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Jung, Oliver ; Haack, Hans Stefan ; Büttner, Maike ; Betz, Christoph ; Stephan, Christoph ; Grützmacher, Peter ; Amann, Kerstin Ute ; Bickel, Markus
Background: Chronic renal disease is a serious complication of long-term intravenous drug use (IVDU). Recent reports have postulated a changing pattern of underlying nephropathy over the last decades.
Methods: Retrospective investigation including all patients with prior or present IVDU that underwent renal biopsy because of chronic kidney disease between 01.04.2002 and 31.03.2012 in the city of Frankfurt/Main, Germany.
Results: Twenty four patients with IVDU underwent renal biopsy because of progressive chronic kidney disease or proteinuria. Renal AA-amyloidosis was the predominant cause of renal failure in 50% of patients. Membranoproliferative glomerulonephritis (GN) was the second most common cause found in 21%. Patients with AA-amyloidosis were more likely to be HIV infected (67 vs.17%; p=0.036) and tended to have a higher rate of repeated systemic infections (92 vs. 50%; p=0.069). Patients with AA-amyloidosis presented with progressive renal disease and nephrotic-range proteinuria but most patients had no peripheral edema or systemic hypertension. Development of proteinuria preceded the decline of GFR for approximately 1--2 years.
Conclusions: AA-amyloidosis was the predominant cause of progressive renal disease in the last 10 years in patients with IVDU. The highest rate of AA-amyloidosis observed was seen in HIV infected patients with IVDU. We speculate that chronic HIV-infection as well as the associated immunosuppression might promote development of AA-amyloidosis by increasing frequency and duration of infections acquired by IVDU.
Thiberville, Simon-Djamel ; Schilling, Stefan ; De Iaco, Giuseppina ; Fusco, Francesco Maria ; Thomson, Gail ; Maltezou, Helen C. ; Gottschalk, René ; Brodt, Hans-Reinhard ; Bannister, Barbara ; Puro, Vincenzo ; Ippolito, Giuseppe ; Brouqui, Philippe
Background: Highly infectious diseases (HIDs) are defined as being transmissible from person to person, causing life-threatening illnesses and presenting a serious public health hazard. The sampling, handling and transport of specimens from patients with HIDs present specific bio-safety concerns. Findings The European Network for HID project aimed to record, in a cross-sectional study, the infection control capabilities of referral centers for HIDs across Europe and assesses the level of achievement to previously published guidelines. In this paper, we report the current diagnostic capabilities and bio-safety measures applied to diagnostic procedures in these referral centers. Overall, 48 isolation facilities in 16 European countries were evaluated. Although 81% of these referral centers are located near a biosafety level 3 laboratory, 11% and 31% of them still performed their microbiological and routine diagnostic analyses, respectively, without bio-safety measures.
Conclusions: The discrepancies among the referral centers surveyed between the level of practices and the European Network of Infectious Diseases (EUNID) recommendations have multiple reasons of which the interest of the individuals in charge and the investment they put in preparedness to emerging outbreaks. Despite the fact that the less prepared centers can improve by just updating their practice and policies any support to help them to achieve an acceptable level of biosecurity is welcome.
"Jüdische Irrlehre" oder exegetisches Experiment? : die Restitution Israels im 16. Jahrhundert
(2011)
Schwiedrzik, Caspar Martin ; Ruff, Christian C. ; Lazar, Andreea ; Leitner, Frauke C. ; Singer, Wolf ; Melloni, Lucia
Perception is an active inferential process in which prior knowledge is combined with sensory input, the result of which determines the contents of awareness. Accordingly, previous experience is known to help the brain “decide” what to perceive. However, a critical aspect that has not been addressed is that previous experience can exert 2 opposing effects on perception: An attractive effect, sensitizing the brain to perceive the same again (hysteresis), or a repulsive effect, making it more likely to perceive something else (adaptation). We used functional magnetic resonance imaging and modeling to elucidate how the brain entertains these 2 opposing processes, and what determines the direction of such experience-dependent perceptual effects. We found that although affecting our perception concurrently, hysteresis and adaptation map into distinct cortical networks: a widespread network of higher-order visual and fronto-parietal areas was involved in perceptual stabilization, while adaptation was confined to early visual areas. This areal and hierarchical segregation may explain how the brain maintains the balance between exploiting redundancies and staying sensitive to new information. We provide a Bayesian model that accounts for the coexistence of hysteresis and adaptation by separating their causes into 2 distinct terms: Hysteresis alters the prior, whereas adaptation changes the sensory evidence (the likelihood function).
We discuss deviations from the exponential decay law which occur when going beyond the BreitWigner distribution for an unstable state. In particular, we concentrate on an oscillating behavior, remisiscent of the Rabi-oscillations, in the short-time region. We propose that these oscillations can explain the socalled GSI anomaly, which measured superimposed oscillations on top of the exponential law for hydrogen-like nuclides decaying via electron-capture. Moreover, we discuss the possibility that the deviations from the Breit-Wigner in the case of the GSI anomaly are (predominantely) caused by the interaction of the unstable state with the measurement apparatus. The consequences of this scenario, such as the non-observation of oscillations in an analogous experiment perfromed at Berkley, are investigated.
We investigate the implications of the r-modes instability on the composition of a compact star rotating at a sub-millisecond period. In particular, the only viable astrophysical scenario for such an object, wich might present inside the Low Mass X-ray Binary associated with the x-ray transient XTE J1739-285, is that it has a strangeness content. Since previous analysis indicate that hyperonic stars or stars containing a kaon condensate are unlikely because of the mass-shedding constraint, the only remaining possibility is that such an object is either a strange quark star or a hybrid quark-hadron star.
Schaffner-Bielich, Jürgen ; Sagert, Irina ; Hempel, Matthias ; Pagliara, Giuseppe ; Fischer, Tobias ; Mezzacappa, Anthony ; Thielemann, Friedrich-Karl ; Liebendörfer, Matthias
The possible role of a first order QCD phase transition at nonvanishing quark chemical potential and temperature for cold neutron stars and for supernovae is delineated. For cold neutron stars, we use the NJL model with nonvanishing color superconducting pairing gaps, which describes the phase transition to the 2SC and the CFL quark matter phases at high baryon densities. We demonstrate that these two phase transitions can both be present in the core of neutron stars and that they lead to the appearance of a third family of solution for compact stars. In particular, a core of CFL quark matter can be present in stable compact star configurations when slightly adjusting the vacuum pressure to the onset of the chiral phase transition from the hadronic model to the NJL model. We show that a strong first order phase transition can have strong impact on the dynamics of core collapse supernovae. If the QCD phase transition sets in shortly after the first bounce, a second outgoing shock wave can be generated which leads to an explosion. The presence of the QCD phase transition can be read off from the neutrino and antineutrino signal of the supernova.
We extend the recently developed strong coupling, dimensionally reduced Polyakov-loop effective theory from finite-temperature pure Yang-Mills to include heavy fermions and nonzero chemical
potential by means of a hopping parameter expansion. Numerical simulation is employed to investigate the weakening of the deconfinement transition as a function of the quark mass. The
tractability of the sign problem in this model is exploited to locate the critical surface in the (M/T,m/T,T) space over the whole range of chemical potentials from zero up to infinity.
Molnar, Wolfgang ; Lugstein, Alois ; Wojcik, Tomasz ; Pongratz, Peter ; Auner, Norbert ; Bauch, Christian ; Bertagnolli, Emmerich
Perchlorinated polysilanes were synthesized by polymerization of tetrachlorosilane under cold plasma conditions with hydrogen as a reducing agent. Subsequent selective cleavage of the resulting polymer yielded oligochlorosilanes SinCl2n+2 (n = 2, 3) from which the octachlorotrisilane (n = 3, Cl8Si3, OCTS) was used as a novel precursor for the synthesis of single-crystalline Si nanowires (NW) by the well-established vapor–liquid–solid (VLS) mechanism. By adding doping agents, specifically BBr3 and PCl3, we achieved highly p- and n-type doped Si-NWs by means of atmospheric-pressure chemical vapor deposition (APCVD). These as grown NWs were investigated by means of scanning electron microscopy (SEM) and transmission electron microscopy (TEM), as well as electrical measurements of the NWs integrated in four-terminal and back-gated MOSFET modules. The intrinsic NWs appeared to be highly crystalline, with a preferred growth direction of [111] and a specific resistivity of ρ = 6 kΩ·cm. The doped NWs appeared to be [112] oriented with a specific resistivity of ρ = 198 mΩ·cm for p-type Si-NWs and ρ = 2.7 mΩ·cm for n-doped Si-NWs, revealing excellent dopant activation.
Muthukumar, Kaliappan ; Jeschke, Harald O. ; Valentí, Roser ; Begun, Evgeniya ; Schwenk, Johannes ; Porrati, Fabrizio ; Huth, Michael
We present experimental results and theoretical simulations of the adsorption behavior of the metal–organic precursor Co2(CO)8 on SiO2 surfaces after application of two different pretreatment steps, namely by air plasma cleaning or a focused electron beam pre-irradiation. We observe a spontaneous dissociation of the precursor molecules as well as autodeposition of cobalt on the pretreated SiO2 surfaces. We also find that the differences in metal content and relative stability of these deposits depend on the pretreatment conditions of the substrate. Transport measurements of these deposits are also presented. We are led to assume that the degree of passivation of the SiO2 surface by hydroxyl groups is an important controlling factor in the dissociation process. Our calculations of various slab settings, using dispersion-corrected density functional theory, support this assumption. We observe physisorption of the precursor molecule on a fully hydroxylated SiO2 surface (untreated surface) and chemisorption on a partially hydroxylated SiO2 surface (pretreated surface) with a spontaneous dissociation of the precursor molecule. In view of these calculations, we discuss the origin of this dissociation and the subsequent autocatalysis.
