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Yver, Camille E. ; Pison, Isabelle C. ; Fortems-Cheiney, Audrey ; Schmidt, Martina ; Chevallier, Frédéric ; Ramonet, Michel ; Jordan, Armin ; Søvde, Ole Amund ; Engel, Andreas ; Fisher, Rebecca E. ; Lowry, David ; Nisbet, Euan G. ; Levin, Ingeborg ; Hammer, Samuel ; Necki, Jaroslaw ; Bartyzel, Jakub ; Reimann, Stefan ; Vollmer, Martin ; Steinbacher, Martin ; Aalto, Tuula ; Maione, Michela ; Arduini, Jgor ; O'Doherty, Simon ; Grant, Aoife ; Sturges, William T. ; Forster, Grant L. ; Lunder, Chris Rene ; Privalov, Viacheslav I. ; Paramonova, Nina N.
This paper presents an analysis of the recent tropospheric molecular hydrogen (H2) budget with a particular focus on soil uptake and surface emissions. A variational inversion scheme is combined with observations from the RAMCES and EUROHYDROS atmospheric networks, which include continuous measurements performed between mid-2006 and mid-2009. Net H2 surface flux, soil uptake distinct from surface emissions and finally, soil uptake, biomass burning, anthropogenic emissions and N2 fixation-related emissions separately were inverted in several scenarios. The various inversions generate an estimate for each term of the H2 budget. The net H2 flux per region (High Northern Hemisphere, Tropics and High Southern Hemisphere) varies between −8 and 8 Tg yr−1. The best inversion in terms of fit to the observations combines updated prior surface emissions and a soil deposition velocity map that is based on soil uptake measurements. Our estimate of global H2 soil uptake is −59 ± 4.0 Tg yr−1. Forty per cent of this uptake is located in the High Northern Hemisphere and 55% is located in the Tropics. In terms of surface emissions, seasonality is mainly driven by biomass burning emissions. The inferred European anthropogenic emissions are consistent with independent H2 emissions estimated using a H2/CO mass ratio of 0.034 and CO emissions considering their respective uncertainties. To constrain a more robust partition of H2 sources and sinks would need additional constraints, such as isotopic measurements.
Feng, Wuhu ; Chipperfield, Martyn P. ; Davies, Stewart ; Sen, Bhaswar ; Toon, Geoffrey C. ; Blavier, Jean-François ; Webster, Christopher R. ; Volk, C.-Michael ; Ulanovsky, Alexey ; Ravegnani, Fabrizio ; Gathen, Peter von der ; Jost, Hans-Jürg ; Richard, Erik C. ; Claude, Hans
We have used the SLIMCAT 3-D off-line chemical transport model (CTM) to quantify the Arctic chemical ozone loss in the year 2002/2003 and compare it with similar calculations for the winters 1999/2000 and 2003/2004. Recent changes to the CTM have improved the model's ability to reproduce polar chemical and dynamical processes. The updated CTM uses σ-θ as a vertical coordinate which allows it to extend down to the surface. The CTM has a detailed stratospheric chemistry scheme and now includes a simple NAT-based denitrification scheme in the stratosphere.
In the model runs presented here the model was forced by ECMWF ERA40 and operational analyses. The model used 24 levels extending from the surface to ~55 km and a horizontal resolution of either 7.5°×7.5° or 2.8°×2.8°. Two different radiation schemes, MIDRAD and the CCM scheme, were used to diagnose the vertical motion in the stratosphere. Based on tracer observations from balloons and aircraft, the more sophisticated CCM scheme gives a better representation of the vertical transport in this model which includes the troposphere. The higher resolution model generally produces larger chemical O3 depletion, which agrees better with observations.
The CTM results show that very early chemical ozone loss occurred in December 2002 due to extremely low temperatures and early chlorine activation in the lower stratosphere. Thus, chemical loss in this winter started earlier than in the other two winters studied here. In 2002/2003 the local polar ozone loss in the lower stratosphere was ~40% before the stratospheric final warming. Larger ozone loss occurred in the cold year 1999/2000 which had a persistently cold and stable vortex during most of the winter. For this winter the current model, at a resolution of 2.8°×2.8°, can reproduce the observed loss of over 70% locally. In the warm and more disturbed winter 2003/2004 the chemical O3 loss was generally much smaller, except above 620 K where large losses occurred due to a period of very low minimum temperatures at these altitudes.
Pätz, Hans-Werner ; Volz-Thomas, Andreas ; Hegglin, Michaela I. ; Brunner, Dominik ; Fischer, Herbert ; Schmidt, Ulrich
Two aircraft instruments for the measurement of total odd nitrogen (NOy) were compared side by side aboard a Learjet A35 in April 2003 during a campaign of the AFO2000 project SPURT (Spurengastransport in der Tropopausenregion). The instruments albeit employing the same measurement principle (gold converter and chemiluminescence) had different inlet configurations. The ECO-Physics instrument operated by ETH-Zürich in SPURT had the gold converter mounted outside the aircraft, whereas the instrument operated by FZ-Jülich in the European project MOZAIC III (Measurements of ozone, water vapour, carbon monoxide and nitrogen oxides aboard Airbus A340 in-service aircraft) employed a Rosemount probe with 80 cm of FEP-tubing connecting the inlet to the gold converter. The NOy concentrations during the flight ranged between 0.3 and 3 ppb. The two data sets were compared in a blind fashion and each team followed its normal operating procedures. On average, the measurements agreed within 6%, i.e. within the combined uncertainty of the two instruments. This puts an upper limit on potential losses of HNO3 in the Rosemount inlet of the MOZAIC instrument. Larger transient deviations were observed during periods after calibrations and when the aircraft entered the stratosphere. The time lag of the MOZAIC instrument observed in these instances is in accordance with the time constant of the MOZAIC inlet line determined in the laboratory for HNO3.
Pätz, Hans-Werner ; Volz-Thomas, Andreas ; Hegglin, Michaela I. ; Brunner, Dominik ; Fischer, Herbert ; Schmidt, Ulrich
Two aircraft instruments for the measurement of total odd nitrogen (NOy) were compared side by side aboard a Learjet A35 in April 2003 during a campaign of the AFO2000 project SPURT (Spurengastransport in der Tropopausenregion). The instruments albeit employing the same measurement principle (gold converter and chemiluminescence) had different inlet configurations. The ECO-Physics instrument operated by ETH-Zürich in SPURT had the gold converter mounted outside the aircraft, whereas the instrument operated by FZ-Jülich in the European project MOZAIC III (Measurements of ozone, water vapour, carbon monoxide and nitrogen oxides aboard Airbus A340 in-service aircraft) employed a Rosemount probe with 80 cm of FEP-tubing connecting the inlet to the gold converter. The NOy concentrations during the flight ranged between 0.3 and 3 ppb. The two data sets were compared in a blind fashion and each team followed its normal operating procedures. On average, the measurements agreed within 7%, i.e. within the combined uncertainty of the two instruments. This puts an upper limit on potential losses of HNO3 in the Rosemount inlet of the MOZAIC instrument. Larger transient deviations were observed during periods after calibrations and when the aircraft entered the stratosphere. The time lag of the MOZAIC instrument observed in these instances is in accordance with the time constant of the MOZAIC inlet line determined in the laboratory for HNO3.
Numerical simulation of flow, H₂SO₄ cycle and new particle formation in the CERN CLOUD chamber
(2011)
To study the effect of galactic cosmic rays on aerosols and clouds, the Cosmic Leaving OUtdoor Droplets (CLOUD) project was established. Experiments are carried out at a 26 m3 tank at CERN (Switzerland). In the experiments, the effect of ionising particle radiation on H2SO4 particle formation and growth is investigated. To evaluate the experimental configuration, the experiment was simulated using a coupled multidimensional CFD – particle model (CLOUD-FPM). In the model the coupled fields of gas/vapour species, temperature, flow velocity and particle properties were computed to investigate the tank's mixing state and mixing times. Simulation results show that the mixing state of the tank's contents largely depends on the characteristics of the mixing fans and a 1-fan configuration, as used in first experiments, may not be sufficient to ensure a homogeneously mixed chamber. To mix the tank properly, 2 fans are necessary. The 1/e response times for instantaneous changes of wall temperature and saturation ratio inside the chamber were found to be in the order of few minutes. Particle nucleation and growth was also simulated and particle number size distribution properties of the freshly nucleated particles (particle number, mean size, standard deviation of the assumed log-normal distribution) were found to be mixed over the tank's volume similar to the gas species.
Voigtländer, Jens ; Duplissy, Jonathan ; Rondo, Linda ; Kürten, Christoph Andreas ; Stratmann, Frank
To study the effect of galactic cosmic rays on aerosols and clouds, the Cosmics Leaving OUtdoor Droplets (CLOUD) project was established. Experiments are carried out at a 26.1 m3 tank at CERN (Switzerland). In the experiments, the effect of ionizing radiation on H2SO4 particle formation and growth is investigated. To evaluate the experimental configuration, the experiment was simulated using a coupled multidimensional computational fluid dynamics (CFD) – particle model. In the model the coupled fields of gas/vapor species, temperature, flow velocity and particle properties were computed to investigate mixing state and mixing times of the CLOUD tank's contents. Simulation results show that a 1-fan configuration, as used in first experiments, may not be sufficient to ensure a homogeneously mixed chamber. To mix the tank properly, two fans and sufficiently high fan speeds are necessary. The 1/e response times for instantaneous changes of wall temperature and saturation ratio were found to be in the order of few minutes. Particle nucleation and growth was also simulated and particle number size distribution properties of the freshly nucleated particles (particle number, mean size, standard deviation of the assumed log-normal distribution) were found to be distributed over the tank's volume similar to the gas species.
In this paper we present evidence that the observed increase in tropical upwelling after the year 2000 may be attributed to a change in the Brewer-Dobson circulation pattern. For this purpose, we use the concept of transit times derived from residual circulation trajectories and different in-situ measurements of ozone and nitrous dioxide. Observations from the Canadian midlatitude ozone profile record, probability density functions of in-situ N2O observations and a shift of the N2O-O3 correlation slopes, taken together, indicate that the increased upwelling in the tropics after the year 2000 appears to have triggered an intensification of tracer transport from the tropics into the extratropics in the lower stratosphere below about 500 K. This finding is corroborated by the fact that transit times along the shallow branch of the residual circulation into the LMS have decreased for the same time period (1993–2003). On a longer time scale (1979–2009), the transit time of the shallow residual circulation branch show a steady decrease of about −1 month/decade over the last 30 years, while the transit times of the deep branch remain unchanged. This highlights the fact that a change in the upwelling across the tropical tropopause is not a direct indicator for changes of the whole Brewer-Dobson circulation.
In this paper we present evidence that the observed increase in tropical upwelling after the year 2000 may be attributed to a change in the Brewer-Dobson circulation pattern. For this purpose, we use the concept of transit times derived from residual circulation trajectories and different in-situ measurements of ozone and nitrous dioxide. Observations from the Canadian midlatitude ozone profile record, probability density functions of in-situ N2O observations and a shift of the N2O-O3 correlation slopes, taken together, indicate that the increased upwelling in the tropics after the year 2000 appears to have triggered an intensification of tracer transport from the tropics into the extratropics in the lower stratosphere below about 500 K. This finding is corroborated by the fact that transit times along the shallow branch of the residual circulation into the LMS have decreased for the same time period (1993–2003). On a longer time scale (1979–2009), the transit time of the shallow residual circulation branch show a steady decrease of about −1 month/decade over the last 30 yr, while the transit times of the deep branch remain unchanged. This highlights that changes in the upwelling across the tropical tropopause are not sufficient as an indicator for changes in the entire Brewer-Dobson circulation.
The title complex, [PdCl2(C18H15P)2]·0.5C6H6, has the PdII ion in a square-planar coordination mode (r.m.s. deviation for Pd, P and Cl atoms = 0.024 Å) with the PPh3 and Cl ligands mutually trans. The benzene solvent molecule is located about a crystallographic inversion centre. The title complex is isostructural with trans-dichloridobis(triphenylphosphane)palladium(II) 1,4-dichlorobenzene sesquisolvate [Kitano et al. (1983 [triangle]). Acta Cryst. C39, 1015–1017].
We present a non-parametric and computationally efficient method that detects spatiotemporal firing patterns and pattern sequences in parallel spike trains and tests whether the observed numbers of repeating patterns and sequences on a given timescale are significantly different from those expected by chance. The method is generally applicable and uncovers coordinated activity with arbitrary precision by comparing it to appropriate surrogate data. The analysis of coherent patterns of spatially and temporally distributed spiking activity on various timescales enables the immediate tracking of diverse qualities of coordinated firing related to neuronal state changes and information processing. We apply the method to simulated data and multineuronal recordings from rat visual cortex and show that it reliably discriminates between data sets with random pattern occurrences and with additional exactly repeating spatiotemporal patterns and pattern sequences. Multineuronal cortical spiking activity appears to be precisely coordinated and exhibits a sequential organization beyond the cell assembly concept.
Introduction: In this article the personal study and life situation of parents who are also medical students at the Medical School of the Goethe University Frankfurt am Main is discussed. There is a special focus on the topics "studying with children" and "family-friendly university", which have been present in discussions about university development and in the daily life of academics, especially during the last decade. The workgroup "Individual Student Services" at the medical faculty at the Goethe University tries to meet the necessities of the individual study courses and to support the study success with a new counselling and student service concept.
Methods: The experience of parents studying medicine was recorded in semi-structured interviews (Date: April 2010), which were held as part of the sponsored pilot project on part-time medical studies ("Pilot Project Part-time Medical Studies"). Additionally, study results from the Medical School of the Goethe University Frankfurt am Main were integrated as well as a literature analysis.
Results: It was found that the teaching demands and support services, which have been suggested and needed for years now, have been partially implemented and are without sufficient support at the faculty level to date. Thus the current situation of medical students with children is still difficult and seems a big challenge for everyone involved.
Solution: As part of the "Individual Student Services" a new pilot project on part-time medical studies was established in November 2009. Only the use of new, unconventional and innovative ideas allows universities to adequately support the changing and heterogeneous student population and support them to successfully completing their medical studies.
