and amorphous lamellae. The average granules radius increases up to the onset of gelatinization at about 500 MPa, but the a axis and the lamellar periodicity remain constant or even show a decrease, suggesting an initial hydration of amorphous growth rings. The onset of gelatinization is accompanied by (i) an increase in the average a axis and lamellar periodicity, (ii) the appearance of an equatorial SAXS streak, and (iii) additional short-range order peaks.

Effect of calcium concentration on the structure of casein micelles in thin films.

The structure of thin casein films prepared with spin-coating is investigated as a function of the calcium concentration. Grazing incidence small-angle x-ray scattering and atomic force microscopy are used to probe the micelle structure. For comparison, the corresponding casein solutions are investigated with dynamic light-scattering experiments. In the thin films with added calcium three types of casein structures, aggregates, micelles, and mini-micelles, are observed in coexistence with atomic force microscopy and grazing incidence small-angle x-ray scattering. With increasing calcium concentration, the size of the aggregates strongly increases, while the size of micelles slightly decreases and the size of the mini-micelles increases. This effect is explained in the framework of the particle-stabilizing properties of the hairy layer of kappa-casein surrounding the casein micelles.

Primary mouse hepatocytes for systems biology approaches: a standardized in vitro system for modelling of signal transduction pathways.

Complex cellular networks regulate regeneration, detoxification and differentiation of hepatocytes. By combining experimental data with mathematical modelling, systems biology holds great promises to elucidate the key regulatory mechanisms involved and predict targets for efficient intervention. For the generation of high-quality quantitative data suitable for mathematical modelling a standardised in vitro system is essential. Therefore the authors developed standard operating procedures for the preparation and cultivation of primary mouse hepatocytes. To reliably monitor the dynamic induction of signalling pathways, the authors established starvation conditions and evaluated the extent of starvation-associated stress by quantifying several metabolic functions of cultured primary hepatocytes, namely activities of glutathione-S-transferase, glutamine synthetase, CYP3A as well as secretion of lactate and urea into the culture medium. Establishment of constant metabolic activities after an initial decrease compared with freshly isolated hepatocytes showed that the cultured hepatocytes achieve a new equilibrium state that was not affected by our starving conditions. To verify the highly reproducible dynamic activation of signalling pathways in the in vitro system, the authors examined the JAK-STAT, SMAD, PI3 kinase, MAP kinase, NF-kappaB and Wnt/beta-catenin signalling pathways. For the induction of gp130, JAK1 and STAT3 phosphorylation IL6 was used, whereas TGFbeta was applied to activate the phosphorylation of SMAD1, SMAD2 and SMAD3. Both Akt/PKB and ERK1/2 phosphorylation were stimulated by the addition of hepatocyte growth factor. The time-dependent induction of a pool of signalling competent beta-catenin was monitored in response to the inhibition of GSK3beta. To analyse whether phosphorylation is actually leading to transcriptional responses, luciferase reporter gene constructs driven by multiple copies of TGFbeta-responsive motives were applied, demonstrating a dose-dependent increase in luciferase activity. Moreover, the induction of apoptosis by the TNF-like cytokine Fas ligand was studied in the in vitro system. Thus, the mouse hepatocyte in vitro system provides an important basis for the generation of high-quality quantitative data under standardised cell culture conditions that is essential to elucidate critical hepatocellular functions by the systems biology approach.

Thin casein films as prepared by spin-coating: influence of film thickness and of pH.

Casein films were successfully prepared with the spin-coating technique of aqueous casein solutions on base-treated glass surfaces. The film structure is investigated in real space with optical microscopy and atomic force microscopy and for the first time in reciprocal space with grazing incidence small-angle X-ray scattering (GISAXS). The size of the substructures detected in the film increases with pH from 170 nm (pH 5.1) up to 490 nm (pH 9.4). Dynamic light scattering experiments reveal that the average diameters of casein micelles in solution exhibit the same quantitative increase. This result suggests that the substructures detected in the bulklike films with GISAXS reflect intact casein micelles. However, with thin homogeneous casein films, the micelle size diminishes with decreasing film thickness. This indicates that the moderate pressures introduced by spin-coating force the micelles to rearrange into a more compact structure.

Enhanced matrix degradation after withdrawal of TGF-beta1 triggers hepatocytes from apoptosis to proliferation and regeneration.

TGF-beta1 is a profibrogenic cytokine participating in deposition of extracellular matrix in fibrotic disorders. In liver, its anti-proliferative/apoptotic effect on hepatocytes promotes fibrosis. The tetracycline-controlled double-transgenic TA(LAP-2)/p(tet)TGF-beta1 mouse provides a model for reversible liver fibrosis. In livers of TGF-beta1-expressing mice, hepatocytes showed synchronous apoptosis detected by DNA laddering and active caspase-3 staining that disappeared when expression of transgenic TGF-beta1 was switched off. In these 'off' mice, perisinusoidal liver fibrosis resolved within 21 days accompanied by elevated proliferation of hepatocytes. Here, we have specified the intermediary stages (2-3 days off and 6 days off) in terms of (i) proliferation (by immunohistochemical staining of proliferating cell nuclear antigen and expression of cyclin D1 mRNA) and (ii) extracellular matrix remodelling processes (by measuring mRNA expression of matrix metalloproteinases-2 and -13 (mmp-2 and mmp-13) and tissue inhibitor of matrix metalloproteinases 1 (timp-1) and quantitative morphometric analysis. In summary, we show a rapidly declining timp-1 mRNA level together with lastingly high mmp-2 and mmp-13 mRNA levels after 2-3 days, suggesting that high matrix-degrading potential represents a prerequisite for the markedly enhanced proliferation of hepatocytes in the early stages after switching off transgenic TGF-beta1.

¿Cuál es el mejor medio para identificar el espacio epidural? / What is the best medium to identify the epidural space?

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Pressure-induced dissociation of casein micelles: size distribution and effect of temperature.

Pressure-induced dissociation of a turbid solution of casein micelles was studied in situ in static and dynamic light scattering experiments. We show that at high pressure casein micelles decompose into small fragments comparable in size to casein monomers. At intermediate pressure we observe particles measuring 15 to 20 nm in diameter. The stability against pressure dissociation increased with temperature, suggesting enhanced hydrophobic contacts. The pressure transition curves are biphasic, compatible with a temperature (but not pressure)-dependent conformational equilibrium of two micelle species. Our thermodynamic model predicts an increase in structural entropy with temperature.

High pressure near infrared study of the mutated light-harvesting complex LH2.

The pressure sensitivities of the near infrared spectra of the light-harvesting (LH2) complex and a mutant complex with a simplified BChl-B850 binding pocket were compared. In the mutant an abrupt change in the spectral properties occurred at 250 MPa, which was not observed with the native sample. Increased disorder due to collapse of the chromophore pocket is suggested.

Pressure-induced dissociation of casein micelles: size distribution and effect of temperature

Pressure-induced dissociation of a turbid solution of casein micelles was studied in situ in static and dynamic light scattering experiments. We show that at high pressure casein micelles decompose into small fragments comparable in size to casein monomers. At intermediate pressure we observe particles measuring 15 to 20 nm in diameter. The stability against pressure dissociation increased with temperature, suggesting enhanced hydrophobic contacts. The pressure transition curves are biphasic, compatible with a temperature (but not pressure)-dependent conformational equilibrium of two micelle species. Our thermodynamic model predicts an increase in structural entropy with temperature.