Bleicher, Marcus ; Burigo, Lucas ; Durante, Marco ; Herrlitz, Maren ; Krämer, Michael ; Mishustin, Igor N. ; Müller, Iris ; Natale, Francesco ; Pshenichnov, Igor A. ; Schramm, Stefan ; Taucher-Scholz, Gisela ; Wälzlein, Cathrin
The biological effects of energetic heavy ions are attracting increasing interest for their applications in cancer therapy and protection against space radiation. The cascade of events leading to cell death or late effects starts from stochastic energy deposition on the nanometer scale and the corresponding lesions in biological molecules, primarily DNA. We have developed experimental techniques to visualize DNA nanolesions induced by heavy ions. Nanolesions appear in cells as “streaks” which can be visualized by using different DNA repair markers. We have studied the kinetics of repair of these “streaks” also with respect to the chromatin conformation. Initial steps in the modeling of the energy deposition patterns at the micrometer and nanometer scale were made with MCHIT and TRAX models, respectively.
Agakishiev, Geydar ; Álvarez-Pol, Héctor ; Balanda, Andrzej ; Bassini, Roberto ; Böhmer, Michael ; Bokemeyer, Helmut ; Boyard, Jean-Louis ; Cabanelas Eiras, Pablo ; Chernenko, Sergey ; Christ, Tassilo ; Destefanis, Marco Giovanni Maria ; Dohrmann, Frank ; Dybczak, Adrian ; Eberl, Thomas ; Fabbietti, Laura ; Fateev, Oleg ; Finocchiaro, Paolo ; Friese, Jürgen ; Fröhlich, Ingo ; Galatyuk, Tetyana ; Garzón, Juan A. ; Gernhäuser, Roman ; Gilardi, Camilla ; Golubeva, Marina ; González-Díaz, Diégo ; Guber, Fedor ; Gumberidze, Malgorzata ; Hennino, Thierry ; Holzmann, Romain ; Ierusalimov, Alexander P. ; Iori, Ileana ; Ivashkin, Alexander ; Jurkovič, Martin ; Kämpfer, Burkhard ; Kanaki, Kalliopi ; Karavicheva, Tatiana L. ; Koenig, Ilse ; Koenig, Wolfgang ; Kolb, Burkhard W. ; Kotte, Roland ; Kozuch, Anna ; Krizek, Filip ; Kühn, Wolfgang ; Kugler, Andrej ; Kurepin, Alexei ; Lang, Simon Martin ; Lapidus, Kirill ; Liu, T. ; Maier, Ludwig W. ; Markert, Jochen ; Metag, Volker ; Michalska, Beata ; Morinière, Emilie ; Mousa, Jehad ; Münch, Mathias ; Müntz, Christian ; Naumann, Lothar ; Otwinowski, Jacek Tomasz ; Pachmayer, Yvonne C. ; Pechenov, Vladimir ; Pechenova, Olga ; Pérez Cavalcanti, Tiago ; Pietraszko, Jerzy ; Pospısil, Vladimir ; Przygoda, Witold ; Ramstein, Béatrice ; Reshetin, Andrey ; Roy-Stephan, M. ; Rustamov, Anar ; Sadovsky, Alexander ; Sailer, Benjamin ; Salabura, Piotr ; Sánchez, M. ; Schmah, Alexander ; Schwab, Erwin ; Sobolev, Yuri G. ; Spataro, Stefano ; Spruck, Björn ; Ströbele, Herbert ; Stroth, Joachim ; Sturm, Christian Thomas ; Tarantola Peloni, Attilio ; Teilab, Khaled ; Tlustý, Pavel ; Toia, Alberica ; Traxler, Michael ; Trebacz, Radoslaw ; Tsertos, Haralabos ; Wagner, Vladimir ; Wisniowski, Marcin ; Wojcik, Tomasz ; Wüstenfeld, Jörn ; Yurevich, Sergey ; Zanevsky, Yuri V. ; Zumbruch, Peter W.
We present measurements of exclusive ensuremathπ+,0 and η production in pp reactions at 1.25GeV and 2.2GeV beam kinetic energy in hadron and dielectron channels. In the case of π+ and π0 , high-statistics invariant-mass and angular distributions are obtained within the HADES acceptance as well as acceptance-corrected distributions, which are compared to a resonance model. The sensitivity of the data to the yield and production angular distribution of Δ (1232) and higher-lying baryon resonances is shown, and an improved parameterization is proposed. The extracted cross-sections are of special interest in the case of pp → pp η , since controversial data exist at 2.0GeV; we find \ensuremathσ=0.142±0.022 mb. Using the dielectron channels, the π0 and η Dalitz decay signals are reconstructed with yields fully consistent with the hadronic channels. The electron invariant masses and acceptance-corrected helicity angle distributions are found in good agreement with model predictions.
Second-order dissipative hydrodynamic equations for each component of a multi-component system are derived using the entropy principle. Comparison of the solutions with kinetic transport results demonstrates validity of the obtained equations. We demonstrate how the shear viscosity of the total system can be calculated in terms of the involved cross-sections and partial densities. The presence of the inter-species interactions leads to a characteristic time dependence of the shear viscosity of the mixture, which also means that the shear viscosity of a mixture cannot be calculated using the Green-Kubo formalism the way it has been done recently. This finding is of interest for understanding of the shear viscosity of a quark-gluon plasma extracted from comparisons of hydrodynamic simulations with experimental results from RHIC and LHC.
Electron beam-induced deposition with tungsten hexacarbonyl W(CO)6 as precursors leads to granular deposits with varying compositions of tungsten, carbon and oxygen. Depending on the deposition conditions, the deposits are insulating or metallic. We employ an evolutionary algorithm to predict the crystal structures starting from a series of chemical compositions that were determined experimentally. We show that this method leads to better structures than structural relaxation based on estimated initial structures. We approximate the expected amorphous structures by reasonably large unit cells that can accommodate local structural environments that resemble the true amorphous structure. Our predicted structures show an insulator-to-metal transition close to the experimental composition at which this transition is actually observed and they also allow comparison with experimental electron diffraction patterns.
A careful analysis of the magneto-transport properties of epitaxial nanostructured Nb thin films in the normal and the mixed state is performed. The nanopatterns were prepared by focused ion beam (FIB) milling. They provide a washboard-like pinning potential landscape for vortices in the mixed state and simultaneously cause a resistivity anisotropy in the normal state. Two matching magnetic fields for the vortex lattice with the underlying nanostructures have been observed. By applying these fields, the most likely pinning sites along which the flux lines move through the samples have been selected. By this, either the background isotropic pinning of the pristine film or the enhanced isotropic pinning originating from the nanoprocessing have been probed. Via an Arrhenius analysis of the resistivity data the pinning activation energies for three vortex lattice parameters have been quantified. The changes in the electrical transport and the pinning properties have been correlated with the results of the microstructural and topographical characterization of the FIB-patterned samples. Accordingly, along with the surface processing, FIB milling has been found to alter the material composition and the degree of disorder in as-grown films. The obtained results provide further insight into the pinning mechanisms at work in FIB-nanopatterned superconductors, e.g. for fluxonic applications.
Erler, Antje ; Beyer, Martin ; Petersen, Juliana ; Saal, Kristina ; Rath, Thomas ; Rochon, Justine ; Haefeli, Walter E. ; Gerlach, Ferdinand M.
Background: Patients with chronic kidney disease (CKD) are at increased risk for inappropriate or potentially harmful prescribing. The aim of this study was to examine whether a multifaceted intervention including the use of a software programme for the estimation of creatinine clearance and recommendation of individual dosage requirements may improve correct dosage adjustment of relevant medications for patients with CKD in primary care.
Methods: A cluster-randomized controlled trial was conducted between January and December 2007 in small primary care practices in Germany. Practices were randomly allocated to intervention or control groups. In each practice, we included patients with known CKD and elderly patients (>=70 years) suffering from hypertension. The practices in the intervention group received interactive training and were provided a software programme to assist with individual dose adjustment. The control group performed usual care. Data were collected at baseline and at 6 months. The outcome measures, analyzed across individual patients, included prescriptions exceeding recommended maximum daily doses, with the primary outcome being prescriptions exceeding recommended standard daily doses by 30% or more.
Results: Data from 44 general practitioners and 404 patients are included. The intervention was effective in reducing prescriptions exceeding the maximum daily dose per patients, with a trend in reducing prescriptions exceeding the standard daily dose by more than 30%.
Conclusions: A multifaceted intervention including the use of a software program effectively reduced inappropriately high doses of renally excreted medications in patients with CKD in the setting of small primary care practices.
Sauerbrei, Andreas ; Schacke, Michael ; Glück, Brigitte ; Bust, Uwe ; Rabenau, Holger ; Wutzler, Peter
BACKGROUND: There is agreement that the infectivity assay with the duck hepatitis B virus (DHBV) is a suitable surrogate test to validate disinfectants for hepatitis B virucidal activity. However, since this test is not widely used, information is necessary whether disinfectants with limited virucidal activity also inactivate DHBV. In general, disinfectants with limited virucidal activity are used for skin and sensitive surfaces while agents with full activity are more aggressive. The present study compares the activity of five different biocides against DHBV and the classical test virus for limited virucidal activity, the vaccinia virus strain Lister Elstree (VACV) or the modified vaccinia Ankara strain (MVA).
METHODS: Virucidal assay was performed as suspension test according to the German DVV/RKI guideline. Duck hepatitis B virus obtained from congenitally infected Peking ducks was propagated in primary duck embryonic hepatocytes and was detected by indirect immunofluorescent antigen staining.