Einleitung: In dem vorliegenden Artikel wird die persönliche Studien- und Lebenssituation von Studierenden mit Kindern am Fachbereich Medizin der Goethe-Universität Frankfurt am Main beleuchtet. Der spezielle Fokus liegt auf den Themen "Studium mit Kind" sowie "familiengerechte Hochschule", welche in Deutschland in der letzten Dekade sehr präsent sowohl in der Hochschulforschung als auch im akademischen Alltag sind. Hier versucht die Arbeitsstelle "Individuelle Studienbegleitung" am FB Medizin der Goethe-Universität durch ein neues Beratungs- und Servicekonzept mit wissenschaftlicher Begleitforschung den individuellen Studienverläufen gerecht zu werden und den Studienerfolg zu fördern.
Methoden: In erster Linie stammen die hier beschriebenen Erfahrungen der Medizinstudierenden mit Kind aus qualitativen Leitfadeninterviews (Stand April 2010), die im Rahmen des Modellprojektes Teilzeitstudium Medizin durchgeführt wurden. Ergänzend wurden die Studienergebnisse des Fachbereichs Medizin der Goethe-Universität Frankfurt am Main herangezogen und eine Literaturanalyse einbezogen.
Ergebnisse: Als Ergebnis kann festgehalten werden, dass die bereits seit mehreren Jahren erhobenen Forderungen und gewünschten Unterstützungsleistungen zwar zum Teil umgesetzt, aber noch nicht ausreichend an allen Fachbereichen implementiert wurden. Somit ist die aktuelle Situation von Studierenden mit Kindern in der Medizin nach wie vor schwierig und stellt für alle Beteiligten eine große Herausforderung dar.
Lösungsansatz: Im Rahmen der Arbeitsstelle "Individuelle Studienbegleitung" konnte im November 2009 das "Modellprojekt Teilzeitstudium Medizin" aufgebaut werden. Nur durch neue, unkonventionelle und innovative Ideen kann man die Sicherstellung der medizinischen Ausbildung erreichen und die heutige heterogene Studierendenschaft adäquat ansprechen sowie Studierende erfolgreich durch ihr Studium begleiten.
During meditation, practitioners are required to center their attention on a specific object for extended periods of time. When their thoughts get diverted, they learn to quickly disengage from the distracter. We hypothesized that learning to respond to the dual demand of engaging attention on specific objects and disengaging quickly from distracters enhances the efficiency by which meditation practitioners can allocate attention. We tested this hypothesis in a global-to-local task while measuring electroencephalographic activity from a group of eight highly trained Buddhist monks and nuns and a group of eight age and education matched controls with no previous meditation experience. Specifically, we investigated the effect of attentional training on the global precedence effect, i.e., faster detection of targets on a global than on a local level. We expected to find a reduced global precedence effect in meditation practitioners but not in controls, reflecting that meditators can more quickly disengage their attention from the dominant global level. Analysis of reaction times confirmed this prediction. To investigate the underlying changes in brain activity and their time course, we analyzed event-related potentials. Meditators showed an enhanced ability to select the respective target level, as reflected by enhanced processing of target level information. In contrast with control group, which showed a local target selection effect only in the P1 and a global target selection effect in the P3 component, meditators showed effects of local information processing in the P1, N2, and P3 and of global processing for the N1, N2, and P3. Thus, meditators seem to display enhanced depth of processing. In addition, meditation altered the uptake of information such that meditators selected target level information earlier in the processing sequence than controls. In a longitudinal experiment, we could replicate the behavioral effects, suggesting that meditation modulates attention already after a 4-day meditation retreat. Together, these results suggest that practicing meditation enhances the speed with which attention can be allocated and relocated, thus increasing the depth of information processing and reducing response latency.
In this study, it is demonstrated that moving sounds have an effect on the direction in which one sees visual stimuli move. During the main experiment sounds were presented consecutively at four speaker locations inducing left or rightward auditory apparent motion. On the path of auditory apparent motion, visual apparent motion stimuli were presented with a high degree of directional ambiguity. The main outcome of this experiment is that our participants perceived visual apparent motion stimuli that were ambiguous (equally likely to be perceived as moving left or rightward) more often as moving in the same direction than in the opposite direction of auditory apparent motion. During the control experiment we replicated this finding and found no effect of sound motion direction on eye movements. This indicates that auditory motion can capture our visual motion percept when visual motion direction is insufficiently determinate without affecting eye movements.
We describe the frog species Diasporus citrinobapheussp. n. from the Cordillera Central of western Panama. The new species differs from all other species in its genus in coloration, disk cover and disk pad shape, skin texture, advertisement call, and size. It is most similar to Diasporus tigrillo, from which it differs in dorsal skin texture, relative tibia length, number of vomerine teeth, ventral coloration, dorsal markings, and relative tympanum size, and to Diasporus gularis, from which it can be distinguished by the lack of membranes between the toes, adult size, posterior thigh coloration, and position of the choanae. We provide data on morpho- logy, vocalization, and distribution of the new species, as well as brief information on its natural history.
Alme, Johan ; Andres, Y. ; Appelshäuser, Harald ; Bablok, Sebastian ; Bialas, Norbert ; Bolgen, Rikard ; Bonnes, Uwe ; Bramm, Roland ; Braun-Munzinger, Peter ; Campagnolo, Roberto ; Christiansen, Peter ; Dobrin, Alexandru Florin ; Engster, Claude ; Fehlker, Dominik ; Foka, Yiota ; Frankenfeld, Ulrich ; Gaardhøje, Jens Joergen ; Garabatos, Chilo ; Glässel, Peter ; Gonzalez Gutierrez, Carmen ; Gros, Philippe ; Gustafsson, Hans-Åke ; Helstrup, Håvard ; Hoch, Michael ; Ivanov, Marian ; Janik, Rudolf ; Junique, Antoine ; Kalweit, Alexander Philipp ; Keidel, Ralf ; Kniege, Stefan ; Kowalski, Marek ; Larsen, Dag Toppe ; Lesenechal, Yannick ; Lenoir, Philippe ; Lindegaard, Niels ; Lippmann, Christian ; Mager, Magnus ; Mast, Manfred ; Matyja, Adam ; Munkejord, Magne ; Musa, Luciano ; Nielsen, Borge Svane ; Nikolic, Vedran ; Oeschler, Helmut ; Olsen, E.K. ; Oskarsson, Anders ; Osterman, Lennart ; Pikna, Miroslav ; Rehman, Attiq ur ; Renault, Gaël ; Renfordt, Rainer Arno Ernst ; Rossegger, Stefan ; Röhrich, Dieter ; Røed, Ketil ; Richter, Mattias ; Rueshmann, G. ; Rybicki, Andrzej ; Sann, Hans ; Schmidt, Hans-Rudolf ; Siska, Martin ; Sitar, Branislav ; Soegaard, Carsten ; Soltveit, Hans Kristian ; Soyk, Daniel ; Stachel, Johanna ; Stelzer, Herbert ; Stenlund, Evert Anders ; Stock, Reinhard ; Strmeň, Peter ; Szarka, Imrich ; Ullaland, Kjetil ; Vranić, Danilo ; Veenhof, Rob ; Westergaard, Joern ; Wiechula, Jens ; Windelband, Bernd
The design, construction, and commissioning of the ALICE Time-Projection Chamber (TPC) is described. It is the main device for pattern recognition, tracking, and identification of charged particles in the ALICE experiment at the CERN LHC. The TPC is cylindrical in shape with a volume close to 90 m3 and is operated in a 0.5 T solenoidal magnetic field parallel to its axis.
In this paper we describe in detail the design considerations for this detector for operation in the extreme multiplicity environment of central Pb–Pb collisions at LHC energy. The implementation of the resulting requirements into hardware (field cage, read-out chambers, electronics), infrastructure (gas and cooling system, laser-calibration system), and software led to many technical innovations which are described along with a presentation of all the major components of the detector, as currently realized. We also report on the performance achieved after completion of the first round of stand-alone calibration runs and demonstrate results close to those specified in the TPC Technical Design Report.
Körner, Christian ; Barrera, Miguel ; Dukanovic, Jovana ; Eydt, Katharina ; Harner, Max ; Rabl, Regina ; Vogel, Frank ; Rapaport, Doron ; Neupert, Walter ; Reichert, Andreas
Crista junctions (CJs) are tubular invaginations of the inner membrane of mitochondria that connect the inner boundary with the cristae membrane. These architectural elements are critical for mitochondrial function. The yeast inner membrane protein Fcj1, called mitofilin in mammals, was reported to be preferentially located at CJs and crucial for their formation. Here we investigate the functional roles of individual domains of Fcj1. The most conserved part of Fcj1, the C-terminal domain, is essential for Fcj1 function. In its absence, formation of CJ is strongly impaired and irregular, and stacked cristae are present. This domain interacts with full-length Fcj1, suggesting a role in oligomer formation. It also interacts with Tob55 of the translocase of outer membrane β-barrel proteins (TOB)/sorting and assembly machinery (SAM) complex, which is required for the insertion of β-barrel proteins into the outer membrane. The association of the TOB/SAM complex with contact sites depends on the presence of Fcj1. The biogenesis of β-barrel proteins is not significantly affected in the absence of Fcj1. However, down-regulation of the TOB/SAM complex leads to altered cristae morphology and a moderate reduction in the number of CJs. We propose that the C-terminal domain of Fcj1 is critical for the interaction of Fcj1 with the TOB/SAM complex and thereby for stabilizing CJs in close proximity to the outer membrane. These results assign novel functions to both the C-terminal domain of Fcj1 and the TOB/SAM complex.
New projects, services and collaborations have recently brought the infrastructural services for African Studies a big step forward. This report gives an account of new subject gateways and digitisation projects. It discusses recent European cooperation ventures in the field of librarianship. Additionally, new developments and services of the Africa Collection at Frankfurt University Library are presented, which help to address the changing needs of researchers and to handle information overload, while keeping up with the latest developments. Nevertheless, the fragmentation and compartmentalisation of the different services still hinder more integrated information services.
Foamy viruses (FVs) are distinct retroviruses classified as Spumaretrovirinae in contrast to the other retroviruses, the Orthoretrovirinae. As a unique feature of FVs, Gag is not sufficient for sub-viral particle (SVP) release. In primate and feline FVs (PFV and FFV), particle budding completely depends on the cognate FV Env glycoproteins. It was recently shown that an artificially added N-terminal Gag myristoylation signal (myr-signal) overcomes this restriction in PFV inducing an Orthoretrovirus-like budding phenotype. Here we show that engineered, heterologous N-terminal myr-signals also induce budding of the distantly related FFV Gag. The budding efficiency depends on the myr-signal and its location relative to the N-terminus of Gag. When the first nine amino acid residues of FFV Gag were replaced by known myr-signals, the budding efficiency as determined by the detection of extracellular SVPs was low. In contrast, adding myr-signals to the intact N-terminus of FFV Gag resulted in a more efficient SVP release. Importantly, budding of myr-Gag proteins was sensitive towards inhibition of cellular N-myristoyltransferases. As expected, the addition or insertion of myr-signals that allowed Env-independent budding of FFV SVPs also retargeted Gag to plasma membrane-proximal sites and other intracellular membrane compartments. The data confirm that membrane-targeted FV Gag has the capacity of SVP formation.
Schwalb, Christian H. ; Grimm, Christina ; Baranowski, Markus ; Sachser, Roland ; Porrati, Fabrizio ; Reith, Heiko ; Das, Pintu ; Müller, Jens ; Völklein, Friedemann ; Kaya, Alexander ; Huth, Michael
This paper introduces a new methodology for the fabrication of strain-sensor elements for MEMS and NEMS applications based on the tunneling effect in nano-granular metals. The strain-sensor elements are prepared by the maskless lithography technique of focused electron-beam-induced deposition (FEBID) employing the precursor trimethylmethylcyclopentadienyl platinum [MeCpPt(Me)3]. We use a cantilever-based deflection technique to determine the sensitivity (gauge factor) of the sensor element. We find that its sensitivity depends on the electrical conductivity and can be continuously tuned, either by the thickness of the deposit or by electron-beam irradiation leading to a distinct maximum in the sensitivity. This maximum finds a theoretical rationale in recent advances in the understanding of electronic charge transport in nano-granular metals.
Introduction. To evaluate clinical feasibility and reproducibility of cytometric bead assay (CBA) in nondiluted vitreous samples of patients with age-related macular degeneration (ARMD), diabetic macular edema (DME), and central retinal vein occlusion (CRVO). Methods. Twelve patients from a single clinics day qualified for intravitreal injections (ARMD n = 6, DME n = 3, CRVO n = 3) and underwent a combination treatment including a single-site 23 gauge core vitrectomy which yielded a volume of 0.6 mL undiluted vitreous per patient. Interleukin-6 (IL-6), vascular endothelial growth factor isoform A (VEGF-A), and monocyte chemo-attractant protein-1 (MCP-1) were assessed directly from 0.3 mL at the same day (fresh samples). To assess the reproducibility 0.3 ml were frozen for 60 days at -80°, on which the CBA was repeated (frozen samples). Results. In the fresh samples IL-6 was highest in CRVO (median IL-6 55.8 pg/mL) > DME (50.6) > ARMD (3.1). Highest VEGF was measured in CRVO (447.4) > DME (3.9) > ARMD (2.0). MCP-1 was highest in CRVO (595.7) > AMD (530.8) > DME (178). The CBA reproducibility after frozen storage was examined to be most accurate for MCP1 (P = 0.91) > VEGF (P = 0.68) > IL-6 (P = 0.49). Conclusions. CBA is an innovative, fast determining, and reliable technology to analyze proteins in fluids, like the undiluted vitreous, which is important to better understand ocular pathophysiology and pharmacology. There is no influence of intermittent storage at -80° for the reproducibility of the CBA.
Bierbach, David ; Klein, Moritz ; Sassmannshausen, Vanessa ; Schlupp, Ingo ; Riesch, Rüdiger ; Parzefall, Jakob ; Plath, Martin
Reproductive isolation among locally adapted populations may arise when immigrants from foreign habitats are selected against via natural or (inter-)sexual selection (female mate choice). We asked whether also intrasexual selection through male-male competition could promote reproductive isolation among populations of poeciliid fishes that are locally adapted to extreme environmental conditions [i.e., darkness in caves and/or toxic hydrogen sulphide (H(2)S)]. We found strongly reduced aggressiveness in extremophile P. oecilia mexicana, and darkness was the best predictor for the evolutionary reduction of aggressiveness, especially when combined with presence of H(2)S. We demonstrate that reduced aggression directly translates into migrant males being inferior when paired with males from non-sulphidic surface habitats. By contrast, the phylogenetically old sulphur endemic P. sulphuraria from another sulphide spring area showed no overall reduced aggressiveness, possibly indicating evolved mechanisms to better cope with H(2)S.