RESULTS: The DHBV was inactivated by the use of 40% ethanol within 1-min and 30% isopropanol within 2-min exposure. In comparison, 40% ethanol within 2-min and 40% isopropanol within 1-min exposure were effective against VACV/MVA. These alcohols only have limited virucidal activity, while the following agents have full activity. 0.01% peracetic acid inactivated DHBV within 2 min and a concentration of 0.005% had virucidal efficacy against VACV/MVA within 1 min. After 2-min exposure, 0.05% glutardialdehyde showed a comparable activity against DHBV and VACV/MVA. This is also the case for 0.7% formaldehyde after a contact time of 30 min.
CONCLUSIONS: Duck hepatitis B virus is at least as sensitive to limited virucidal activity as VACV/MVA. Peracetic acid is less effective against DHBV, while the alcohols are less effective against VACV/MVA. It can be expected that in absence of more direct tests the results may be extrapolated to HBV.
Fungal populations that reproduce sexually are likely to be genetically more diverse and have a higher adaptive potential than asexually reproducing populations. Mating systems of fungal species can be self-incompatible, requiring the presence of isolates of different mating-type genes for sexual reproduction to occur, or self-compatible, requiring only one. Understanding the distribution of mating-type genes in populations can help to assess the potential of self-incompatible species to reproduce sexually. In the locally threatened epiphytic lichen-forming fungus Lobaria pulmonaria (L.) Hoffm., low frequency of sexual reproduction is likely to limit the potential of populations to adapt to changing environmental conditions. Our study provides direct evidence of self-incompatibility (heterothallism) in L. pulmonaria. It can thus be hypothesized that sexual reproduction in small populations might be limited by an unbalanced distribution of mating-type genes. We therefore assessed neutral genetic diversity (using microsatellites) and mating-type ratio in 27 lichen populations (933 individuals). We found significant differences in the frequency of the two mating types in 13 populations, indicating a lower likelihood of sexual reproduction in these populations. This suggests that conservation translocation activities aiming at maximizing genetic heterogeneity in threatened and declining populations should take into account not only presence of fruiting bodies in transplanted individuals, but also the identity and balanced representation of mating-type genes.
Brauer, Age ; Kurz, Alexander ; Stockwell, Tim ; Baden-Tillson, Holly ; Heidler, Juliana ; Wittig, Ilka ; Kauferstein, Silke ; Mebs, Dietrich ; Stöcklin, Reto ; Remm, Maido
Cone snails are venomous predatory marine neogastropods that belong to the species-rich superfamily of the Conoidea. So far, the mitochondrial genomes of two cone snail species (Conus textile and Conus borgesi) have been described, and these feed on snails and worms, respectively. Here, we report the mitochondrial genome sequence of the fish-hunting cone snail Conus consors and describe a novel putative control region (CR) which seems to be absent in the mitochondrial DNA (mtDNA) of other cone snail species. This possible CR spans about 700 base pairs (bp) and is located between the genes encoding the transfer RNA for phenylalanine (tRNA-Phe, trnF) and cytochrome c oxidase subunit III (cox3). The novel putative CR contains several sequence motifs that suggest a role in mitochondrial replication and transcription.
Romero-Brey, Inés ; Merz, Andreas ; Chiramel, Abhilash ; Lee, Ji-Young ; Chlanda, Petr ; Haselman, Uta ; Santarella-Mellwig, Rachel ; Habermann, Anja ; Hoppe, Simone ; Kallis, Stephanie ; Walther, Paul ; Antony, Claude ; Krijnse-Locker, Jacomine ; Bartenschlager, Ralf
All positive strand RNA viruses are known to replicate their genomes in close association with intracellular membranes. In case of the hepatitis C virus (HCV), a member of the family Flaviviridae, infected cells contain accumulations of vesicles forming a membranous web (MW) that is thought to be the site of viral RNA replication. However, little is known about the biogenesis and three-dimensional structure of the MW. In this study we used a combination of immunofluorescence- and electron microscopy (EM)-based methods to analyze the membranous structures induced by HCV in infected cells. We found that the MW is derived primarily from the endoplasmic reticulum (ER) and contains markers of rough ER as well as markers of early and late endosomes, COP vesicles, mitochondria and lipid droplets (LDs). The main constituents of the MW are single and double membrane vesicles (DMVs). The latter predominate and the kinetic of their appearance correlates with kinetics of viral RNA replication. DMVs are induced primarily by NS5A whereas NS4B induces single membrane vesicles arguing that MW formation requires the concerted action of several HCV replicase proteins. Three-dimensional reconstructions identify DMVs as protrusions from the ER membrane into the cytosol, frequently connected to the ER membrane via a neck-like structure. In addition, late in infection multi-membrane vesicles become evident, presumably as a result of a stress-induced reaction. Thus, the morphology of the membranous rearrangements induced in HCV-infected cells resemble those of the unrelated picorna-, corona- and arteriviruses, but are clearly distinct from those of the closely related flaviviruses. These results reveal unexpected similarities between HCV and distantly related positive-strand RNA viruses presumably reflecting similarities in cellular pathways exploited by these viruses to establish their membranous replication factories.
O artigo investiga a formação, a carreira e os trabalhos de Max Weber como jurista, assim como delineia as linhas gerais do impacto e das influências de sua formação jurídica na sua obra em geral. Especial atenção merece sua tese de doutorado sobre as sociedades comerciais na Idade Média, que é apresentada em sua problematização geral e em suas principais ideias. Com isso, procura-se indicar como os problemas tratados por Weber em sua tese de doutorado - sua principal obra jurídica - antecipam temas e problemas que serão desenvolvidos na obra posterior de modo ampliado e aprofundado.
A intenção do presente trabalho é apresentar uma discussão sobre as análises de como a modificação de futuros potenciais de conhecimento influenciaram, por um lado, os novos conceitos de currículo e didática e, por outro lado, as reformas pedagógicas efetuadas no sistema educacional na Alemanha, a partir de um projeto desenvolvido pelo autor - pesquisador do Instituto Federal de Formação Profissional/BIBB/Berlin. Ao longo do texto procurar-se-á indicar que, como conseqüência das inovações pedagógicas ligadas ao conceito de qualificação-chave, ou seja competência profissional para a ação, ocorreu decisivamente uma nova orientação na construção de currículos e na teoria didática do referido país.
Trabalho e consciência : mudanças na sociedade do trabalho e a reconstrução da teoria de classe
(2002)
Este artigo busca discutir as possibilidades e limitações de se utilizar para a análise das sociedades industriais modernas o conceito de classe advindo das determinações econômicas do marxismo. Com a aumento da complexidade destas sociedades e de suas formas de produzir, com a predominância de novos setores como o de serviços no processo de reprodução do capital, como dar conta e criar um conceito que integre todos os excluídos e incluídos no sistema capitalista de trabalho e que dê conta das novas possibilidades de constituição de uma consciência política comum. Tendo por referência a discussão alemã contemporânea sobre a questão, busca–se entender que as tendências da reorganização sistêmica da produção em empresas modernas, provocam, na sua forma inovadora, uma mudança no status do trabalhador na fábrica e na sua consciência tradicional.
"Entre direitos iguais, a força decide", proferiu karl marx ao descrever a antinomia do direito em situações antagônicas das relações de produção capitalistas, em que "o direito [oferece resistência] ao direito" nesse ponto, marx aborda uma questão que se situa no centro de todas as teorias jurídicas críticas: que tipo de violência é velada por meio do mecanismo de ocultação denominado "direito"? Para responder a esta questão, tentar-se-á, a seguir, tornar a teoria da hegemonia de antonio gramsci e seu modelo de direito hegemônico produtivos para o campo da teoria do direito. Tal tarefa tem de lidar com a dupla dificuldade de que, por um lado, gramsci não foi um teórico do direito no sentido mais estrito, razão pela qual o potencial de sua teoria para uma análise do direito raramente foi utilizada. Por outro lado, sua abordagem só pode ser empregada por meio de uma crítica às restrições relacionadas a seu tempo. isso se aplica especialmente à sua concepção de economia como a base e a núcleo essencialista oculto (laclau; mouffe, 2001:69), assim como à sua ideia de 'classismo' sob a forma de um enfoque unilateral das classes, em que há preferencialmente mais de um "pluralismo de poder" e inúmeras lutas (litowitz, 2000: 536). Recuperar-se-á, consequentemente, argumentos-chave, ampliando-os pela utilização das recentes descobertas feitas pelas abordagens feminista e neomaterialista da teoria jurídica, bem como as análises de foucault acerca das tecnologias de poder. por fim, uma interpretação da teoria sistêmica das autonomizações comunicativas.
O 11 de setembro acelerou o desenvolvimento de uma arquitetura transnacional de segurança que intervém profundamente nas liberdades civis individuais, tanto nos direitos básicos dos cidadãos dos Estados como nos direitos humanos dos cidadãos mundiais. O artigo delineia essa arquitetura, mostra como ela dissolve as categorias jurídicas tradicionais que preservam a liberdade e discute por que hoje se aceita amplamente a prioridade da segurança sobre a liberdade.
Os limites da tolerância
(2009)
Este artigo apresenta os elementos constitutivos do conceito de tolerância e discute duas concepções diferentes do termo, como permissão e como respeito moral, que expressam modos diversos de demarcar os limites da tolerância. A tolerância é apresentada como um conceito que, para ganhar algum conteúdo, depende normativamente de um direito à justificação baseado na idéia de um uso público da razão segundo o qual as práticas e as instituições político-jurídicas que determinam a vida social dos cidadãos devem ser justificáveis à luz de normas que eles não podem recíproca e genericamente rejeitar.