Integrin-mediated cell-matrix interaction in physiological and pathological blood vessel formation
(2011)
Physiological as well as pathological blood vessel formation are fundamentally dependent on cell-matrix interaction. Integrins, a family of major cell adhesion receptors, play a pivotal role in development, maintenance, and remodeling of the vasculature. Cell migration, invasion, and remodeling of the extracellular matrix (ECM) are integrin-regulated processes, and the expression of certain integrins also correlates with tumor progression. Recent advances in the understanding of how integrins are involved in the regulation of blood vessel formation and remodeling during tumor progression are highlighted. The increasing knowledge of integrin function at the molecular level, together with the growing repertoire of integrin inhibitors which allow their selective pharmacological manipulation, makes integrins suited as potential diagnostic markers and therapeutic targets.
Although throughout the history of anthropology the ethnography of urban societies was never an important topic, investigations on cities in Africa contributed to the early theoretical development of urban studies in social sciences. As the ethnography of rural migrants in towns made clear, cultural diversity and creativity are foundational and permanent elements of urban cultures in Africa (and beyond). Currently, two new aspects complement these insights: 1) Different forms of mobility have received a new awareness through the concept of transnationalism. They are much more complex, including not only rural–urban migration, but also urban–urban migration, and migrations with a destination beyond the continent. 2) Urban life-worlds also include the appropriation of globally circulating images and lifestyles, which contribute substantially to the current cultural dynamics of cities in Africa. These two aspects are the reasons for the high complexity of urban contexts in Africa. Therefore, whether it is still appropriate to speak about the “locality” of these life-worlds has become questionable. At the same time, these new aspects explain the self-consciousness of members of urban cultures in Africa. They contribute to the expansive character of these societies and to the impression that cities in Africa host the most innovative and creative societies worldwide.
My contribution focuses on the relationship between theory and praxis, since the task of a “critical archaeology” is to mediate between these two spheres. Its target audience is the public, not other scholars. Critical archaeology is not part of scientific practice, but rather is part of intellectual reasoning that is both value-laden and that exercises practical critique. Respect for the specific logics of theory and praxis is crucial for its success. A “critical archaeology” that merits its name must steer its way between the Scylla of a technocratic paternalism that limits praxis and the Charybdis of submission to theory under the presumption of the “relevance of praxis.”
BACKGROUND: The identification of beta-barrel membrane proteins out of a genomic/proteomic background is one of the rapidly developing fields in bioinformatics. Our main goal is the prediction of such proteins in genome/proteome wide analyses.
RESULTS: For the prediction of beta-barrel membrane proteins within prokaryotic proteomes a set of parameters was developed. We have focused on a procedure with a low false positive rate beside a procedure with lowest false prediction rate to obtain a high certainty for the predicted sequences. We demonstrate that the discrimination between beta-barrel membrane proteins and other proteins is improved by analyzing a length limited region. The developed set of parameters is applied to the proteome of E. coli and the results are compared to four other described procedures.
CONCLUSION: Analyzing the beta-barrel membrane proteins revealed the presence of a defined membrane inserted beta-barrel region. This information can now be used to refine other prediction programs as well. So far, all tested programs fail to predict outer membrane proteins in the proteome of the prokaryote E. coli with high reliability. However, the reliability of the prediction is improved significantly by a combinatory approach of several programs. The consequences and usability of the developed scores are discussed.
Schmidt von Braun, Serena ; Sabetti, Antonino ; Hanic-Joyce, Pamela J. ; Gu, Jun ; Schleiff, Enrico ; Joyce, Paul B. M.
Enzymes involved in tRNA maturation are essential for cytosolic, mitochondrial, and plastid protein synthesis and are therefore localized to these different compartments of the cell. Interestingly, only one isoform of tRNA nucleotidyltransferase (responsible for adding the 3′-terminal cytidine–cytidine–adenosine to tRNAs) has been identified in plants. The present study therefore explored how signals contained on this enzyme allow it to be distributed among the different cell compartments. It is demonstrated that the N-terminal portion of the protein acts as an organellar targeting signal and that differential use of multiple in-frame start codons alters the localization of the protein. Moreover, it is shown that the mature domain has a major impact on the distribution of the protein within the cell. These data indicate that regulation of dual localization involves not only specific N-terminal signals, but also additional factors within the protein or the cell.
Veith, Thomas ; Martin, Roman ; Wurm, Jan Philip ; Weis, Benjamin L. ; Duchardt-Ferner, Elke ; Safferthal, Charlotta ; Hennig, Raoul ; Mirus, Oliver ; Bohnsack, Markus ; Wöhnert, Jens ; Schleiff, Enrico
Eukaryotic ribosome biogenesis requires the concerted action of numerous ribosome assembly factors, for most of which structural and functional information is currently lacking. Nob1, which can be identified in eukaryotes and archaea, is required for the final maturation of the small subunit ribosomal RNA in yeast by catalyzing cleavage at site D after export of the preribosomal subunit into the cytoplasm. Here, we show that this also holds true for Nob1 from the archaeon Pyrococcus horikoshii, which efficiently cleaves RNA-substrates containing the D-site of the preribosomal RNA in a manganese-dependent manner. The structure of PhNob1 solved by nuclear magnetic resonance spectroscopy revealed a PIN domain common with many nucleases and a zinc ribbon domain, which are structurally connected by a flexible linker. We show that amino acid residues required for substrate binding reside in the PIN domain whereas the zinc ribbon domain alone is sufficient to bind helix 40 of the small subunit rRNA. This suggests that the zinc ribbon domain acts as an anchor point for the protein on the nascent subunit positioning it in the proximity of the cleavage site.
Machettira, Anu Bheemaiah ; Groß, Lucia E. ; Tillmann, Bodo ; Weis, Benjamin L. ; Englich, Gisela ; Sommer, Maik Sascha ; Königer, Martina ; Schleiff, Enrico
Organelles are surrounded by membranes with a distinct lipid and protein composition. While it is well established that lipids affect protein functioning and vice versa, it has been only recently suggested that elevated membrane protein concentrations may affect the shape and organization of membranes. We therefore analyzed the effects of high chloroplast envelope protein concentrations on membrane structures using an in vivo approach with protoplasts. Transient expression of outer envelope proteins or protein domains such as CHUP1-TM–GFP, outer envelope protein of 7 kDa–GFP, or outer envelope protein of 24 kDa–GFP at high levels led to the formation of punctate, circular, and tubular membrane protrusions. Expression of inner membrane proteins such as translocase of inner chloroplast membrane 20, isoform II (Tic20-II)–GFP led to membrane protrusions including invaginations. Using increasing amounts of DNA for transfection, we could show that the frequency, size, and intensity of these protrusions increased with protein concentration. The membrane deformations were absent after cycloheximide treatment. Co-expression of CHUP1-TM–Cherry and Tic20-II–GFP led to membrane protrusions of various shapes and sizes including some stromule-like structures, for which several functions have been proposed. Interestingly, some structures seemed to contain both proteins, while others seem to contain one protein exclusively, indicating that outer and inner envelope dynamics might be regulated independently. While it was more difficult to investigate the effects of high expression levels of membrane proteins on mitochondrial membrane shapes using confocal imaging, it was striking that the expression of the outer membrane protein Tom20 led to more elongate mitochondria. We discuss that the effect of protein concentrations on membrane structure is possibly caused by an imbalance in the lipid to protein ratio and may be involved in a signaling pathway regulating membrane biogenesis. Finally, the observed phenomenon provides a valuable experimental approach to investigate the relationship between lipid synthesis and membrane protein expression in future studies.
Sensitivity of output of a linear operator to its input can be quantified in various ways. In Control Theory, the input is usually interpreted as disturbance and the output is to be minimized in some sense. In stochastic worst-case design settings, the disturbance is considered random with imprecisely known probability distribution. The prior set of probability measures can be chosen so as to quantify how far the disturbance deviates from the white-noise hypothesis of Linear Quadratic Gaussian control. Such deviation can be measured by the minimal Kullback-Leibler informational divergence from the Gaussian distributions with zero mean and scalar covariance matrices. The resulting anisotropy functional is defined for finite power random vectors. Originally, anisotropy was introduced for directionally generic random vectors as the relative entropy of the normalized vector with respect to the uniform distribution on the unit sphere. The associated a-anisotropic norm of a matrix is then its maximum root mean square or average energy gain with respect to finite power or directionally generic inputs whose anisotropy is bounded above by a >= 0. We give a systematic comparison of the anisotropy functionals and the associated norms. These are considered for unboundedly growing fragments of homogeneous Gaussian random fields on multidimensional integer lattice to yield mean anisotropy. Correspondingly, the anisotropic norms of finite matrices are extended to bounded linear translation invariant operators over such fields.
Czerny, Christoph ; Kholmukhamedov, Andaleb ; Theruvath, Tom Prakash ; Maldonado, Eduardo N. ; Ramshesh, Venkat K. ; Lehnert, Mark ; Marzi, Ingo ; Zhong, Zhi ; Lemasters, John J.
Patients that survive hemorrhage and resuscitation (H/R) may develop a systemic inflammatory response syndrome (SIRS) that leads to dysfunction of vital organs (multiple organ dysfunction syndrome, MODS). SIRS and MODS may involve mitochondrial dysfunction. Under pentobarbital anesthesia, C57BL6 mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer’s solution containing minocycline, tetracycline (both 10 mg/kg body weight) or vehicle. Serum alanine aminotransferase (ALT), necrosis, apoptosis and oxidative stress were assessed 6 h after resuscitation. Mitochondrial polarization was assessed by intravital microscopy. After H/R with vehicle or tetracycline, ALT increased to 4538 U/L and 3999 U/L, respectively, which minocycline decreased to 1763 U/L (P<0.01). Necrosis and TUNEL also decreased from 24.5% and 17.7 cells/field, respectively, after vehicle to 8.3% and 8.7 cells/field after minocycline. Tetracycline failed to decrease necrosis (23.3%) but decreased apoptosis to 9 cells/field (P<0.05). Minocycline and tetracycline also decreased caspase-3 activity in liver homogenates. Minocycline but not tetracycline decreased lipid peroxidation after resuscitation by 70% (P<0.05). Intravital microscopy showed that minocycline preserved mitochondrial polarization after H/R (P<0.05). In conclusion, minocycline decreases liver injury and oxidative stress after H/R by preventing mitochondrial dysfunction.
Michaelis, Martin ; Barth, Susanne ; Breitling, Rainer ; Bruch, Jochen ; Steinberger, Daniela ; Rothweiler, Florian ; Hackmann, Karl ; Schröck, Evelin ; Doerr, Hans Wilhelm ; Griffin, Darren K. ; Cinatl, Jindrich ; Cinatl, Jindrich
The human cytomegalovirus (HCMV) is suspected to increase tumour malignancy by infection of cancer and/or stroma cells (oncomodulation). So far, oncomodulatory mechanisms have been attributed to the presence of HCMV and direct action of its gene products on cancer cells. Here, we investigated whether the prolonged presence of HCMV can result in the irreversible selection of a cancer cell population with increased malignancy. The neuroblastoma cell line UKF-NB-4 was long-term (200 passages) infected with the HCMV strain Hi91 (UKF-NB-4Hi) before virus eradication using ganciclovir (UKF-NB-4HiGCV). Global gene expression profiling of UKF-NB-4, UKF-NB-4Hi and UKF-NB-4HiGCV cells and subsequent bioinformatic signal transduction pathway analysis revealed clear differences between UKF-NB-4 and UKF-NB-4Hi, as well as between UKF-NB-4 and UKF-NB-4HiGCV cells, but only minor differences between UKF-NB-4Hi and UKF-NB-4HiGCV cells. Investigation of the expression of a subset of five genes in different chronically HCMV-infected cell lines before and after virus eradication suggested that long-term HCMV infection reproducibly causes specific changes. Array comparative genomic hybridisation showed virtually the same genomic differences for the comparisons UKF-NB-4Hi/UKF-NB-4 and UKF-NB-4HiGCV/UKF-NB-4. UKF-NB-4Hi cells are characterised by an increased invasive potential compared with UKF-NB-4 cells. This phenotype was completely retained in UKF-NB-4HiGCV cells. Moreover, there was a substantial overlap in the signal transduction pathways that differed significantly between UKF-NB-4Hi/UKF-NB-4HiGCV and UKF-NB-4 cells and those differentially regulated between tumour tissues from neuroblastoma patients with favourable or poor outcome. In conclusion, we present the first experimental evidence that long-term HCMV infection can result in the selection of tumour cell populations with enhanced malignancy.
Photoinduced electron transfer from organic dye molecules to semiconductor nanoparticles is the first and most important reaction step for the mechanism in the so called “wet solar cells” [1]. The time scale between the photoexcitation of the dye and the electron injection into the conduction band of the
semiconductor colloid varies from a few tens of femtoseconds to nanoseconds, depending on the specific electron transfer parameters of the system, e.g., electronic coupling or free energy values of donor and acceptor molecules [2–10]. We show that visible pump/ white light probe is a very efficient tool to investigate the electron injection reaction allowing to observe simultaneously the relaxation of the excited dye, the injection process of the electron, the cooling of the injected electron and the charge recombination reaction.
The conformational dynamics induced by ligand binding to the tetracycline-binding aptamer is monitored via stopped-flow fluorescence spectroscopy and time-correlated single photon counting experiments. The fluorescence of the ligand is sensitive to changes within the tertiary structure of the aptamer during and after the binding process. In addition to the wild-type aptamer, the mutants A9G, A13U and A50U are examined, where bases important for regulation are changed to inhibit the aptamer’s function. Our results suggest a very fast two-step-mechanism for the binding of the ligand to the aptamer that can be interpreted as a binding step followed by a reorganization of the aptamer to accommodate the ligand. Binding to the two direct contact points A13 and A50 was found to occur in the first binding step. The exchange of the structurally important base A9 for guanine induces an enormous deceleration of the overall binding process, which is mainly rooted in an enhancement of the back reaction of the first binding step by several orders of magnitude. This indicates a significant loss of tertiary structure of the aptamer in the absence of the base A9, and underlines the importance of pre-organization on the overall binding process of the tetracycline-binding aptamer.