Otterbein, Sascha ; Abel, Cornelius Benjamin ; Heinemann, Linda Verena ; Kaiser, Jochen ; Schmidt-Kassow, Maren
Temporal predictability is thought to affect stimulus processing by facilitating the allocation of attentional resources. Recent studies have shown that periodicity of a tonal sequence results in a decreased peak latency and a larger amplitude of the P3b compared with temporally random, i.e., aperiodic sequences. We investigated whether this applies also to sequences of linguistic stimuli (syllables), although speech is usually aperiodic. We compared aperiodic syllable sequences with two temporally regular conditions. In one condition, the interval between syllable onset was fixed, whereas in a second condition the interval between the syllables’ perceptual center (p-center) was kept constant. Event-related potentials were assessed in 30 adults who were instructed to detect irregularities in the stimulus sequences. We found larger P3b amplitudes for both temporally predictable conditions as compared to the aperiodic condition and a shorter P3b latency in the p-center condition than in both other conditions. These findings demonstrate that even in acoustically more complex sequences such as syllable streams, temporal predictability facilitates the processing of deviant stimuli. Furthermore, we provide first electrophysiological evidence for the relevance of the p-center concept in linguistic stimulus processing.
While the general elections in Myanmar in November 2010 were widely condemned, both national and international actors approached the by-elections of April 2012 as a political rite-de-passage to improve relations between the government and the opposition inside, and between the former pariah state and the international community outside the country. An undercurrent to the government-led transition process from an authoritarian to a formally more democratic regime was the development of a politically oriented civil society that found ways to engage in the electoral process. This article describes the emerging spaces of election-related civil society activism in the forms of civic and voter education, national election observation, and election-related agency in the media. Noting that, in particular, election observation offers connections for civil society to regional and international debates, the paper draws preliminary conclusions about further developments ahead of the general elections in Myanmar expected for 2015.
Peifer, Christian ; Sharma, Sunny ; Watzinger, Peter ; Lamberth, Stefanie ; Kötter, Peter ; Entian, Karl-Dieter
Ribosomal RNA undergoes various modifications to optimize ribosomal structure and expand the topological potential of RNA. The most common nucleotide modifications in ribosomal RNA (rRNA) are pseudouridylations and 2'-O methylations (Nm), performed by H/ACA box snoRNAs and C/D box snoRNAs, respectively. Furthermore, rRNAs of both ribosomal subunits also contain various base modifications, which are catalysed by specific enzymes. These modifications cluster in highly conserved areas of the ribosome. Although most enzymes catalysing 18S rRNA base modifications have been identified, little is known about the 25S rRNA base modifications. The m(1)A modification at position 645 in Helix 25.1 is highly conserved in eukaryotes. Helix formation in this region of the 25S rRNA might be a prerequisite for a correct topological framework for 5.8S rRNA to interact with 25S rRNA. Surprisingly, we have identified ribosomal RNA processing protein 8 (Rrp8), a nucleolar Rossman-fold like methyltransferase, to carry out the m(1)A base modification at position 645, although Rrp8 was previously shown to be involved in A2 cleavage and 40S biogenesis. In addition, we were able to identify specific point mutations in Rrp8, which show that a reduced S-adenosyl-methionine binding influences the quality of the 60S subunit. This highlights the dual functionality of Rrp8 in the biogenesis of both subunits.
Helfrich, Christian ; Pierau, Simone S. ; Freitag, Christine M. ; Roeper, Jochen ; Ziemann, Ulf ; Bender, Stephan
Background: Repetitive transcranial magnetic stimulation (rTMS) allows non-invasive stimulation of the human brain. However, no suitable marker has yet been established to monitor the immediate rTMS effects on cortical areas in children.
Objective: TMS-evoked EEG potentials (TEPs) could present a well-suited marker for real-time monitoring. Monitoring is particularly important in children where only few data about rTMS effects and safety are currently available.
Methods: In a single-blind sham-controlled study, twenty-five school-aged children with ADHD received subthreshold 1 Hz-rTMS to the primary motor cortex. The TMS-evoked N100 was measured by 64-channel-EEG pre, during and post rTMS, and compared to sham stimulation as an intraindividual control condition.
Results: TMS-evoked N100 amplitude decreased during 1 Hz-rTMS and, at the group level, reached a stable plateau after approximately 500 pulses. N100 amplitude to supra-threshold single pulses post rTMS confirmed the amplitude reduction in comparison to the pre-rTMS level while sham stimulation had no influence. EEG source analysis indicated that the TMS-evoked N100 change reflected rTMS effects in the stimulated motor cortex. Amplitude changes in TMS-evoked N100 and MEPs (pre versus post 1 Hz-rTMS) correlated significantly, but this correlation was also found for pre versus post sham stimulation.
Conclusion: The TMS-evoked N100 represents a promising candidate marker to monitor rTMS effects on cortical excitability in children with ADHD. TMS-evoked N100 can be employed to monitor real-time effects of TMS for subthreshold intensities. Though TMS-evoked N100 was a more sensitive parameter for rTMS-specific changes than MEPs in our sample, further studies are necessary to demonstrate whether clinical rTMS effects can be predicted from rTMS-induced changes in TMS-evoked N100 amplitude and to clarify the relationship between rTMS-induced changes in TMS-evoked N100 and MEP amplitudes. The TMS-evoked N100 amplitude reduction after 1 Hz-rTMS could either reflect a globally decreased cortical response to the TMS pulse or a specific decrease in inhibition.
Heeg, Annika ; Kuchler, Laura ; Eifler, Lisa ; Knape, Tilo ; Heide, Hermann ; Brüne, Bernhard ; Knethen, Andreas von
Background: In macrophages Toll-like receptor 4 (TLR4) is activated in response to lipopolysaccharide (LPS) and induces proinflammatory cytokine expression. Therefore, mechanisms terminating proinflammatory gene expression are important. Autophagy plays a central role in controlling innate immune responses by lysosomal degradation of signaling proteins, thus contributing to the resolution of inflammation. Autophagic proteins like p62 directly interact with molecules involved in the TLR4-signaling pathway, but a correlation with the IRAK E3 ligase and scaffold protein Pellino3 remains obscure. Hence, we are interested in elucidating the function of Pellino3 to prove our hypothesis that it is a key regulator in the TLR4-signaling cascade.
Methods: We used the cecal ligation and puncture (CLP) mouse model causing polymicrobial sepsis to analyze Pellino3 protein and mRNA expression. Furthermore, we induced endotoxemia in RAW264.7 mouse macrophages by LPS treatment to verify in vivo experiments. Lentiviral Pellino3 knockdown in RAW264.7 macrophages was used for cytokine measurements at mRNA level. To analyze potential Pellino3 binding partners in TLR4-signaling by mass spectrometry (MS), we overexpressed FLAG-tagged Pellino3 in RAW264.7 macrophages, treated cells for 3, 6 and 24 hours with LPS and immunoprecipitated Pellino3 via its FLAG-tag. To consider Pellino3 degradation as a result of p62-mediated autophagy, we transiently knocked down p62 by siRNA in RAW264.7 macrophages and also pharmacologically blocked LPS-induced autophagy by Bafilomycin A1.
Results: We demonstrated Pellino3 protein degradation in primary CD11b+ splenocytes after 24 hours following CLP operation and confirmed this in RAW264.7 macrophages after 24-hour LPS stimulation. Knockdown of Pellino3 attenuates proinflammatory cytokines, for example IL-6 mRNA, after 6 hours of LPS. Furthermore, we found by MS and verifying immunoprecipitation experiments that p62 is a Pellino3 binding partner, thus targeting Pellino3 for degradation. In line, both p62 knockdown and Bafilomycin A1 treatment prevent Pellino3 degradation, supporting an autophagic mechanism.
Conclusion: Our observations highlight a regulatory role of Pellino3 on TLR4 signaling. Thus, antagonism of Pellino3 in the hyperinflammatory phase of sepsis may counteract the cytokine storm. Furthermore, stabilization of Pellino3 by inhibition of autophagy in the hypoinflammatory phase of sepsis may improve immunity. In consideration of these two conflictive sepsis phases, modulation of Pellino3 may provide a new strategy for the development of a therapy approach in sepsis.
Attenuated NOX2 expression impairs ROS production during the hypoinflammatory phase of sepsis
(2012)
Kuchler, Laura ; Morbitzer, Virginie ; Heeg, Annika ; Eifler, Lisa ; Knape, Tilo ; Brüne, Bernhard ; Knethen, Andreas von
Background: The multicomponent phagocytic NADPH oxidase produces reactive oxygen species (ROS) after activation by microorganisms or inflammatory mediators. In the hypoinflammatory phase of sepsis, macrophages are alternatively activated by contact with apoptotic cells or their secretion products. This inhibits NADPH oxidase and leads to attenuated ROS production and furthermore contributes among others to a hyporeactive host defense. Due to this immune paralysis, sepsis patients suffer from recurrent and secondary infections. We focused on the catalytic subunit of NADPH oxidase, the transmembrane protein NOX2. We assume that after induction of sepsis the expression of NOX2 is reduced and hence ROS production is decreased.
Methods: We induced polymicrobial sepsis in mice by cecal ligation and puncture. The ability of peritoneal macrophages (PMs) to produce ROS was determined by FACS via hydroethidine assay. NOX2 expression of PMs was determined by western blot and qPCR. To elucidate the mechanism causing mRNA destabilization, we performed in vitro experiments using J774 macrophages. To obtain an alternatively activated phenotype, macrophages were stimulated with conditioned medium from apoptotic T cells (CM). By luciferase assays we figured out a 3'UTR-dependent regulation of NOX2 mRNA stability. Assuming that a protein is involved in the mRNA degradation, we performed a RNA pulldown with biotinylated NOX2-3'UTR constructs followed by mass spectrometry. We verified the role of SYNCRIP by siRNA approach. Additionally, we overexpressed NOX2 in J774 cells and analyzed the ROS production (w/wo CM treatment) by FACS.