Nordgård, Lise ; Brusetti, Lorenzo ; Raddadi, Noura ; Traavik, Terje ; Averhoff, Beate ; Nielsen, Kaare Magne
BACKGROUND:
Horizontal gene transfer through natural transformation of members of the microbiota of the lower gastrointestinal tract (GIT) of mammals has not yet been described. Insufficient DNA sequence similarity for homologous recombination to occur has been identified as the major barrier to interspecies transfer of chromosomal DNA in bacteria. In this study we determined if regions of high DNA similarity between the genomes of the indigenous bacteria in the GIT of rats and feed introduced DNA could lead to homologous recombination and acquisition of antibiotic resistance genes.
RESULTS:
Plasmid DNA with two resistance genes (nptI and aadA) and regions of high DNA similarity to 16S rRNA and 23S rRNA genes present in a broad range of bacterial species present in the GIT, were constructed and added to standard rat feed. Six rats, with a normal microbiota, were fed DNA containing pellets daily over four days before sampling of the microbiota from the different GI compartments (stomach, small intestine, cecum and colon). In addition, two rats were included as negative controls. Antibiotic resistant colonies growing on selective media were screened for recombination with feed introduced DNA by PCR targeting unique sites in the putatively recombined regions. No transformants were identified among 441 tested isolates.
CONCLUSIONS:
The analyses showed that extensive ingestion of DNA (100 μg plasmid) per day did not lead to increased proportions of kanamycin resistant bacteria, nor did it produce detectable transformants among the aerobic microbiota examined for 6 rats (detection limit < 1 transformant per 1,1 × 108 cultured bacteria). The key methodological challenges to HGT detection in animal feedings trials are identified and discussed. This study is consistent with other studies suggesting natural transformation is not detectable in the GIT of mammals.
Nijkamp, Jurgen F. ; Broek, Marcel van den ; Datema, Erwin ; Kok, Stefan de ; Bosman, Lizanne ; Luttik, M. Louise ; Daran-Lapujade, Pascale ; Vongsangnak, Wanwipa ; Nielsen, Jens ; Heijne, Wilbert H. M. ; Klaassen, Paul ; Paddon, Chris J. ; Platt, Darren ; Kötter, Peter ; Ham, Roeland C. van ; Reinders, Marcel J. T. ; Pronk, Jack T. ; Ridder, Dick de ; Daran, Jean-Marc
Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization compared to the reference strain S. cerevisiae S288C were analyzed. In addition to a few large deletions and duplications, nearly 3000 indels were identified in the CEN.PK113-7D genome relative to S288C. These differences were overrepresented in genes whose functions are related to transcriptional regulation and chromatin remodelling. Some of these variations were caused by unstable tandem repeats, suggesting an innate evolvability of the corresponding genes. Besides a previously characterized mutation in adenylate cyclase, the CEN.PK113-7D genome sequence revealed a significant enrichment of non-synonymous mutations in genes encoding for components of the cAMP signalling pathway. Some phenotypic characteristics of the CEN.PK113-7D strains were explained by the presence of additional specific metabolic genes relative to S288C. In particular, the presence of the BIO1 and BIO6 genes correlated with a biotin prototrophy of CEN.PK113-7D. Furthermore, the copy number, chromosomal location and sequences of the MAL loci were resolved. The assembled sequence reveals that CEN.PK113-7D has a mosaic genome that combines characteristics of laboratory strains and wild-industrial strains.
Acute ethanol gavage attenuates hemorrhage/resuscitation-induced hepatic oxidative stress in rats
(2012)
Acute ethanol intoxication increases the production of reactive oxygen species (ROS). Hemorrhagic shock with subsequent resuscitation (H/R) also induces ROS resulting in cellular and hepatic damage in vivo. We examined the role of acute ethanol intoxication upon oxidative stress and subsequent hepatic cell death after H/R. 14 h before H/R, rats were gavaged with single dose of ethanol or saline (5 g/kg, EtOH and ctrl; H/R_EtOH or H/R_ctrl, resp.). Then, rats were hemorrhaged to a mean arterial blood pressure of 30 ± 2 mmHg for 60 min and resuscitated. Two control groups underwent surgical procedures without H/R (sham_ctrl and sham_EtOH, resp.). Liver tissues were harvested at 2, 24, and 72 h after resuscitation. EtOH-gavage induced histological picture of acute fatty liver. Hepatic oxidative (4-hydroxynonenal, 4-HNE) and nitrosative (3-nitrotyrosine, 3-NT) stress were significantly reduced in EtOH-gavaged rats compared to controls after H/R. Proapoptotic caspase-8 and Bax expressions were markedly diminished in EtOH-gavaged animals compared with controls 2 h after resuscitation. EtOH-gavage increased antiapoptotic Bcl-2 gene expression compared with controls 2 h after resuscitation. iNOS protein expression increased following H/R but was attenuated in EtOH-gavaged animals after H/R. Taken together, the data suggest that acute EtOH-gavage may attenuate H/R-induced oxidative stress thereby reducing cellular injury in rat liver.
This special issue focuses on aging in place in late life. Aging in place is about being able to continue living in one’s own home or neighborhood and to adapt to changing needs and conditions. It is of high concern due to the increasing number of old and very old people in all societies and challenges researchers, practitioners, and policy makers in many societal and scientific areas and disciplines. We invited authors to contribute original research papers as well as conceptually driven review papers that would stimulate the continuing efforts to understand the different aspects of aging in place in late life. The papers that were submitted came from very diverse disciplines, such as sociology, psychology, occupational therapy, nursing, architecture, public planning, and social work. Given the number and diversity of papers submitted, we can conclude that aging in place is an important concern throughout the world and that different kinds of measures are taken to come up with local, national, and international solutions that enhance aging in place. [...]
Müller, Iris ; Freitag, Michael H. ; Poggensee, Gabriele ; Scharnetzky, Elke ; Straube, Eberhard ; Schoerner, Christof ; Hlobil, Harald ; Hagedorn, Hans-Jochen ; Stanek, Gerold ; Schubert-Unkmeir, Alexandra ; Norris, Douglas E. ; Gensichen, Jochen ; Hunfeld, Klaus-Peter
Background: Data on the economic impact of Lyme borreliosis (LB) on European health care systems is scarce. This project focused on the epidemiology and costs for laboratory testing in LB patients in Germany.
Materials and Methods: We performed a sentinel analysis of epidemiological and medicoeconomic data for 2007 and 2008. Data was provided by a German statutory health insurance (DAK) company covering approx. 6.04 million members. In addition, the quality of diagnostic testing for LB in Germany was studied.
Results: In 2007 and 2008, the incident diagnosis LB was coded on average for 15,742 out of 6.04 million insured members (0.26%). 20,986 EIAs and 12,558 immunoblots were ordered annually for these patients. For all insured members in the outpatient sector, a total of 174,820 EIAs and 52,280 immunoblots were reimbursed annually to health care providers (cost: 2,600,850€). For Germany, the overall expected cost is estimated at 51,215,105€. However, proficiency testing data questioned test quality and standardization of diagnostic assays used.
Conclusion: Findings from this study suggest ongoing issues related to care for LB and may help to improve future LB disease management.
Leblond, Claire S. ; Heinrich, Jutta ; Delorme, Richard ; Proepper, Christian ; Betancur, Catalina ; Huguet, Guillaume ; Konyukh, Marina ; Chaste, Pauline ; Ey, Elodie ; Rastam, Maria ; Anckarsäter, Henrik ; Nygren, Gudrun ; Gillberg, I. Carina ; Melke, Jonas ; Toro, Roberto ; Regnault, Beatrice ; Fauchereau, Fabien ; Mercati, Oriane ; Lemière, Nathalie ; Skuse, David ; Poot, Martin ; Holt, Richard ; Monaco, Anthony P. ; Järvelä, Irma ; Kantojärvi, Katri ; Vanhala, Raija ; Curran, Sarah ; Collier, David A. ; Bolton, Patrick F. ; Geburtig-Chiocchetti, Andreas ; Klauck, Sabine M. ; Poustka, Fritz ; Freitag, Christine M. ; Waltes, Regina ; Kopp, Marnie ; Duketis, Eftichia ; Bacchelli, Elena ; Minopoli, Fiorella ; Ruta, Liliana ; Battaglia, Agatino ; Mazzone, Luigi ; Maestrini, Elena ; Sequeira, Ana F. ; Oliveira, Barbara ; Vicente, Astrid M. ; Oliveira, Guiomar ; Pinto, Dalila ; Scherer, Stephen W. ; Zelenika, Diana ; Delepine, Marc ; Lathrop, Mark ; Bonneau, Dominique ; Guinchat, Vincent ; Devillard, Françoise ; Assouline, Brigitte ; Mouren, Marie-Christine ; Leboyer, Marion ; Gillberg, Christopher ; Böckers, Tobias M. ; Bourgeron, Thomas
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Introduction: Febrile neutropenia is a common and potentially life-threatening complication of treatment for childhood cancer, which has increasingly been subject to targeted treatment based on clinical risk stratification. Our previous meta-analysis demonstrated 16 rules had been described and 2 of them subject to validation in more than one study. We aimed to advance our knowledge of evidence on the discriminatory ability and predictive accuracy of such risk stratification clinical decision rules (CDR) for children and young people with cancer by updating our systematic review.
Methods: The review was conducted in accordance with Centre for Reviews and Dissemination methods, searching multiple electronic databases, using two independent reviewers, formal critical appraisal with QUADAS and meta-analysis with random effects models where appropriate. It was registered with PROSPERO: CRD42011001685.
Results: We found 9 new publications describing a further 7 new CDR, and validations of 7 rules. Six CDR have now been subject to testing across more than two data sets. Most validations demonstrated the rule to be less efficient than when initially proposed; geographical differences appeared to be one explanation for this.
Conclusion: The use of clinical decision rules will require local validation before widespread use. Considerable uncertainty remains over the most effective rule to use in each population, and an ongoing individual-patient-data meta-analysis should develop and test a more reliable CDR to improve stratification and optimise therapy. Despite current challenges, we believe it will be possible to define an internationally effective CDR to harmonise the treatment of children with febrile neutropenia.
Pancreatic resections for advanced M1-pancreatic carcinoma : the value of synchronous metastasectomy
(2010)
Seelig, Stefanie Katharina ; Burkert, Björn ; Chromik, Ansgar Michael ; Tannapfel, Andrea ; Uhl, Waldemar ; Seelig, Mathias H.
Background: For M1 pancreatic adenocarcinomas pancreatic resection is usually not indicated. However, in highly selected patients synchronous metastasectomy may be appropriate together with pancreatic resection when operative morbidity is low.
Materials and Methods: From January 1, 2004 to December, 2007 a total of 20 patients with pancreatic malignancies were retrospectively evaluated who underwent pancreatic surgery with synchronous resection of hepatic, adjacent organ, or peritoneal metastases for proven UICC stage IV periampullary cancer of the pancreas. Perioperative as well as clinicopathological parameters were evaluated.
Results: There were 20 patients (9 men, 11 women; mean age 58 years) identified. The primary tumor was located in the pancreatic head (n=9, 45%), in pancreatic tail (n=9, 45%), and in the papilla Vateri (n=2, 10%). Metastases were located in the liver (n=14, 70%), peritoneum (n=5, 25%), and omentum majus (n=2, 10%). Lymphnode metastases were present in 16 patients (80%). All patients received resection of their tumors together with metastasectomy. Pylorus preserving duodenopancreatectomy was performed in 8 patients, distal pancreatectomy in 8, duodenopancreatectomy in 2, and total pancreatectomy in 2. Morbidity was 45% and there was no perioperative mortality. Median postoperative survival was 10.7 months (2.6–37.7 months) which was not significantly different from a matched-pair group of patients who underwent pancreatic resection for UICC adenocarcinoma of the pancreas (median survival 15.6 months; =.1).
Conclusion: Pancreatic resection for M1 periampullary cancer of the pancreas can be performed safely in well-selected patients. However, indication for surgery has to be made on an individual basis.
Ehrlich, Hermann ; Janussen, Dorte ; Simon, Paul ; Bazhenov, Vasily V. ; Shapkin, Nikolay P. ; Erler, Christiane ; Mertig, Michael ; Born, René ; Heinemann, Sascha ; Hanke, Thomas ; Worch, Hartmut ; Vournakis, John N.
Investigations of the micro- and nanostructures and chemical composition of the sponge skeletons as examples for natural structural biocomposites are of fundamental scientific relevance. Recently, we show that some demosponges (Verongula gigantea, Aplysina sp.) and glass sponges (Farrea occa, Euplectella aspergillum) possess chitin as a component of their skeletons. The main practical approach we used for chitin isolation was based on alkali treatment of corresponding external layers of spicules sponge material with the aim of obtaining alkali-resistant compounds for detailed analysis. Here, we present a detailed study of the structural and physicochemical properties of spicules of the glass sponge Rossella fibulata. The structural similarity of chitin derived from this sponge to invertebrate alpha chitin has been confirmed by us unambiguously using physicochemical and biochemical methods. This is the first report of a silica-chitin composite biomaterial found in Rossella species. Finally, the present work includes a discussion related to strategies for the practical application of silica-chitin-based composites as biomaterials.
Functional magnetic resonance imaging (fMRI) has been used for more than a decade to investigate possible supraspinal mechanisms of acupuncture stimulation. More than 60 studies and several review articles have been published on the topic. However, till now some acupuncture-fMRI studies have not adopted all methodological standards applied to most other fMRI studies. In this critical review, we comment on some of the problems including the choice of baseline, interpretation of deactivations, attention control and implications of different group statistics. We illustrate the possible impact of these problems by focussing on some early findings, namely activations of visual and auditory cortical areas, when acupoints were stimulated that are believed to have a therapeutic effect on vision or hearing in traditional Chinese medicine. While we are far from questioning the validity of using fMRI for the study of acupuncture effects, we think that activations reported by some of these studies were probably not a direct result of acupuncture stimulation but rather attributable to one or more of the methodological problems covered here. Finally, we try to offer solutions for these problems where possible.
Weber, Heike ; Scholz, Claus Jürgen ; Domschke, Katharina ; Baumann, Christian ; Klauke, Benedikt ; Jacob, Christian P. ; Maier, Wolfgang ; Fritze, Jürgen ; Bandelow, Borwin ; Zwanzger, Peter M. ; Lang, Thomas ; Fehm, Lydia ; Ströhle, Andreas ; Hamm, Alfons ; Gerlach, Alexander ; Alpers, Georg W. ; Kircher, Tilo ; Wittchen, Hans-Ulrich ; Arolt, Volker ; Pauli, Paul ; Deckert, Jürgen ; Reif, Andreas
Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females.
Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score.
Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
The neurexin genes (NRXN1/2/3) encode two families (α and β) of highly polymorphic presynaptic proteins that are involved in excitatory/inhibitory synaptic balance. Recent studies indicate that neuronal activation and memory formation affect NRXN1/2/3α expression and alternative splicing at splice sites 3 and 4 (SS#3/SS#4). Neurons in the biological clock residing in the suprachiasmatic nuclei of the hypothalamus (SCN) act as self-sustained oscillators, generating rhythms in gene expression and electrical activity, to entrain circadian bodily rhythms to the 24 hours day/night cycles. Cell autonomous oscillations in NRXN1/2/3α expression and SS#3/SS#4 exons splicing and their links to rhythms in excitatory/inhibitory synaptic balance in the circadian clock were explored. NRXN1/2/3α expression and SS#3/SS#4 splicing, levels of neurexin-2α and the synaptic scaffolding proteins PSD-95 and gephyrin (representing excitatory and inhibitory synapses, respectively) were studied in mRNA and protein extracts obtained from SCN of C3H/J mice at different times of the 24 hours day/night cycle. Further studies explored the circadian oscillations in these components and causality relationships in immortalized rat SCN2.2 cells. Diurnal rhythms in mNRXN1α and mNRXN2α transcription, SS#3/SS#4 exon-inclusion and PSD-95 gephyrin and neurexin-2α levels were found in the SCN in vivo. No such rhythms were found with mNRXN3α. SCN2.2 cells also exhibited autonomous circadian rhythms in rNRXN1/2 expression SS#3/SS#4 exon inclusion and PSD-95, gephyrin and neurexin-2α levels. rNRXN3α and rNRXN1/2β were not expressed. Causal relationships were demonstrated, by use of specific siRNAs, between rNRXN2α SS#3 exon included transcripts and gephyrin levels in the SCN2.2 cells. These results show for the first time dynamic, cell autonomous, diurnal rhythms in expression and splicing of NRXN1/2 and subsequent effects on the expression of neurexin-2α and postsynaptic scaffolding proteins in SCN across the 24-h cycle. NRXNs gene transcripts may have a role in coupling the circadian clock to diurnal rhythms in excitatory/inhibitory synaptic balance.
Kautz, Stefanie ; Ballhorn, Daniel J. ; Kroiss, Johannes ; Pauls, Steffen U. ; Moreau, Corrie S. ; Eilmus, Sascha ; Strohm, Erhard ; Heil, Martin
Protective ant-plant mutualisms that are exploited by non-defending parasitic ants represent prominent model systems for ecology and evolutionary biology. The mutualist Pseudomyrmex ferrugineus is an obligate plant-ant and fully depends on acacias for nesting space and food. The parasite Pseudomyrmex gracilis facultatively nests on acacias and uses host-derived food rewards but also external food sources. Integrative analyses of genetic microsatellite data, cuticular hydrocarbons and behavioral assays showed that an individual acacia might be inhabited by the workers of several P. gracilis queens, whereas one P. ferrugineus colony monopolizes one or more host trees. Despite these differences in social organization, neither of the species exhibited aggressive behavior among conspecific workers sharing a tree regardless of their relatedness. This lack of aggression corresponds to the high similarity of cuticular hydrocarbon profiles among ants living on the same tree. Host sharing by unrelated colonies, or the presence of several queens in a single colony are discussed as strategies by which parasite colonies could achieve the observed social organization. We argue that in ecological terms, the non-aggressive behavior of non-sibling P. gracilis workers — regardless of the route to achieve this social structure — enables this species to efficiently occupy and exploit a host plant. By contrast, single large and long-lived colonies of the mutualist P. ferrugineus monopolize individual host plants and defend them aggressively against invaders from other trees. Our findings highlight the necessity for using several methods in combination to fully understand how differing life history strategies affect social organization in ants.
Yao, Yi-Feng ; Bruch, Angela A. ; Cheng, Ye-Ming ; Mosbrugger, Volker ; Wang, Yu-Fei ; Li, Cheng-Sen
Yuanmou Basin of Yunnan, SW China, is a famous locality with hominids, hominoids, mammals and plant fossils. Based on the published megaflora and palynoflora data from Yuanmou Basin, the climate of Late Pliocene is reconstructed using the Coexistence Approach. The results indicate a warm and humid subtropical climate with a mean annual temperature of ca. 16–17°C and a mean annual precipitation of ca. 1500–1600 mm in the Late Pliocene rather than a dry, hot climate today, which may be due to the local tectonic change and gradual intensification of India monsoon. The comparison of Late Pliocene climate in Eryuan, Yangyi, Longling, and Yuanmou Basin of Yunnan Province suggests that the mean annual temperatures generally show a latitudinal gradient and fit well with their geographic position, while the mean annual precipitations seem to be related to the different geometries of the valleys under the same monsoon system.
Bender, Stephan ; Rellum, Thomas ; Freitag, Christine M. ; Resch, Franz ; Rietschel, Marcella ; Treutlein, Jens ; Jennen-Steinmetz, Christine ; Brandeis, Daniel ; Banaschewski, Tobias ; Laucht, Manfred
Background: Dopamine plays an important role in orienting, response anticipation and movement evaluation. Thus, we examined the influence of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of motor processing in a contingent negative variation (CNV) task.
Methods: 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as motor postimperative negative variation were assessed. Adolescents were genotyped for the COMT Val158Met and two DAT1 polymorphisms (variable number tandem repeats in the 3′-untranslated region and in intron 8).
Results: The results revealed a significant interaction between COMT and DAT1, indicating that COMT exerted stronger effects on lateralized motor post-processing (centro-parietal motor postimperative negative variation) in homozygous carriers of a DAT1 haplotype increasing DAT1 expression. Source analysis showed that the time interval 500–1000 ms after the motor response was specifically affected in contrast to preceding movement anticipation and programming stages, which were not altered.
Conclusions: Motor slow negative waves allow the genomic imaging of dopamine inactivation effects on cortical motor post-processing during response evaluation. This is the first report to point towards epistatic effects in the motor system during response evaluation, i.e. during the post-processing of an already executed movement rather than during movement programming.
Lerosey-Aubril, Rudy ; Hegna, Thomas A. ; Kier, Carlo ; Bonino, Enrico ; Habersetzer, Jörg ; Carré, Matthieu
Despite being internal organs, digestive structures are frequently preserved in Cambrian Lagerstätten. However, the reasons for their fossilisation and their biological implications remain to be thoroughly explored. This is particularly true with arthropods--typically the most diverse fossilised organisms in Cambrian ecosystems--where digestive structures represent an as-yet underexploited alternative to appendage morphology for inferences on their biology. Here we describe the phosphatised digestive structures of three trilobite species from the Cambrian Weeks Formation Lagerstätte (Utah). Their exquisite, three-dimensional preservation reveals unique details on trilobite internal anatomy, such as the position of the mouth and the absence of a differentiated crop. In addition, the presence of paired pygidial organs of an unknown function is reported for the first time. This exceptional material enables exploration of the relationships between gut phosphatisation and the biology of organisms. Indeed, soft-tissue preservation is unusual in these fossils as it is restricted to the digestive structures, which indicates that the gut played a central role in its own phosphatisation. We hypothesize that the gut provided a microenvironment where special conditions could develop and harboured a source of phosphorus. The fact that gut phosphatization has almost exclusively been observed in arthropods could be explained by their uncommon ability to store ions (including phosphorous) in their digestive tissues. However, in some specimens from the Weeks Formation, the phosphatisation extends to the entire digestive system, suggesting that trilobites might have had some biological particularities not observed in modern arthropods. We speculate that one of them might have been an increased capacity for ion storage in the gut tissues, related to the moulting of their heavily-mineralised carapace.
Nickel, Thomas ; Pfeiler, Susanne ; Summo, Claudia ; Kopp, Reinhard ; Meimarakis, Georgios ; Sicic, Zeljka ; Lambert, Marius ; Lackermair, Korbinian Johannes ; David, Robert ; Beiras Fernández, Andrés ; Kaczmarek, Ingo ; Weis, Michael
Dendritic cells (DCs) and oxLDL play an important role in the atherosclerotic process with DCs accumulating in the plaques during plaque progression. Our aim was to investigate the role of oxLDL in the modulation of the DC homing-receptor CCR7 and endothelial-ligand CCL21. Methods and Results. The expression of the DC homing-receptor CCR7 and its endothelial-ligand CCL21 was examined on atherosclerotic carotic plaques of 47 patients via qRT-PCR and immunofluorescence. In vitro, we studied the expression of CCR7 on DCs and CCL21 on human microvascular endothelial cells (HMECs) in response to oxLDL. CCL21- and CCR7-mRNA levels were significantly downregulated in atherosclerotic plaques versus non-atherosclerotic controls [90% for CCL21 and 81% for CCR7 (P<0.01)]. In vitro, oxLDL reduced CCR7 mRNA levels on DCs by 30% and protein levels by 46%. Furthermore, mRNA expression of CCL21 was significantly reduced by 50% (P<0.05) and protein expression by 24% in HMECs by oxLDL (P<0.05). Conclusions. The accumulation of DCs in atherosclerotic plaques appears to be related to a downregulation of chemokines and their ligands, which are known to regulate DC migration. oxLDL induces an in vitro downregulation of CCR7 and CCL21, which may play a role in the reduction of DC migration from the plaques.
Hammerschmidt, Claudia ; Hallström, Teresia ; Skerka, Christine ; Wallich, Reinhard ; Stevenson, Brian ; Zipfel, Peter F. ; Kraiczy, Peter
Borrelia burgdorferi evades complement-mediated killing by interacting with complement regulators through distinct complement regulator-acquiring surface proteins (CRASPs). Here, we extend our analyses to the contribution of CRASP-4 in mediating complement resistance of B. burgdorferi and its interaction with human complement regulators. CRASP-4 (also known as ErpC) was immobilized onto magnetic beads and used to capture proteins from human serum. Following Western blotting, factor H (CFH), CFH-related protein 1 (CFHR1), CFHR2, and CFHR5 were identified as ligands of CRASP-4. To analyze the impact of native CRASP-4 on mediating survival of serum-sensitive cells in human serum, a B. garinii strain was generated that ectopically expresses CRASP-4. CRASP-4-producing bacteria bound CFHR1, CFHR2, and CFHR5 but not CFH. In addition, transformed spirochetes deposited significant amounts of lethal complement components on their surface and were susceptible to human serum, thus indicating that CRASP-4 plays a subordinate role in complement resistance of B. burgdorferi.
Auner, Birgit ; Geiger, Emanuel Valentin ; Henrich, Dirk ; Lehnert, Mark ; Marzi, Ingo ; Relja, Borna
Background. Leukotriene B4 (LTB4), a proinflammatory lipid mediator correlates well with the acute phase of Acute Respiratory Distress Syndrome (ARDS). Therefore, LTB4-levels were investigated to determine whether they might be a useful clinical marker in predicting pulmonary complications (PC) in multiply traumatized patients. Methods: Plasma levels of LTB4 were determined in 100 patients on admission (ED) and for five consecutive days (daily). Twenty healthy volunteers served as control. LTB4-levels were measured by ELISA. Thirty patients developed PC (pneumonia, respiratory failure, acute lung injury (ALI), ARDS, pulmonary embolism) and 70 had no PC (ØPC). Results. LTB4-levels in the PC-group [127.8 pg/mL, IQR: 104–200pg/ml] were significantly higher compared to the ØPC-group on admission [95.6 pg/mL, IQR: 55–143 pg/mL] or control-group [58.4 pg/mL, IQR: 36–108 pg/mL]. LTB4 continuously declined to basal levels from day 1 to 5 without differences between the groups. The cutoff to predict PC was calculated at 109.6 pg/mL (72% specificity, 67% sensitivity). LTB4 was not influenced by overall or chest injury severity, age, gender or massive transfusion. Patients with PC received mechanical ventilation for a significantly longer period of time, and had prolonged intensive care unit and overall hospital stay. Conclusion. High LTB4-levels indicate risk for PC development in multiply traumatized patients
Statistical analysis on various stocks reveals long range dependence behavior of the stock prices that is not consistent with the classical Black and Scholes model. This memory or nondeterministic trend behavior is often seen as a reflection of market sentiments and causes that the historical volatility estimator becomes unreliable in practice. We propose an extension of the Black and Scholes model by adding a term to the original Wiener term involving a smoother process which accounts for these effects. The problem of arbitrage will be discussed. Using a generalized stochastic integration theory [8], we show that it is possible to construct a self financing replicating portfolio for a European option without any further knowledge of the extension and that, as a consequence, the classical concept of volatility needs to be re-interpreted.
AMS subject classifications: 60H05, 60H10, 90A09.
Integral equations for the mean-square estimate are obtained for the linear filtering problem, in which the noise generating the signal is a fractional Brownian motion with Hurst index h∈(3/4,1) and the noise in the observation process includes a fractional Brownian motion as well as a Wiener process. AMS subject classifications: 93E11, 60G20, 60G35.
Acupuncture is a therapy based on sensory stimulation of the human
body by means of metal needles. The exact underlying mechanisms of
acupuncture have not been clarified so far. Functional magnetic
resonance imaging (fMRI) has become an important tool in
acupuncture research. Standard acupuncture needles, which are made
of ferromagnetic steel, however, are problematic in
acupuncture-fMRI studies for several reasons, such as attraction
by the scanner's magnetic field, significant image distortions and
signal-dropouts, when positioned close to the head or even heating
due to absorption of radio frequency (RF). The aim of this study
was to compare two novel types of acupuncture needles with a
standard needle for their effect on MRI image quality. The
standard needle severely reduced image quality, when located
inside the RF coil. The nonferromagnetic metal needle may pose a
risk due to RF heating, while the plastic needle has a
significantly larger diameter. In conclusion, our recommendations
are: (1) standard needles should not be used in MRI; (2)
Nonferromagnetic metal needles seem to be the best choice for
acupoints outside of the transmitter coil; and (3) only plastic
needles are suited for points inside the coil. Laser acupuncture
may be a safe alternative, too.