Results: We found an impaired expression of NOX2 at RNA and protein level along with decreased ROS production after induction of sepsis in mice as well as stimulating J774 macrophages with CM of apoptotic T cells. This is due to a time-dependent NOX2 mRNA degradation depending on SYNCRIP, a RNA-binding protein, which stabilizes NOX2 mRNA through binding to its 3'UTR under normal conditions. In line, knockdown of SYNCRIP also decreases NOX2 mRNA expression. We assume that a CM-dependent modification or degradation of SYNCRIP prevents its stabilizing function. As the overexpression of NOX2 restores ROS production of CM-treated J774 cells, we assume that NOX2 expression is crucial for maintaining NADPH activity during the hypoinflammatory phase of sepsis.
Conclusion: Our data imply a regulatory impact of SYNCRIP on NOX2 stability during the late phase of sepsis. Therefore, further understanding of the regulation of NADPH oxidase could lead to the design of a therapy to reconstitute NADPH oxidase function, finally improving immune function in sepsis patients.
Knape, Tilo ; Eifler, Lisa ; Heeg, Annika ; Kuchler, Laura ; Brüne, Bernhard ; Parnham, Michael J. ; Knethen, Andreas von
Background: The ligand-activated transcription factor, peroxisome-proliferator-activated receptor gamma (PPARγ), has been shown to play an essential role in immunosuppression during sepsis. PPARγ is upregulated in T cells of septic patients, sensitizing these cells to PPARγ-dependent apoptosis and thus contributing to T-cell depletion. In the polymicrobial cecum ligation and puncture (CLP) sepsis model in mice, both T-cell-specific gene knockout (Lck-Cre PPARγfl/fl) and systemic pharmacological PPARγ antagonism by GW9662 improved survival. Because GW9662 was only effective when applied 3 hours after CLP, we were interested to extend this time frame. For this reason we characterized the kinetics of SPPARγMs when administered before or in combination with the agonist thiazolidinedione, rosiglitazone.
Methods: A PPARγ-dependent transactivation assay was used in HEK293T cells. It is based on the vector pFA-PPARγ-LBD-GAL4-DBD encoding the hybrid protein PPARγ-LBD-GAL4-DBD and the reporter vector pFR-Luc, carrying a GAL4-responsive element in front of the Firefly luciferase gene. These two vectors were co-transfected, in combination with a control vector encoding Renilla luciferase (pRL-CMV) to normalize Firefly luciferase activity for transfection efficiency. Following transfection, cells were incubated with the SPPARγMs F-MOC and MCC-555 and the PPARγ antagonist GW9662 for different times (2 to 48 hours) and at increasing doses (0.01 to 10 μM), with or without rosiglitazone (0.01 to 10 μM). Transactivation was analyzed using a 96-well plate format.
Results: Rosiglitazone transactivated PPARγ in a time-dependent and dose-dependent manner, the response gradually increasing to a maximum at 48 hours with 10 μM. Low concentrations (0.01 to 0.1 μM) of SPPARγMs F-MOC and MCC-555 and the PPARγ antagonist GW9662 all exerted dose-independent antagonistic effects at an early incubation time point (2 hours). From 10 hours onwards, MCC-555 and GW9662, given alone, both exerted PPARγ agonistic effects, MCC-555 in parallel to responses to rosiglitazone, but GW9662 with characteristics of partial antagonism. F-MOC showed no dose-dependent effect at any concentration at later time points. Only GW9662 (1 to 10 μM) was able to inhibit rosiglitazone (0.1 to 1 μM)-induced PPARγ transactivation after 10 hours.
Conclusion: Our kinetic analysis reveals clear differences in the modulatory characteristics of PPARγ inhibitors, with previously unreported early inhibitory effects and late agonistic or partial agonistic activity. New SPPARγMs with extended inhibitory activity may prove useful in the therapy of sepsis.
5-Lipoxygenase contributes to PPAR [gamma] activation in macrophages in response to apoptotic cells
(2012)
Knethen, Andreas von ; Eifler, Lisa ; Kuchler, Laura ; Heeg, Annika ; Heide, Heinrich ; Wittig, Ilka ; Maier, Thorsten Jürgen ; Steinhilber, Dieter ; Brüne, Bernhard
Background: One hallmark contributing to immune suppression during the late phase of sepsis is macrophage polarization to an anti-inflammatory phenotype upon contact with apoptotic cells (AC). Taking the important role of the nuclear receptor PPARγ for this phenotype switch into consideration, it remains elusive how AC activate PPARγ in macrophages. Therefore, we were interested to characterize the underlying principle.
Methods: Apoptosis was induced by treatment of Jurkat T cells for 3 hours with 0.5 μg/ml staurosporine. Necrotic cells (NC) were prepared by heating cells for 20 minutes to 65°C. PPARγ activation was followed by stably transducing RAW264.7 macrophages with a vector encoding the red fluorescent protein mRuby after PPARγ binding to 4 × PPRE sites downstream of the reporter gene sequence. This readout was established by treatment with the PPARγ agonist rosiglitazone (1 μM) and AC (5:1). Twenty-four hours after stimulation, mRuby expression was analysed by fluorescence microscopy. Lipid rafts of AC, NC, as well as living cells (LC) were enriched by sucrose gradient centrifugation. Fractions were analysed for lipid raft-associated marker proteins. Lipid rafts were incubated with transduced RAW264.7 macrophages as described above. 5-Lipoxygenase (5-LO) involvement was verified by pharmacological inhibition (MK-866, 1 μM) and overexpression.
Results: Assuming that the molecule responsible for PPARγ activation in macrophages is localized in the cell membrane of AC, most probably associated to lipid rafts, we isolated lipid rafts from AC, NC and LC. Mass spectrometric analysis of lipid rafts of AC showed the expression of 5-LO, whereas lipid rafts of LC did not. Moreover, incubating macrophages with lipid rafts of AC induced mRuby expression. In contrast, lipid rafts of NC and LC did not. To verify the involvement of 5-LO in activating PPARγ in macrophages, Jurkat T cells were incubated for 30 minutes with the 5-LO inhibitor MK-866 (1 μM) before apoptosis induction. In line with our hypothesis, these AC did not induce mRuby expression. Finally, although living Jurkat T cells overexpressing 5-LO did not activate PPARγ in macrophages, mRuby expression was significantly increased when AC were generated from 5-LO overexpressing compared with wild-type Jurkat cells.
Conclusion: Our results suggest that induction of apoptosis activates 5-LO, localizing to lipid rafts, necessary for PPARγ activation in macrophages. Therefore, it will be challenging to determine whether 5-LO activity in AC, generated from other cell types, correlates with PPARγ activation, contributing to an immune-suppressed phenotype in macrophages.
Siebenhofer-Kroitzsch, Andrea ; Ulrich-Müssig, Lisa-Rebekka ; Mergenthal, Karola ; Roehl, Ina ; Rauck, Sandra ; Berghold, Andrea ; Harder, Sebastian ; Gerlach, Ferdinand M. ; Petersen, Juliana
Background: Antithrombotic treatment is a continuous therapy that is often performed in general practice and requires careful safety management. The aim of this study is to investigate whether a best practice model that applies major elements of case management, including patient education, can improve antithrombotic management in primary health care in terms of reducing major thromboembolic and bleeding events.
Methods: This 24-month cluster-randomized trial will be performed in 690 adult patients from 46 practices. The trial intervention will be a complex intervention involving general practitioners, health care assistants and patients with an indication for oral anticoagulation. To assess adherence to medication and symptoms in patients, as well as to detect complications early, health care assistants will be trained in case management and will use the Coagulation-Monitoring-List (Co-MoL) to regularly monitor patients. Patients will receive information (leaflets and a video), treatment monitoring via the Co-MoL and be motivated to perform self-management. Patients in the control group will continue to receive treatment-as-usual from their general practitioners. The primary endpoint is the combined endpoint of all thromboembolic events requiring hospitalization, and all major bleeding complications. Secondary endpoints are mortality, hospitalization, strokes, major bleeding and thromboembolic complications, severe treatment interactions, the number of adverse events, quality of anticoagulation, health-related quality of life and costs. Further secondary objectives will be investigated to explain the mechanism by which the intervention is effective: patients' assessment of chronic illness care, self-reported adherence to medication, general practitioners' and health care assistants' knowledge, patients' knowledge and satisfaction with shared decision making. Practice recruitment is expected to take place between July and December 2012. Recruitment of eligible patients will start in July 2012. Assessment will occur at three time points: baseline (T0), follow-up after 12 (T1) and after 24 months (T2).
Discussion: The efficacy and effectiveness of individual elements of the intervention, such as antithrombotic interventions, self-management concepts in orally anticoagulated patients and the methodological tool, case-management, have already been extensively demonstrated. This project foresees the combination of several proven instruments, as a result of which we expect to profit from a reduction in the major complications associated with antithrombotic treatment.
Rody, Achim ; Karn, Thomas ; Liedtke, Cornelia ; Pusztai, Lajos ; Ruckhäberle, Eugen ; Hanker, Lars ; Gätje, Regine ; Solbach, Christine ; Ahr, André ; Metzler, Dirk ; Schmidt, Marcus ; Müller, Volkmar ; Holtrich, Uwe ; Kaufmann, Manfred
Introduction: Current prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple negative breast cancers (TNBC) are clinically heterogeneous and prognostic markers and biology-based therapies are needed to better treat this disease.