P-type ATPases are membrane proteins acting as ion pumps that drive an active transport of cations across the membrane against a concentration gradient. The required energy for the ion transport is provided by binding and hydrolysis of ATP. A reaction mechanism of ion transport and energy transduction is assumed to be common for all P-type ATPases and generally described by the Post-Albers cycle. Transient currents and charge translocation of P-type ATPases were extensively investigated by electrical measurements that apply voltage jumps to initiate the reaction cycle. In this study, we simulate an applied voltage across the membrane by an electric field and perform electrostatic calculations in order to verify the experimentally-driven hypothesis that the energy transduction mechanism is regulated by specific structural elements. Side chain conformational and ionization changes induced by the electric field are evaluated for each transmembrane helix and the selectivity in response is qualitatively analyzed for the Ca2+-ATPase as well as for structural models of the Na+/K+-ATPase. Helix M5 responds with more conformer changes as compared to the other transmembrane helices what is even more emphasized when the stalk region is included. Thus our simulations support experimental results and indicate a crucial role for the highly conserved transmembrane helix M5 in the energy transduction mechanism of P-type ATPases.
Seitz, Oliver ; Schürmann, Christoph ; Hermes, Nadine ; Müller, Elke ; Pfeilschifter, Josef ; Frank, Stefan ; Goren, Itamar
In the past, the genetically diabetic-obese diabetes/diabetes (db/db) and obese/obese (ob/ob) mouse strains were used to investigate mechanisms of diabetes-impaired wound healing. Here we determined patterns of skin repair in genetically normal C57Bl/6J mice that were fed using a high fat diet (HFD) to induce a diabetes-obesity syndrome. Wound closure was markedly delayed in HFD-fed mice compared to mice which had received a standard chow diet (CD). Impaired wound tissue of HFD mice showed a marked prolongation of wound inflammation. Expression of vascular endothelial growth factor (VEGF) was delayed and associated with the disturbed formation of wound margin epithelia and an impaired angiogenesis in the reduced granulation tissue. Normal wound contraction was retarded and disordered. Wound disorders in obese C57Bl/6J mice were paralleled by a prominent degradation of the inhibitor of NFκB (IκB-α) in the absence of an Akt activation. By contrast to impaired wound conditions in ob/ob mice, late wounds of HFD mice did not develop a chronic inflammatory state and were epithelialized after 11 days of repair. Thus, only genetically obese and diabetic ob/ob mice finally developed chronic wounds and therefore represent a better suited experimental model to investigate diabetes-induced wound healing disorders.
Côté, Jérôme ; Bovenzi, Veronica ; Savard, Martin ; Dubuc, Céléna ; Fortier, Audrey ; Neugebauer, Witold ; Tremblay, Luc ; Müller-Esterl, Werner ; Tsanaclis, Ana-Maria ; Lepage, Martin ; Fortin, David ; Gobeil, Fernand
Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[DPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites.
Maga, Giovanni ; Garbelli, Anna ; Radi, Marco ; Falchi, Federico ; Samuele, Alberta ; Paolucci, Stefania ; Baldanti, Fausto ; Manetti, Fabrizio ; Beermann, Sandra ; Dietrich, Ursula ; Botta, Maurizio
Introduction: Efficacy of currently approved anti-HIV drugs is hampered by mutations of the viral enzymes, leading invariably to drug resistance and chemotherapy failure. Recent data suggest that cellular co-factors also represent useful targets for anti-HIV therapy. We have recently provided evidence for the possibility to block HIV-1 replication by targeting its cellular cofactor DDX3.
Material and methods: Molecular modeling and in silico technologies were applied to rationally design small molecules specifically targeting the RNA binding site of human DDX3. Biochemical studies of mutated DDX3 enzymes were also used to identify additional potential drug binding sites.
Results
Optimization of compounds identified by application of a high-throughput docking approach afforded a promising lead compound which proved to inhibit both the helicase and ATPase activity of DDX3 and to reduce the viral load of peripheral blood mononuclear cells (PBMC) infected with HIV-1. A novel interaction site has been also identified in DDX3, which, when blocked, can reduce viral replication, representing an additional target for small molecules inhibitors.
Conclusions: We have identified the first inhibitors of HIV-1 replication targeting the RNA binding site of the cellular cofactor human DDX3. These compounds may offer superior selectivity over the ATP-competitive inhibitors previously developed. In addition, a novel RNA interacting motif specific to DDX3 has been identified, opening new venues for HIV-1 drug development.
We have analysed the microseismic activity within the Rwenzori Mountains area in the western branch of the East African Rift. Seismogram recordings from a temporary array of up to 27 stations reveal approximately 800 events per month with local magnitudes ranging from –0.5 to 5.1. The earthquake distribution is highly heterogeneous. The majority of located events lie within faults zones to the East and West of the Rwenzoris with the highest seismic activity observed in the northeastern area, where the mountains are in contact with the rift shoulders. The hypocentral depth distribution exhibits a pronounced peak of seismic energy release at 15 km depth. The maximum extent of seismicity ranges from 20 to 32 km and correlates well with Moho depths that were derived from teleseismic receiver functions. We observe two general features: (i) beneath the rift shoulders seismicity extends from the surface down to ca. 30 km depth; (ii) beneath the rift valley seismicity is confined to depths greater than 10 km. From the observations there is no indication for a crustal root beneath the Rwenzori Mountains. The magnitude frequency distribution reveals a b-value of 1.1, which is consistent with the hypothesis that part of the seismicity is caused by magmatic processes within the crust. Fault plane solutions of 304 events were derived from P-polarities and SV/P amplitude ratios. More than 70 % of the source mechanisms exhibit pure or predominantly normal faulting. T-axis trends are highly uniform and oriented WNW-ESE, which is perpendicular to the rift axis and in good agreement with kinematic rift models. At the northernmost part of the region we observe a rotation of the T-axis trends to NEN-SWS, which may be indicative of a local perturbation of the regional stress field.
The neuroendocrine substance melatonin is a hormone synthesized rhythmically by the pineal gland under the influence of the circadian system and alternating light/dark cycles. Melatonin has been shown to have broad applications, and consequently becoming a molecule of great controversy. Undoubtedly, however, melatonin plays an important role as a time cue for the endogenous circadian system. This review focuses on melatonin as a regulator in the circadian modulation of memory processing. Memory processes (acquisition, consolidation, and retrieval) are modulated by the circadian system. However, the mechanism by which the biological clock is rhythmically influencing cognitive processes remains unknown. We also discuss, how the circadian system by generating cycling melatonin levels can implant information about daytime into memory processing, depicted as day and nighttime differences in acquisition, memory consolidation and/or retrieval.
Oncolytic effects of a novel Influenza A virus expressing Interleukin-15 from the NS reading frame
(2012)
Rikxoort, Marijke van ; Michaelis, Martin ; Wolschek, Markus ; Muster, Thomas ; Egorov, Andrej ; Seipelt, Joachim ; Doerr, Hans Wilhelm ; Cinatl, Jindrich
Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.
CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling
(2009)
Strauss, Gudrun ; Lindquist, Jonathan A. ; Arhel, Nathalie ; Felder, Edward ; Karl, Sabine ; Haas, Tobias L. ; Fulda, Simone ; Walczak, Henning ; Kirchhoff, Frank ; Debatin, Klaus-Michael
CD95 is a multifunctional receptor that induces cell death or proliferation depending on the signal, cell type, and cellular context. Here, we describe a thus far unknown function of CD95 as a silencer of T cell activation. Naive human T cells triggered by antigen-presenting cells expressing a membrane-bound form of CD95 ligand (CD95L) or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant CD95L had reduced activation and proliferation, whereas preactivated, CD95-sensitive T cells underwent apoptosis. Triggering of CD95 during T cell priming interfered with proximal T cell receptor signaling by inhibiting the recruitment of ζ-chain–associated protein of 70 kD, phospholipase-γ, and protein kinase C-θ into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca2+ mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-κB were strongly reduced, leading to impaired cytokine secretion. CD95-mediated inhibition of proliferation in naive T cells could not be reverted by the addition of exogenous interleukin-2 and T cells primed by CD95 co-stimulation remained partially unresponsive upon secondary T cell stimulation. HIV infection induced CD95L expression in primary human antigeen-presenting cells, and thereby suppressed T cell activation, suggesting that CD95/CD95L-mediated silencing of T cell activation represents a novel mechanism of immune evasion.
O'Dwyer, Laurence ; Lamberton, Franck ; Matura, Silke ; Scheibe, Monika ; Miller, Julia ; Rujescu, Dan ; Prvulovic, David ; Hampel, Harald
The apolipoprotein E4 (ApoE4) is an established risk factor for Alzheimer's disease (AD). Previous work has shown that this allele is associated with functional (fMRI) changes as well structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess the diffusion characteristics and the white matter (WM) tracts of healthy young (20-38 years) ApoE4 carriers and non-carriers. No significant differences in diffusion indices were found between young carriers (ApoE4+) and non-carriers (ApoE4-). There were also no significant differences between the groups in terms of normalised GM or WM volume. A feature selection algorithm (ReliefF) was used to select the most salient voxels from the diffusion data for subsequent classification with support vector machines (SVMs). SVMs were capable of classifying ApoE4 carrier and non-carrier groups with an extremely high level of accuracy. The top 500 voxels selected by ReliefF were then used as seeds for tractography which identified a WM network that included regions of the parietal lobe, the cingulum bundle and the dorsolateral frontal lobe. There was a non-significant decrease in volume of this WM network in the ApoE4 carrier group. Our results indicate that there are subtle WM differences between healthy young ApoE4 carriers and non-carriers and that the WM network identified may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age.
Der Aufsatz weist zunächst die bipolare Dependenz von Moral und Recht in Kants praktischer Philosophie nach. Durch eine Analyse von Kants Neuinterpretation der ulpianischen Rechtsregeln ist es möglich aufzuzeigen, dass Kant eine moralphilosophische Argumentation entwickelt, die mittels der intersubjektiven Anwendung des kategorischen Imperativs in der Selbstzweckvariante auf die Notwendigkeit von Rechtsverhältnissen rekurriert, die angeborene Freiheit aller Menschen sichert. Gleichwohl ist die normative Differenz von moralischer und rechtlicher Freiheit zu beachten.
Zudem zeichnet sich Kants spezifische Eigentumstheorie durch eine dynamische Entwicklung vom 'ursprünglichen' Gesamteigentum über den 'provisorischen' Ersterwerb hin zum 'ursprünglichen' Vertrag, der die Freiheit der Staatbürger sichert sowie den Staat als 'Obereigentümer' institutionalisiert.
Das Spannungsverhältnis von individuellen Staatbürgerrechten und staatlichen Handlungsbefugnissen verliert seine scheinbare Widersprüchlichkeit, sofern Freiheit sowohl als negatives wie als positives Recht verstanden wird. Ausschließlich in dem Kontext positiver Freiheitsrechte dürfte es möglich sein, die von Kant aufgeführten staatlichen Pflichten, wie beispielsweise die Pflicht des Staates, das Dasein aller Staatsbürger zu sichern, in Kants allgemeines Rechtsprinzip zu integrieren.
Striatal dopamine transmission is subtly modified in human A53Tα-synuclein overexpressing mice
(2012)
Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn), cause familial Parkinson's disease (PD). Mouse lines overexpressing the mutant human A53Tα-syn may represent a model of early PD. They display progressive motor deficits, abnormal cellular accumulation of α-syn, and deficits in dopamine-dependent corticostriatal plasticity, which, in the absence of overt nigrostriatal degeneration, suggest there are age-related deficits in striatal dopamine (DA) signalling. In addition A53Tα-syn overexpression in cultured rodent neurons has been reported to inhibit transmitter release. Therefore here we have characterized for the first time DA release in the striatum of mice overexpressing human A53Tα-syn, and explored whether A53Tα-syn overexpression causes deficits in the release of DA. We used fast-scan cyclic voltammetry to detect DA release at carbon-fibre microelectrodes in acute striatal slices from two different lines of A53Tα-syn-overexpressing mice, at up to 24 months. In A53Tα-syn overexpressors, mean DA release evoked by a single stimulus pulse was not different from wild-types, in either dorsal striatum or nucleus accumbens. However the frequency responsiveness of DA release was slightly modified in A53Tα-syn overexpressors, and in particular showed slight deficiency when the confounding effects of striatal ACh acting at presynaptic nicotinic receptors (nAChRs) were antagonized. The re-release of DA was unmodified after single-pulse stimuli, but after prolonged stimulation trains, A53Tα-syn overexpressors showed enhanced recovery of DA release at old age, in keeping with elevated striatal DA content. In summary, A53Tα-syn overexpression in mice causes subtle changes in the regulation of DA release in the striatum. While modest, these modifications may indicate or contribute to striatal dysfunction.
The Alpine Region, constituting the Alps and the Dinaric Alps, has played a major role in the formation of current patterns of biodiversity either as a contact zone of postglacial expanding lineages or as the origin of genetic diversity. In our study, we tested these hypotheses for two widespread, sympatric microgastropod taxa - Carychium minimum O.F. Müller, 1774 and Carychium tridentatum (Risso, 1826) (Gastropoda, Eupulmonata, Carychiidae) - by using COI sequence data and species potential distribution models analyzed in a statistical phylogeographical framework. Additionally, we examined disjunct transatlantic populations of those taxa from the Azores and North America. In general, both Carychium taxa demonstrate a genetic structure composed of several differentiated haplotype lineages most likely resulting from allopatric diversification in isolated refugial areas during the Pleistocene glacial periods. However, the genetic structure of Carychium minimum is more pronounced, which can be attributed to ecological constraints relating to habitat proximity to permanent bodies of water. For most of the Carychium lineages, the broader Alpine Region was identified as the likely origin of genetic diversity. Several lineages are endemic to the broader Alpine Region whereas a single lineage per species underwent a postglacial expansion to (re)colonize previously unsuitable habitats, e.g. in Northern Europe. The source populations of those expanding lineages can be traced back to the Eastern and Western Alps. Consequently, we identify the Alpine Region as a significant 'hot-spot' for the formation of genetic diversity within European Carychium lineages. Passive dispersal via anthropogenic means best explains the presence of transatlantic European Carychium populations on the Azores and in North America. We conclude that passive (anthropogenic) transport could mislead the interpretation of observed phylogeographical patterns in general.
Resistance of rhabdomyosarcoma to current therapies remains one of the key issues in pediatric oncology. Since the success of most cytotoxic therapies in the treatment of cancer, for example, chemotherapy, depends on intact signaling pathways that mediate programmed cell death (apoptosis), defects in apoptosis programs in cancer cells may result in resistance. Evasion of apoptosis in rhabdomyosarcoma may be caused by defects in the expression or function of critical mediators of apoptosis or in aberrant expression of antiapoptotic proteins. Therefore, the identification of the molecular mechanisms that confer primary or acquired resistance to apoptosis in rhabdomyosarcoma presents a critical step for the rational development of molecular targeted drugs. This approach will likely open novel perspectives for the treatment of rhabdomyosarcoma.
Betulinic acid is a natural product with a range of biological effects, for example potent antitumor activity. This anticancer property is linked to its ability to induce apoptotic cell death in cancer cells by triggering the mitochondrial pathway of apoptosis. In contrast to the cytotoxicity of betulinic acid against a variety of cancer types, normal cells and tissue are relatively resistant to betulinic acid, pointing to a therapeutic window. Compounds that exert a direct action on mitochondria present promising experimental cancer therapeutics, since they may trigger cell death under circumstances in which standard chemotherapeutics fail. Thus, mitochondrion-targeted agents such as betulinic acid hold great promise as a novel therapeutic strategy in the treatment of human cancers.
Keywords: apoptosis, cancer, betulinic acid, mitochondria
Keywords: AIF, apoptosis inducing factor; Apaf-1, Apoptotic protease activating factor-1; BA, betulinic acid; DIABLO, direct IAP Binding protein with Low PI; HtrA2, high temperature requirement protein A; IAPs, Inhibitor of Apoptosis Proteins; MOMP, mitochondrial outer membrane permeabilization; ROS, reactive oxygen species; PARP, Poly (ADP-ribose) Polymerase; Smac, second mitochondria-derived activator of caspase; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; zVAD.fmk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone
Cells can respond to stress in various ways ranging from the activation of survival pathways to the initiation of cell death that eventually eliminates damaged cells. Whether cells mount a protective or destructive stress response depends to a large extent on the nature and duration of the stress as well as the cell type. Also, there is often the interplay between these responses that ultimately determines the fate of the stressed cell. The mechanism by which a cell dies (i.e., apoptosis, necrosis, pyroptosis, or autophagic cell death) depends on various exogenous factors as well as the cell's ability to handle the stress to which it is exposed. The implications of cellular stress responses to human physiology and diseases are manifold and will be discussed in this review in the context of some major world health issues such as diabetes, Parkinson's disease, myocardial infarction, and cancer.
One of the hallmarks of human cancers is the intrinsic or acquired resistance to apoptosis. Evasion of apoptosis can be part of a cellular stress response to ensure the cell's survival upon exposure to stressful stimuli. Apoptosis resistance may contribute to carcinogenesis, tumor progression, and also treatment resistance, since most current anticancer therapies including chemotherapy as well as radio- and immunotherapies primarily act by activating cell death pathways including apoptosis in cancer cells. Hence, a better understanding of the molecular mechanisms regarding how cellular stress stimuli trigger antiapoptotic mechanisms and how this contributes to tumor resistance to apoptotic cell death is expected to provide the basis for a rational approach to overcome apoptosis resistance mechanisms in cancers.
Autophagy has long been thought to be an essential but unselective bulk degradation pathway. However, increasing evidence suggests selective autophagosomal turnover of a broad range of substrates. Bifunctional autophagy receptors play a key role in selective autophagy by tethering cargo to the site of autophagosomal engulfment. While the identity of molecular components involved in selective autophagy has been revealed at least to some extent, we are only beginning to understand how selectivity is achieved in this process. Here, we summarize the mechanistic and structural basis of receptor-mediated selective autophagy.
Brügmann, Gerhard ; Krause, Joachim ; Brachert, Thomas C. ; Stoll, Brigitte ; Weis, Ulrike ; Kullmer, Ottmar ; Ssemmanda, Immaculate ; Mertz, Dieter F.
For reconstructing environmental change in terrestrial realms the geochemistry of fossil bioapatite in bones and teeth is among the most promising applications. This study demonstrates that alkaline earth elements in enamel of Hippopotamids, in particular Ba and Sr are tracers for water provenance and hydrochemistry. The studied specimens are molar teeth from Hippopotamids found in modern and fossil lacustrine settings of the Western Branch of the East African Rift system (Lake Kikorongo, Lake Albert, and Lake Malawi) and from modern fluvial environments of the Nile River.
Concentrations in enamel vary by ca. two orders of magnitude for Ba (120–9336 μg g−1) as well as for Sr (9–2150 μg g−1). Concentration variations in enamel are partly induced during post-mortem alteration and during amelogenesis, but the major contribution originates from the variable water chemistry in the habitats of the Hippopotamids which is dominated by the lithologies and weathering processes in the watershed areas. Amelogenesis causes a distinct distribution of Ba and Sr in modern and fossil enamel, in that element concentrations increase along profiles from the outer rim towards the enamel-dentin junction by a factor of 1.3–1.5. These elements are well correlated with MgO and Na2O in single specimens, thus suggesting that their distribution is determined by a common, single process. Presuming that the shape of the tooth is established at the end of the secretion process and apatite composition is in equilibrium with the enamel fluid, the maturation process can be modeled by closed system Rayleigh crystallization.
Enamel from many Hippopotamid specimens has Sr/Ca and Ba/Ca which are typical for herbivores, but the compositions extend well into the levels of plants and carnivores. Within enamel from single specimens these element ratios covary and provide a specific fingerprint of the Hippopotamid habitat. All specimens together, however, define subparallel trends with different Ba/Sr ranging from 0.1 to 3. This ratio varies on spatial and temporal scales and traces provenance signals as well as the fractionation of the elements in the hydrological cycle. Thus, Sr concentrations and Ba/Sr in enamel differentiate between habitats having basaltic or Archean crustal rocks as the ultimate sources of Sr and Ba. The provenance signal is modulated by climate change. In Miocene to Pleistocene enamel from the Lake Albert region, Ba/Sr decreases systematically with time from about 2 to 0.5. This trend can be correlated with changes in climate from humid to arid in vegetation from C3 to C4 biomass as well as with increasing evaporation of the lake water. The most plausible explanation is that with time, Ba mobility decreased relative to that of Sr. This can arise if preferential adsorption of Ba to clay and Fe-oxide-hydroxide is related to increasing aridification. Additionally, weathering solutions and lake water can become increasingly alkaline and barite becomes stable. In this case, Ba will be preferentially deposited on the watershed of Lake Albert and rivers with low Ba/Sr will feed the habitats of the Hippopotamids.
Spatial variations of nitrogen trace gas emissions from tropical mountain forests in Nyungwe, Rwanda
(2012)
Gharahi Ghehi, Nasrin ; Werner, Christian ; Cizungu Ntaboba, Landry ; Mbonigaba Muhinda, Jean Jacques ; Van Ranst, Eric ; Butterbach-Bahl, Klaus ; Kiese, Ralf ; Boeckx, Pascal
Globally, tropical forest soils represent the second largest source of N2O and NO. However, there is still considerable uncertainty on the spatial variability and soil properties controlling N trace gas emission. Therefore, we carried out an incubation experiment with soils from 31 locations in the Nyungwe tropical mountain forest in southwestern Rwanda. All soils were incubated at three different moisture levels (50, 70 and 90 % water filled pore space (WFPS)) at 17 °C. Nitrous oxide emission varied between 4.5 and 400 μg N m−2 h−1, while NO emission varied from 6.6 to 265 μg N m−2 h−1. Mean N2O emission at different moisture levels was 46.5 ± 11.1 (50 %WFPS), 71.7 ± 11.5 (70 %WFPS) and 98.8 ± 16.4 (90 %WFPS) μg N m−2 h−1, while mean NO emission was 69.3 ± 9.3 (50 %WFPS), 47.1 ± 5.8 (70 %WFPS) and 36.1 ± 4.2 (90 %WFPS) μg N m−2 h−1. The latter suggests that climate (i.e. dry vs. wet season) controls N2O and NO emissions. Positive correlations with soil carbon and nitrogen indicate a biological control over N2O and NO production. But interestingly N2O and NO emissions also showed a positive correlation with free iron and a negative correlation with soil pH (only N2O). The latter suggest that chemo-denitrification might, at least for N2O, be an important production pathway. In conclusion improved understanding and process based modeling of N trace gas emission from tropical forests will benefit from spatially explicit trace gas emission estimates linked to basic soil property data and differentiating between biological and chemical pathways for N trace gas formation.
Smith, Tanya M. ; Bacon, Anne-Marie ; Demeter, Fabrice ; Kullmer, Ottmar ; Nguyen, Kim Thuy ; Vos, John de ; Wei, Wang ; Zermeno, John P. ; Zhao, Lingxia
Orangutans (Pongo) are the only great ape genus with a substantial Pleistocene and Holocene fossil record, demonstrating a much larger geographic range than extant populations. In addition to having an extensive fossil record, Pongo shows several convergent morphological similarities with Homo, including a trend of dental reduction during the past million years. While studies have documented variation in dental tissue proportions among species of Homo, little is known about variation in enamel thickness within fossil orangutans. Here we assess dental tissue proportions, including conventional enamel thickness indices, in a large sample of fossil orangutan postcanine teeth from mainland Asia and Indonesia. We find few differences between regions, except for significantly lower average enamel thickness (AET) values in Indonesian mandibular first molars. Differences between fossil and extant orangutans are more marked, with fossil Pongo showing higher AET in most postcanine teeth. These differences are significant for maxillary and mandibular first molars. Fossil orangutans show higher AET than extant Pongo due to greater enamel cap areas, which exceed increases in enamel-dentine junction length (due to geometric scaling of areas and lengths for the AET index calculation). We also find greater dentine areas in fossil orangutans, but relative enamel thickness indices do not differ between fossil and extant taxa. When changes in dental tissue proportions between fossil and extant orangutans are compared with fossil and recent Homo sapiens, Pongo appears to show isometric reduction in enamel and dentine, while crown reduction in H. sapiens appears to be due to preferential loss of dentine. Disparate selective pressures or developmental constraints may underlie these patterns. Finally, the finding of moderately thick molar enamel in fossil orangutans may represent an additional convergent dental similarity with Homo erectus, complicating attempts to distinguish these taxa in mixed Asian faunas.
Background: Mammalian fossils from the Eppelsheim Formation (Dinotheriensande) have been a benchmark for Neogene vertebrate palaeontology since 200 years. Worldwide famous sites like Eppelsheim serve as key localities for biochronologic, palaeobiologic, environmental, and mammal community studies. So far the formation is considered to be of early Late Miocene age (~9.5 Ma, Vallesian), representing the oldest sediments of the Rhine River. The stratigraphic unity of the formation and of its fossil content was disputed at times, but persists unresolved.
Principal Findings: Here we investigate a new fossil sample from Sprendlingen, composed by over 300 mammalian specimens and silicified wood. The mammals comprise entirely Middle Miocene species, like cervids Dicrocerus elegans, Paradicrocerus elegantulus, and deinotheres Deinotherium bavaricum and D. levius. A stratigraphic evaluation of Miocene Central European deer and deinothere species proof the stratigraphic inhomogenity of the sample, and suggest late Middle Miocene (~12.5 Ma) reworking of early Middle Miocene (~15 Ma) sediments. This results agree with taxonomic and palaeoclimatic analysis of plant fossils from above and within the mammalian assemblage. Based on the new fossil sample and published data three biochronologic levels within the Dinotheriensand fauna can be differentiated, corresponding to early Middle Miocene (late Orleanian to early Astaracian), late Middle Miocene (late Astaracian), and early Late Miocene (Vallesian) ages.
Conclusions/Significance: This study documents complex faunal mixing of classical Dinotheriensand fauna, covering at least six million years, during a time of low subsidence in the Mainz Basin and shifts back the origination of the Rhine River by some five million years. Our results have severe implications for biostratigraphy and palaeobiology of the Middle to Late Miocene. They suggest that turnover events may be obliterated and challenge the proposed ‘supersaturated’ biodiversity, caused by Middle Miocene superstites, of Vallesian ecosystems in Central Europe.
Volcic, Meta ; Karl, Sabine ; Baumann, Bernd ; Salles, Daniela ; Daniel, Peter ; Fulda, Simone ; Wiesmüller, Lisa
NF-κB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosis. Even though NF-κB can be activated by DNA damage via Ataxia telangiectasia-mutated (ATM) signalling, little was known about an involvement in DNA repair. In this work, we dissected distinct DNA double-strand break (DSB) repair mechanisms revealing a stimulatory role of NF-κB in homologous recombination (HR). This effect was independent of chromatin context, cell cycle distribution or cross-talk with p53. It was not mediated by the transcriptional NF-κB targets Bcl2, BAX or Ku70, known for their dual roles in apoptosis and DSB repair. A contribution by Bcl-xL was abrogated when caspases were inhibited. Notably, HR induction by NF-κB required the targets ATM and BRCA2. Additionally, we provide evidence that NF-κB interacts with CtIP-BRCA1 complexes and promotes BRCA1 stabilization, and thereby contributes to HR induction. Immunofluorescence analysis revealed accelerated formation of replication protein A (RPA) and Rad51 foci upon NF-κB activation indicating HR stimulation through DSB resection by the interacting CtIP-BRCA1 complex and Rad51 filament formation. Taken together, these results define multiple NF-κB-dependent mechanisms regulating HR induction, and thereby providing a novel intriguing explanation for both NF-κB-mediated resistance to chemo- and radiotherapies as well as for the sensitization by pharmaceutical intervention of NF-κB activation
Rettinger, Eva ; Meyer, Vida ; Kreyenberg, Hermann ; Volk, Andreas ; Kuçi, Selim ; Willasch, Andre Manfred ; Koscielniak, Ewa ; Fulda, Simone ; Wels, Winfried ; Bönig, Halvard-Björn ; Klingebiel, Thomas ; Bader, Peter
Allogeneic stem cell transplantation (allo-SCT) has become an important treatment modality for patients with high-risk acute myeloid leukemia (AML) and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD) status ultimately leading to patients’ relapse. Adoptive donor lymphocyte infusions based on MRD status using IL-15-expanded cytokine-induced killer (CIK) cells may prevent relapse without causing graft-versus-host-disease (GvHD). To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL-2Rγc−, NSG) were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS) cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow followed by liver, lung, spleen, peripheral blood (PB), and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at equal amounts were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells 250 times more CIK than THP-1 cells were needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliable 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells have potent cytotoxic capacity against AML and RMS cells without causing GvHD.