Methods: We assembled Affymetrix gene expression data for 579 TNBC and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n = 394 cases for discovery and n = 185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations, including immune cells, blood, adipocytes, stroma, angiogenesis and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed, including routine clinical and pathological variables.
Results: Seventy-three percent of TNBC displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (hazard ratio (HR) 0.37, 95% CI 0.22 to 0.61; P < 0.001) and was the only significant predictor in multivariate analysis including routine clinicopathological variables.
Conclusions: We describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease.
Loibl, Sibylle ; Minckwitz, Gunter von ; Harbeck, Nadia ; Janni, Wolfgang ; Elling, Dirk ; Kaufmann, Manfred ; Eggemann, Holm ; Nekljudova, Valentina ; Sommer, Harald ; Kiechle, Marion ; Kümmel, Sherko
Introduction: Despite the fact that people older than 65 years of age have the highest incidence of developing breast cancer, these patients are excluded from clinical trials in most cases. Furthermore, most physicians tend towards therapy regimens without the use of dose-dense, highly active taxane-based treatments because of a lack of data regarding toxicities of these compounds in older patients.
Methods: Pooled side-effect data were analyzed from four prospective, randomized clinical trials in which patients of different age groups (< 60 years, between 60 and 64 years, and > 64 years) with primary breast cancer received taxane-based chemotherapy.
Results: Dose delays, dose reductions, hospitalization, and therapy discontinuation increased with age. Hematologic toxicities and some nonhematologic toxicities were generally more common in older patients. Leucopenia increased from 55.3% in patients aged < 60 years to 65.5% in patients aged > 64 years (P < 0.001), and neutropenia increased from 46.9% to 57.4% (P < 0.001). There was no difference, however, in clinically more relevant febrile neutropenia between the different age groups. Thrombopenia shows a similar age-dependent increase, whereas there is no difference between the age groups concerning anemia. Hot flushes and elevated liver enzymes decreased with increasing age.
Conclusions: The present pooled analysis of a substantial cohort of older primary breast cancer patients demonstrates that taxane-containing (neo)adjuvant chemotherapy is feasible in older patients and that toxicity can be reduced by sequential therapy regimens.
Novel chalcone-based fluorescent human histamine H 3 receptor ligands as pharmacological tools
(2012)
Novel fluorescent chalcone-based ligands at human histamine H(3) receptors (hH(3)R) have been designed, synthesized, and characterized. Compounds described are non-imidazole analogs of ciproxifan with a tetralone motif. Tetralones as chemical precursors and related fluorescent chalcones exhibit affinities at hH(3)R in the same concentration range like the reference antagonist ciproxifan (hH(3)R pK(i) value of 7.2). Fluorescence characterization of our novel ligands shows emission maxima about 570 nm for yellow fluorescent chalcones and ≥600 nm for the red fluorescent derivatives. Interferences to cellular autofluorescence could be excluded. All synthesized chalcone compounds could be used to visualize hH(3)R proteins in stably transfected HEK-293 cells using confocal laser scanning fluorescence microscopy. These novel fluorescent ligands possess high potential to be used as pharmacological tools for hH(3)R visualization in different tissues.
Before the advent of molecular phylogenetics, species concepts in the downy mildews, an economically important group of obligate biotrophic oomycete pathogens, have mostly been based upon host range and morphology. While molecular phylogenetic studies have confirmed a narrow host range for many downy mildew species, others, like Pseudoperonospora cubensis affect even different genera. Although often morphological differences were found for new, phylogenetically distinct species, uncertainty prevails regarding their host ranges, especially regarding related plants that have been reported as downy mildew hosts, but were not included in the phylogenetic studies. In these cases, the basis for deciding if the divergence in some morphological characters can be deemed sufficient for designation as separate species is uncertain, as observed morphological divergence could be due to different host matrices colonised. The broad host range of P. cubensis (ca. 60 host species) renders this pathogen an ideal model organism for the investigation of morphological variations in relation to the host matrix and to evaluate which characteristics are best indicators for conspecificity or distinctiveness. On the basis of twelve morphological characterisitcs and a set of twelve cucurbits from five different Cucurbitaceae tribes, including the two species, Cyclanthera pedata and Thladiantha dubia, hitherto not reported as hosts of P. cubensis, a significant influence of the host matrix on pathogen morphology was found. Given the high intraspecific variation of some characteristics, also their plasticity has to be taken into account. The implications for morphological species determination and the confidence limits of morphological characteristics are discussed. For species delimitations in Pseudoperonospora it is shown that the ratio of the height of the first ramification to the sporangiophore length, ratio of the longer to the shorter ultimate branchlet, and especially the length and width of sporangia, as well as, with some reservations, their ratio, are the most suitable characteristics for species delimitation.
Mache, Stefanie ; Vitzthum, Karin ; Nienhaus, Albert ; Klapp, Burghard F. ; Groneberg, Jan David Alexander
Background: A growing number of German hospitals have been privatized with the intention of increasing cost effectiveness and improving the quality of health care. Numerous studies investigated what possible qualitative and economic consequences these changes issues might have on patient care. However, little is known about how this privatization trend relates to physicians' working conditions and job satisfaction. It was anticipated that different working conditions would be associated with different types of hospital ownership. To that end, this study's purpose is to compare how physicians, working for both public and privatized hospitals, rate their respective psychosocial working conditions and job satisfaction.
Methods: The study was designed as a cross-sectional comparison using questionnaire data from 203 physicians working at German hospitals of different ownership types (private for-profit, public and private nonprofit).
Results: The present study shows that several aspects of physicians' perceived working conditions differ significantly depending on hospital ownership. However, results also indicated that physicians' job satisfaction does not vary between different types of hospital ownership. Finally, it was demonstrated that job demands and resources are associated with job satisfaction, while type of ownership is not.
Conclusion: This study represents one of a few studies that investigate the effect of hospital ownership on physicians work situation and demonstrated that the type of ownership is a potential factor accounting for differences in working conditions. The findings provide an informative basis to find solutions improving physicians' work at German hospitals.
Müller, Daniel ; Schulze, Johannes B. ; Ackermann, Hanns ; Klingelhöfer, Doris ; Uibel, Stefanie ; Groneberg, Jan David Alexander
Introduction: Potential health damage by environmental emission of tobacco smoke (environmental tobacco smoke, ETS) has been demonstrated convincingly in numerous studies. People, especially children, are still exposed to ETS in the small space of private cars. Although major amounts of toxic compounds from ETS are likely transported into the distal lung via particulate matter (PM), few studies have quantified the amount of PM in ETS. Study aim The aim of this study was to determine the ETS-dependent concentration of PM from both a 3R4F reference cigarette (RC) as well as a Marlboro Red brand cigarette (MRC) in a small enclosed space under different conditions of ventilation to model car exposure.
Method: In order to create ETS reproducibly, an emitter (ETSE) was constructed and mounted on to an outdoor telephone booth with an inner volume of 1.75 m3. Cigarettes were smoked under open- and closed-door condition to imitate different ventilation scenarios. PM2.5 concentration was quantified by a laser aerosol spectrometer (Grimm; Model 1.109), and data were adjusted for baseline values. Simultaneously indoor and outdoor climate parameters were recorded. The time of smoking was divided into the ETS generation phase (subset "emission") and a declining phase of PM concentration (subset "elimination"); measurement was terminated after 10 min. For all three time periods the average concentration of PM2.5 (Cmean-PM2.5) and the area under the PM2.5 concentration curve (AUC-PM2.5) was calculated. The maximum concentration (Cmax-PM2.5) was taken from the total interval.
Results: For both cigarette types open-door ventilation reduced the AUC-PM2.5 (RC: from 59 400 +/- 14 600 to 5 550 +/- 3 900 mug*sec/m3; MRC: from 86 500 +/- 32 000 to 7 300 +/- 2 400 mug*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 600 +/- 150 to 56 +/- 40 mug/m3, MRC from 870 +/- 320 to 75 +/- 25 mug/m3; p < 0.001) by about 90%. Cmax-PM2.5 was reduced by about 80% (RC: from 1 050 +/- 230 to 185 +/- 125 mug/m3; MRC: from 1 560 +/-500 mug/m3 to 250 +/- 85 mug/m3; p < 0.001). In the subset "emission" we identified a 78% decrease in AUC-PM2.5 (RC: from 18 600 +/- 4 600 to 4 000 +/- 2 600 mug*sec/m3; MRC: from 26 600 +/- 7 200 to 5 800 +/- 1 700 mug*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 430 +/- 108 to 93 +/- 60 mug/m3; MRC: from 620 +/- 170 to 134 +/- 40 mug/m3; p < 0.001). In the subset "elimination" we found a reduction of about 96-98% for AUC-PM2.5 (RC: from 40 800 +/- 11 100 to 1 500 +/- 1 700 mug*sec/m3; MRC: from 58 500 +/- 25 200 to 1 400 +/- 800 mug*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 730 +/- 200 to 27 +/- 29 mug/m3; MRC: from 1 000 +/- 450 to 26 +/- 15 mug/m3; p < 0.001). Throughout the total interval Cmax-PM2.5 of MRC was about 50% higher (1 550 +/- 500 mug/m3) compared to RC (1 050 +/- 230 mug/m3; p < 0.05). For the subset "emission" - but not for the other periods - AUC-PM2.5 for MRC was 43% higher (MRC: 26 600 +/- 7 200 mug*sec/m3; RC: 18 600 +/- 4 600 mug*sec/m3; p < 0.05) and 44% higher for Cmean-PM2.5 (MRC: 620 +/- 170 mug/m3; RC: 430 +/- 108 mug/m3; p < 0.05).
Conclusion: This method allows reliable quantification of PM2.5-ETS exposure under various conditions, and may be useful for ETS risk assessment in realistic exposure situations. The findings demonstrate that open-door condition does not completely remove ETS from a defined indoor space of 1.75 m3. Because there is no safe level of ETS exposure ventilation is not adequate enough to prevent ETS exposure in confined spaces, e.g. private cars. Additionally, differences in the characteristics of cigarettes affect the amount of ETS particle emission and need to be clarified by ongoing investigations.
The regulation of cellular copper homeostasis is crucial in biology. Impairments lead to severe dysfunctions and are known to affect aging and development. Previously, a loss-of-function mutation in the gene encoding the copper-sensing and copper-regulated transcription factor GRISEA of the filamentous fungus Podospora anserina was reported to lead to cellular copper depletion and a pleiotropic phenotype with hypopigmentation of the mycelium and the ascospores, affected fertility and increased lifespan by approximately 60% when compared to the wild type. This phenotype is linked to a switch from a copper-dependent standard to an alternative respiration leading to both a reduced generation of reactive oxygen species (ROS) and of adenosine triphosphate (ATP). We performed a genome-wide comparative transcriptome analysis of a wild-type strain and the copper-depleted grisea mutant. We unambiguously assigned 9,700 sequences of the transcriptome in both strains to the more than 10,600 predicted and annotated open reading frames of the P. anserina genome indicating 90% coverage of the transcriptome. 4,752 of the transcripts differed significantly in abundance with 1,156 transcripts differing at least 3-fold. Selected genes were investigated by qRT-PCR analyses. Apart from this general characterization we analyzed the data with special emphasis on molecular pathways related to the grisea mutation taking advantage of the available complete genomic sequence of P. anserina. This analysis verified but also corrected conclusions from earlier data obtained by single gene analysis, identified new candidates of factors as part of the cellular copper homeostasis system including target genes of transcription factor GRISEA, and provides a rich reference source of quantitative data for further in detail investigations. Overall, the present study demonstrates the importance of systems biology approaches also in cases were mutations in single genes are analyzed to explain the underlying mechanisms controlling complex biological processes like aging and development.
Kuçi, Selim ; Rettinger, Eva ; Voß, Bernhard ; Weber, Gerrit ; Stais, Miriam ; Kreyenberg, Hermann ; Willasch, Andre Manfred ; Kuçi, Zyrafete ; Koscielniak, Ewa ; Klöß, Stephan ; Laer, Dorothee von ; Klingebiel, Thomas ; Bader, Peter
Background: Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and has a poor prognosis. Here we assessed the capability of ex vivo expanded cytokine-induced killer cells to lyse both alveolar and embryonic rhabdomyosarcoma cell lines and investigated the mechanisms involved.
Design and Methods: Peripheral blood mononuclear cells from six healthy donors were used to generate and expand cytokine-induced killer cells. The phenotype and composition of these cells were determined by multiparameter flow cytometry, while their cytotoxic effect against rhabdomyosarcoma cells was evaluated by a europium release assay.
Results: Cytokine-induced killer cells efficiently lysed cells from both rhabdomyosarcoma cell lines. Antibody-mediated masking of either NKG2D molecule on cytokine-induced killer cells or its ligands on rhabdomyosarcoma cells (major histocompatibility antigen related chain A and B and UL16 binding protein 2) diminished this effect by 50%, suggesting a major role for the NKG2D molecule in rhabdomyosarcoma cell killing. No effect was observed after blocking CD11a, CD3 or TCRαβ molecules on cytokine-induced killer cells or CD1d on rhabdomyosar-coma cells. Remarkably, cytokine-induced killer cells used tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to activate caspase-3, as the main caspase responsible for the execution of apoptosis. Accordingly, blocking TRAIL receptors on embryonic rhabdomyosarcoma cell lines significantly reduced the anti-tumor effect of cytokine-induced killer cells. About 50% of T cells within the cytokine-induced killer population had an effector memory phenotype, 20% had a naïve phenotype and approximately 30% of the cells had a central memory phenotype. In addition, cytokine-induced killer cells expressed low levels of activation-induced markers CD69 and CD137 and demonstrated a low alloreactive potential.
Conclusions: Our data suggest that cytokine-induced killer cells may be used as a novel adoptive immunotherapy for the treatment of patients with rhabdomyosarcoma after allogeneic stem cell transplantation.
O'Dwyer, Laurence ; Lamberton, Franck ; Matura, Silke ; Tanner, Colby ; Scheibe, Monika ; Miller, Julia ; Rujescu, Dan ; Prvulovic, David ; Hampel, Harald
The E4 allele of the ApoE gene has consistently been shown to be related to an increased risk of Alzheimer's disease (AD). The E4 allele is also associated with functional and structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess volumes of deep grey matter structures of 22 healthy younger ApoE4 carriers and 22 non-carriers (20–38 years). Volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen, thalamus and brain stem were calculated by FMRIB's Integrated Registration and Segmentation Tool (FIRST) algorithm. A significant drop in volume was found in the right hippocampus of ApoE4 carriers (ApoE4+) relative to non-carriers (ApoE4−), while there was a borderline significant decrease in the volume of the left hippocampus of ApoE4 carriers. The volumes of no other structures were found to be significantly affected by genotype. Atrophy has been found to be a sensitive marker of neurodegenerative changes, and our results show that within a healthy young population, the presence of the ApoE4+ carrier gene leads to volume reduction in a structure that is vitally important for memory formation. Our results suggest that the hippocampus may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age. Although volume reductions were noted bilaterally in the hippocampus, atrophy was more pronounced in the right hippocampus. This finding relates to previous work which has noted a compensatory increase in right hemisphere activity in ApoE4 carriers in response to preclinical declines in memory function. Possession of the ApoE4 allele may lead to greater predilection for right hemisphere atrophy even in healthy young subjects in their twenties.
In acute promyelocytic leukemia (APL), hematopoietic differentiation is blocked and immature blasts accumulate in the bone marrow and blood. APL is associated with chromosomal aberrations, including t(15;17) and t(11;17). For these two translocations, the retinoic acid receptor alpha (RARα) is fused to the promyelocytic leukemia (PML) gene or the promyelocytic zinc finger (PLZF) gene, respectively. Both fusion proteins lead to the formation of a high-molecular-weight complex. High-molecular-weight complexes are caused by the “coiled-coil” domain of PML or the BTB/POZ domain of PLZF. PML/RARα without the “coiled-coil” fails to block differentiation and mediates an all-trans retinoic acid-response. Similarly, mutations in the BTB/POZ domain disrupt the high-molecular-weight complex, abolishing the leukemic potential of PLZF/RARα. Specific interfering polypeptides were used to target the oligomerization domain of PML/RARα or PLZF/RARα. PML/RARα and PLZF/RARα were analyzed for the ability to form high-molecular-weight complexes, the protein stability and the potential to induce a leukemic phenotype in the presence of the interfering peptides. Expression of these interfering peptides resulted in a reduced replating efficiency and overcame the differentiation block induced by PML/RARα and PLZF/RARα in murine hematopoietic stem cells. This expression also destabilized the PLZF/RARα-induced high-molecular-weight complex formation and caused the degradation of the fusion protein. Targeting fusion proteins through interfering peptides is a promising approach to further elucidate the biology of leukemia.
Röser, Claudia ; Jordan, Nadine ; Balfanz, Sabine ; Baumann, Arnd ; Walz, Bernd ; Baumann, Otto ; Blenau, Wolfgang
Secretion in blowfly (Calliphora vicina) salivary glands is stimulated by the biogenic amine serotonin (5-hydroxytryptamine, 5-HT), which activates both inositol 1,4,5-trisphosphate (InsP3)/Ca2+ and cyclic adenosine 3′,5′-monophosphate (cAMP) signalling pathways in the secretory cells. In order to characterize the signal-inducing 5-HT receptors, we cloned two cDNAs (Cv5-ht2α, Cv5-ht7) that share high similarity with mammalian 5-HT2 and 5-HT7 receptor genes, respectively. RT-PCR demonstrated that both receptors are expressed in the salivary glands and brain. Stimulation of Cv5-ht2α-transfected mammalian cells with 5-HT elevates cytosolic [Ca2+] in a dose-dependent manner (EC50 = 24 nM). In Cv5-ht7-transfected cells, 5-HT produces a dose-dependent increase in [cAMP]i (EC50 = 4 nM). We studied the pharmacological profile for both receptors. Substances that appear to act as specific ligands of either Cv5-HT2α or Cv5-HT7 in the heterologous expression system were also tested in intact blowfly salivary gland preparations. We observed that 5-methoxytryptamine (100 nM) activates only the Cv5-HT2α receptor, 5-carboxamidotryptamine (300 nM) activates only the Cv5-HT7 receptor, and clozapine (1 µM) antagonizes the effects of 5-HT via Cv5-HT7 in blowfly salivary glands, providing means for the selective activation of each of the two 5-HT receptor subtypes. This study represents the first comprehensive molecular and pharmacological characterization of two 5-HT receptors in the blowfly and permits the analysis of the physiological role of these receptors, even when co-expressed in cells, and of the modes of interaction between the Ca2+- and cAMP-signalling cascades.
Japtok, Lukasz ; Schaper, Katrin ; Bäumer, Wolfgang ; Radeke, Heinfried H. ; Jeong, Se Kyoo ; Kleuser, Burkhard
Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions.