Pape, Andreas ; Kutschker, Saskia ; Kertscho, Harry ; Stein, Peter ; Horn, Oliver ; Lossen, Mischa ; Zwißler, Bernhard ; Habler, Oliver
The correction of hypovolemia with acellular fluids results in acute normovolemic anemia. Whether the choice of the infusion fluid has an impact on the maintenance of oxygen (O2) supply during acute normovolemic anemia has not been investigated so far.
Methods:
Thirty-six anesthetized and mechanically ventilated pigs were hemodiluted to their physiological limit of anemia tolerance, reflected by the individual critical hemoglobin concentration (Hbcrit). Hbcrit was defined as the Hb-concentration corresponding with the onset of supply-dependency of total body O2-consumption (VO2). The hemodilution protocol was randomly performed with either Tetrastarch (6% HES 130/0.4, TS-group, n=9), Gelatin (3.5% urea-crosslinked polygeline, GEL-group, n=9), Hetastarch (6% HES 450/0.7, HS-group, n=9) or Ringer's solution (RS-group, n=9). The primary endpoint was the dimension of Hbcrit, secondary endpoints were parameters of central hemodynamics, O2-transport and tissue oxygenation.
Results:
In each animal, normovolemia was maintained throughout the protocol. Hbcrit was met at 3.7+/-0.6 g/dl (RS), 3.0+/-0.6 g/dl (HS P<0.05 vs. RS), 2.7+/-0.6 g/dl (GEL, P<0.05 vs. RS) and 2.1+/-0.4 g/dl (TS, P<0.05 vs. GEL, HS and RS). Hemodilution with RS resulted in a significant increase of extravascular lung water index (EVLWI) and a decrease of arterial oxygen partial pressure (paO2), O2-extraction ratio was increased, when animals of the TS-, GEL- and HS-groups met their individual Hbcrit.
Conclusions:
The choice of the intravenous (i.v) fluid has an impact on the tolerance of acute normovolemic anemia induced by acellular volume replacement. Third-generation Tetrastarch preparations (e.g., HES 130/0.4) appear most advantageous regarding maintenance of tissue oxygenation during progressive anemia. The underlying mechanism includes a lower degree of extravasation and favourable effects on microcirculatory function.
Schimanski, Carl Christoph ; Möhler, Markus ; Schön, Michael ; Van Cutsem, Eric ; Greil, Richard ; Bechstein, Wolf Otto ; Hegewisch-Becker, Susanna ; Wichert, Götz Peter Lothar von ; Vöhringer, Matthias ; Heike, Michael ; Heinemann, Volker ; Peeters, Marc ; Kanzler, Stephan ; Kasper, Stefan ; Overkamp, Friedrich ; Schröder, Jan ; Seehofer, Daniel ; Kullmann, Frank ; Linz, Bernhard ; Schmidtmann, Irene ; Smith-Machnow, Victoria ; Gockel, Ines ; Lang, Hauke ; Galle, Peter R.
Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.
Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.
Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-20
Schäfer, Ingmar ; Hansen, Heike ; Schön, Gerhard ; Höfels, Susanne ; Altiner, Attila ; Dahlhaus, Anne Maren ; Gensichen, Jochen ; Riedel-Heller, Steffi Gerlinde ; Weyerer, Siegfried ; Blank, Wolfgang A. ; König, Hans-Helmut ; Knesebeck, Olaf von dem ; Wegscheider, Karl ; Scherer, Martin ; Bussche, Hendrik van den ; Wiese, Birgitt
Background: Multimorbidity is a phenomenon with high burden and high prevalence in the elderly. Our previous research has shown that multimorbidity can be divided into the multimorbidity patterns of 1) anxiety, depression, somatoform disorders (ADS) and pain, and 2) cardiovascular and metabolic disorders. However, it is not yet known, how these patterns are influenced by patient characteristics. The objective of this paper is to analyze the association of socio-demographic variables, and especially socio-economic status with multimorbidity in general and with each multimorbidity pattern.
Methods: The MultiCare Cohort Study is a multicentre, prospective, observational cohort study of 3.189 multimorbid patients aged 65+ randomly selected from 158 GP practices. Data were collected in GP interviews and comprehensive patient interviews. Missing values have been imputed by hot deck imputation based on Gower distance in morbidity and other variables. The association of patient characteristics with the number of chronic conditions is analysed by multilevel mixed-effects linear regression analyses.
Results: Multimorbidity in general is associated with age (+0.07 chronic conditions per year), gender (-0.27 conditions for female), education (-0.26 conditions for medium and -0.29 conditions for high level vs. low level) and income (-0.27 conditions per logarithmic unit). The pattern of cardiovascular and metabolic disorders shows comparable associations with a higher coefficient for gender (-1.29 conditions for female), while multimorbidity within the pattern of ADS and pain correlates with gender (+0.79 conditions for female), but not with age or socioeconomic status.
Conclusions: Our study confirms that the morbidity load of multimorbid patients is associated with age, gender and the socioeconomic status of the patients, but there were no effects of living arrangements and marital status. We could also show that the influence of patient characteristics is dependent on the multimorbidity pattern concerned, i.e. there seem to be at least two types of elderly multimorbid patients. First, there are patients with mainly cardiovascular and metabolic disorders, who are more often male, have an older age and a lower socio-economic status. Second, there are patients mainly with ADS and pain-related morbidity, who are more often female and equally distributed across age and socio-economic groups.
Because of the imbalance in the supply and demand of red blood cells (RBCs), especially for alloimmunized patients or patients with rare blood phenotypes, extensive research has been done to generate therapeutic quantities of mature RBCs from hematopoietic stem cells of various sources, such as bone marrow, peripheral blood, and cord blood. Since human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) can be maintained indefinitely in vitro, they represent potentially inexhaustible sources of donor-free RBCs. In contrast to other ex vivo stem-cell-derived cellular therapeutics, tumorigenesis is not a concern, as RBCs can be irradiated without marked adverse effects on in vivo function. Here, we provide a comprehensive review of the recent publications relevant to the generation and characterization of hESC- and iPSC-derived erythroid cells and discuss challenges to be met before the eventual realization of clinical usage of these cells.
Adipose tissue as a stem cell source is ubiquitously available and has several advantages compared to other sources. It is easily accessible in large quantities with minimal invasive harvesting procedure, and isolation of adipose-derived mesenchymal stromal/stem cells (ASCs) yields a high amount of stem cells, which is essential for stem-cell-based therapies and tissue engineering. Several studies have provided evidence that ASCs in situ reside in a perivascular niche, whereas the exact localization of ASCs in native adipose tissue is still under debate. ASCs are isolated by their capacity to adhere to plastic. Nevertheless, recent isolation and culture techniques lack standardization. Cultured cells are characterized by their expression of characteristic markers and their capacity to differentiate into cells from meso-, ecto-, and entodermal lineages. ASCs possess a high plasticity and differentiate into various cell types, including adipocytes, osteoblasts, chondrocytes, myocytes, hepatocytes, neural cells, and endothelial and epithelial cells. Nevertheless, recent studies suggest that ASCs are a heterogeneous mixture of cells containing subpopulations of stem and more committed progenitor cells. This paper summarizes and discusses the current knowledge of the tissue localization of ASCs in situ, their characterization and heterogeneity in vitro, and the lack of standardization in isolation and culture methods.
Wie aus dem Nichts heraus entstanden zu Anfang des 2. Jahrtausends v. Chr. befestigte Siedlungen, die eine ganze Region im Trans-Ural vollständig veränderten. Im »Land der Städte« erblühte an der Grenze zwischen Europa und Asien für mehr als zwei Jahrhunderte eine Kulturlandschaft, die ihresgleichen sucht. Wer waren ihre Bewohner, und woher kamen sie? Was wollten sie in dieser bis dato nahezu unbesiedelten Region? Wie kommt es zu den zahlreichen Innovationen, zu denen neue Pferdeschirrungen und die ältesten Streitwagen der Welt
zählen? Ein deutsch-russisches Forscherteam ist angetreten, diese Rätsel zu lösen.
Das Hessische Ried war nur dünn besiedelt, als die Römer kurz vor der Zeitenwende die Garnisonsstadt Mogontiacum/Mainz gründeten. Gelegen im rechtsrheinischen Vorfeld der neuen Metropole, profitierte das Ried von der Wirtschaftskraft der dort stationierten Legionen, denen es als Nutzland und Manövergebiet diente. Vollständig erschlossen wurde das Gebiet aber erst durch die zivile Besiedlungsphase im frühen zweiten Jahrhundert n. Chr. mit der Gründung von Dörfern und zahlreichen Gutshöfen. Nach zwischenzeitlichem Rückgang der Besiedlung erlebte das Ried im vierten Jahrhundert eine neue Blütezeit. Das Institut für Archäologische Wissenschaften hat die Entwicklung dieser Region bis um 500 n. Chr. in einem mehrjährigen Projekt rekonstruiert. Nach dem rheinischen Kohleabbaugebiet ist das Hessische Ried die am intensivsten
erforschte Landschaft im römischen Deutschland.
1993 stellte die Entdeckung winziger Stückchen von Ribonukleinsäuren, heute als microRNAs bekannt, die Wissenschaftler vor ein Rätsel. Erstmals beobachtet wurden sie in dem Fadenwurm C. elegans, einem einfachen, vergleichsweise leicht durchschaubaren Organismus. Was die Wissenschaftler verwirrte, war die Tatsache, dass diese microRNAs ganz offensichtlich nicht für Proteine kodierten. Welche Funktion haben sie dann? Inzwischen weiß man, dass sie eine wichtige Rolle bei der Genregulation spielen. Und das nicht nur im Fadenwurm: MicroRNAs sind evolutionär hoch konserviert, sie kommen auch in höheren Organismen vor. Im Menschen sind mehr als 1500 microRNAs beschrieben, und man geht davon aus, dass mindestens 30 Prozent der Gene direkt durch microRNAs reguliert werden. Das lässt sich auch für therapeutische Zwecke nutzen. In unserer Arbeitsgruppe erforschen wir insbesondere die Rolle der microRNAs bei Herz- und Gefäß-Erkrankungen.
Fettleibigkeit, Bluthochdruck, erhöhte Blutfettwerte und Insulin-Resistenz – diese als »Metabolisches Syndrom« bezeichnete Kombination von Risikofaktoren ist auch als »tödliches Quartett« bekannt. Typ-II-Diabetes und Herz-Kreislauf-Erkrankungen sind die Folge. Doch wie hängen diese auf den ersten Blick recht unterschiedlichen Phänomene zusammen? Neuere Untersuchungen zeigen, dass Diabetes und ein gestörter Fettstoffwechsel mehr gemeinsam haben, als man bisher annahm.
Schutz oder Schaden für die Gefäße? : Bei Sauerstoffradikalen kommt es auf das Gleichgewicht an
(2012)
Sauerstoffradikale werden für Alterung, Krebs und Herz-Kreislauf-Erkrankungen verantwortlich gemacht. Von diesem schlechten Image profitiert der große Markt der Nahrungszusatzstoffe wie Vitamine, die Radikale im Körper einfangen. Doch in klinischen Studien können keine positiven Effekte durch die Einnahme von Vitaminpräparaten nachgewiesen werden. Warum? Weil Sauerstoffradikale nicht nur schädliche Nebenprodukte des Stoffwechsels sind, sondern auch lebensnotwendige Funktionen wie die Abwehr von Krankheitserregern übernehmen. Sie werden daher im Körper in einem eng regulierten Bereich aktiv produziert. Unsere Arbeitsgruppe am Institut für Kardiovaskuläre Physiologie untersucht Mechanismen der Radikalproduktion durch Nox-Enzyme und erforscht ihre physiologische Bedeutung im Herz-Kreislauf-System.
Jährlich erkranken etwa 80 000 Deutsche an einer Thrombose, die meisten trifft es im höheren Lebensalter, als Folge einer längeren Immobilisation oder der Einnahme von Hormonpräparaten. Bei einigen aber wird das Gerinnsel, das Venen oder Arterien verstopft, durch eine angeborene oder erworbene Thrombophilie verursacht. Manche dieser Gerinnungsneigungen sind häufig, andere sehen selbst die Ärzte im Schwerpunkt Angiologie/Hämostaseologie des Gefäßzentrums der Frankfurter Uniklinik höchstens ein-, zweimal im Monat. Weshalb belastbare Erkenntnisse auch zur Therapie dieser seltenen Thromboseformen fehlen. Dies zu ändern, ist das Ziel des Teams um Professor Edelgard Lindhoff-Last an der Frankfurter Uniklinik.
Viele Chemotherapeutika zerstören nicht nur Krebszellen, sondern beschädigen auch Eizellen, die dann durch ein körpereigenes Qualitätskontrollsystem aussortiert werden. Die Arbeitsgruppe von Prof. Dr. Volker Dötsch am Institut für Biophysikalische Chemie will diesen Mechanismus nun im Rahmen eines Koselleck-Projekts der Deutschen Forschungsgemeinschaft
genauer untersuchen.
In den Tiefen der Ozeane gewinnen Methan-bildende Archaeen Energie aus Kohlendioxid und Wasser. Wie die Methanbildung mit der Synthese von ATP, der zellulären Energiewährung, einhergeht, haben Mikrobiologen der Goethe-Universität zusammen mit Kollegen vom Frankfurter Max-Planck-Institut für Biophysik geklärt.