Becker, Denise ; Willems, Laurent Maximilian ; Vnenčák, Matej ; Zahn, Nadine ; Schuldt, Gerlind ; Jedlička, Peter ; Maggio, Nicola ; Deller, Thomas ; Vlachos, Andreas
During postnatal development hippocampal dentate granule cells (GCs) often extend dendrites from the basal pole of their cell bodies into the hilar region. These so-called hilar basal dendrites (hBD) usually regress with maturation. However, hBDs may persist in a subset of mature GCs under certain conditions (both physiological and pathological). The functional role of these hBD-GCs remains not well understood. Here, we have studied hBD-GCs in mature (≥18 days in vitro) mouse entorhino-hippocampal slice cultures under control conditions and have compared their basic functional properties (basic intrinsic and synaptic properties) and structural properties (dendritic arborisation and spine densities) to those of neighboring GCs without hBDs in the same set of cultures. Except for the presence of hBDs, we did not detect major differences between the two GC populations. Furthermore, paired recordings of neighboring GCs with and without hBDs did not reveal evidence for a heavy aberrant GC-to-GC connectivity. Taken together, our data suggest that in control cultures the presence of hBDs on GCs is neither sufficient to predict alterations in the basic functional and structural properties of these GCs nor indicative of a heavy GC-to-GC connectivity between neighboring GCs.
Reichl, Lars ; Heide, Dominik ; Löwel, Siegrid ; Crowley, Justin C. ; Kaschube, Matthias ; Wolf, Fred
In the juvenile brain, the synaptic architecture of the visual cortex remains in a state of flux for months after the natural onset of vision and the initial emergence of feature selectivity in visual cortical neurons. It is an attractive hypothesis that visual cortical architecture is shaped during this extended period of juvenile plasticity by the coordinated optimization of multiple visual cortical maps such as orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we introduced a class of analytically tractable coordinated optimization models and solved representative examples, in which a spatially complex organization of the OP map is induced by interactions between the maps. We found that these solutions near symmetry breaking threshold predict a highly ordered map layout. Here we examine the time course of the convergence towards attractor states and optima of these models. In particular, we determine the timescales on which map optimization takes place and how these timescales can be compared to those of visual cortical development and plasticity. We also assess whether our models exhibit biologically more realistic, spatially irregular solutions at a finite distance from threshold, when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. We show that, although maps typically undergo substantial rearrangement, no other solutions than pinwheel crystals and stripes dominate in the emerging layouts. Pinwheel crystallization takes place on a rather short timescale and can also occur for detuned wavelengths of different maps. Our numerical results thus support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the architecture of the visual cortex. We discuss several alternative scenarios that may improve the agreement between model solutions and biological observations.
Reichl, Lars ; Heide, Dominik ; Löwel, Siegrid ; Crowley, Justin C. ; Kaschube, Matthias ; Wolf, Fred
In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be interpreted as optima of a specific energy functional that summarizes the design principles of cortical functional architecture. A rigorous evaluation of this optimization hypothesis is particularly demanded by recent evidence that the functional architecture of orientation columns precisely follows species invariant quantitative laws. Because it would be desirable to infer the form of such an optimization principle from the biological data, the optimization approach to explain cortical functional architecture raises the following questions: i) What are the genuine ground states of candidate energy functionals and how can they be calculated with precision and rigor? ii) How do differences in candidate optimization principles impact on the predicted map structure and conversely what can be learned about a hypothetical underlying optimization principle from observations on map structure? iii) Is there a way to analyze the coordinated organization of cortical maps predicted by optimization principles in general? To answer these questions we developed a general dynamical systems approach to the combined optimization of visual cortical maps of OP and another scalar feature such as OD or spatial frequency preference. From basic symmetry assumptions we obtain a comprehensive phenomenological classification of possible inter-map coupling energies and examine representative examples. We show that each individual coupling energy leads to a different class of OP solutions with different correlations among the maps such that inferences about the optimization principle from map layout appear viable. We systematically assess whether quantitative laws resembling experimental observations can result from the coordinated optimization of orientation columns with other feature maps.
In its admissibility decision in the Al-Saadoon case the ECtHR held that the United Kingdom had jurisdiction over the applicants, who had been arrested by British forces and kept in a British-run military prison in Iraq. Just before the respective mandate of the Security Council expired on 31 December 2008, the applicants were transferred to Iraqi custody at Iraqi request and thereby exposed to the risk of an unfair trial followed by capital punishment. In this respect, the case resembles the Soering case, although the applicants were, unlike Soering, not on British territory but on occupied Iraqi soil before they were handed over. This aspect raises the question of Iraqi sovereignty as a norm competing with the UK's human rights obligations. The authors trace back the ECtHR's case law concerning the extraterritorial application of the Convention and analyse the UK judgments and the ECtHR's admissibility decision in the Al-Saadoon affair from this angle. Furthermore they consider the doctrinal consequences of the ECHR's extraterritorial effect in cases like Soering and Al-Saadoon, where contracting parties violate guarantees of the Convention by exposing a person within their jurisdiction to a risk of a treatment contrary to these guarantees by a third state. Finally, they test the argument brought forward by the UK that not transferring the applicants would have violated Iraqi sovereignty and establish patterns how the ECtHR and the UK Courts did cope in the past with international law norms potentially competing with the Convention.
Wijk, Sjoerd van ; Melquiond, Adrien S. J. ; Vries, Sjoerd J. de ; Timmers, H. Th. Marc ; Bonvin, Alexandre M. J. J.
Ubiquitination relies on a subtle balance between selectivity and promiscuity achieved through specific interactions between ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). Here, we report how a single aspartic to glutamic acid substitution acts as a dynamic switch to tip the selectivity balance of human E2s for interaction toward E3 RING-finger domains. By combining molecular dynamic simulations, experimental yeast-two-hybrid screen of E2-E3 (RING) interactions and mutagenesis, we reveal how the dynamics of an internal salt-bridge network at the rim of the E2-E3 interaction surface controls the balance between an “open”, binding competent, and a “closed”, binding incompetent state. The molecular dynamic simulations shed light on the fine mechanism of this molecular switch and allowed us to identify its components, namely an aspartate/glutamate pair, a lysine acting as the central switch and a remote aspartate. Perturbations of single residues in this network, both inside and outside the interaction surface, are sufficient to switch the global E2 interaction selectivity as demonstrated experimentally. Taken together, our results indicate a new mechanism to control E2-E3 interaction selectivity at an atomic level, highlighting how minimal changes in amino acid side-chain affecting the dynamics of intramolecular salt-bridges can be crucial for protein-protein interactions. These findings indicate that the widely accepted sequence-structure-function paradigm should be extended to sequence-structure-dynamics-function relationship and open new possibilities for control and fine-tuning of protein interaction selectivity.
Nölscher, Anke Christine ; Bourtsoukidis, Efstratios ; Bonn, Boris ; Kesselmeier, Jürgen ; Lelieveld, Johannes ; Williams, Jonathan
Numerous reactive volatile organic compounds (VOCs) are emitted into the atmosphere by vegetation. Most biogenic VOCs are highly reactive towards the atmosphere's most important oxidant, the hydroxyl (OH) radical. One way to investigate the chemical interplay between biosphere and atmosphere is through the measurement of total OH reactivity, the total loss rate of OH radicals. This study presents the first determination of total OH reactivity emission rates (measurements via the Comparative Reactivity Method) based on a branch cuvette enclosure system mounted on a Norway spruce (Picea abies) throughout spring, summer and autumn 2011. In parallel separate VOC emission rates were monitored by a Proton Transfer Reaction-Mass Spectrometer (PTR-MS), and total ozone (O3) loss rates were obtained inside the cuvette. Total OH reactivity emission rates were in general temperature and light dependent, showing strong diel cycles with highest values during daytime. Monoterpene emissions contributed most, accounting for 56–69% of the measured total OH reactivity flux in spring and early summer. However, during late summer and autumn the monoterpene contribution decreased to 11–16%. At this time, a large missing fraction of the total OH reactivity emission rate (70–84%) was found when compared to the VOC budget measured by PTR-MS. Total OH reactivity and missing total OH reactivity emission rates reached maximum values in late summer corresponding to the period of highest temperature. Total O3 loss rates within the closed cuvette showed similar diel profiles and comparable seasonality to the total OH reactivity fluxes.
Total OH reactivity fluxes were also compared to emissions from needle storage pools predicted by a temperature-only dependent algorithm. Deviations of total OH reactivity fluxes from the temperature-only dependent emission algorithm were observed for occasions of mechanical and heat stress. While for mechanical stress, induced by strong wind, measured VOCs could explain total OH reactivity emissions, during heat stress they could not. The temperature driven algorithm matched the diel course much better in spring than in summer, indicating a different production and emission scheme for summer and early autumn. During these times, unmeasured and possibly unknown primary biogenic emissions contributed significantly to the observed total OH reactivity flux.
Brandt, Tobias ; Townsley, Fiona M. ; Teufel, Daniel P. ; Freund, Stefan M. V. ; Veprintsev, Dmitry B.
The tumour suppressor p53 controls transcription of various genes involved in apoptosis, cell-cycle arrest, DNA repair and metabolism. However, its DNA-recognition specificity is not nearly sufficient to explain binding to specific locations in vivo. Here, we present evidence that KLF4 increases the DNA-binding affinity of p53 through the formation of a loosely arranged ternary complex on DNA. This effect depends on the distance between the response elements of KLF4 and p53. Using nuclear magnetic resonance and fluorescence techniques, we found that the amino-terminal domain of p53 interacts with the KLF4 zinc fingers and mapped the interaction site. The strength of this interaction was increased by phosphorylation of the p53 N-terminus, particularly on residues associated with regulation of cell-cycle arrest genes. Taken together, the cooperative binding of KLF4 and p53 to DNA exemplifies a regulatory mechanism that contributes to p53 target selectivity.
Mian, Afsar Ali ; Metodieva, Anna ; Badura, Susanne ; Khateb, Mamduh ; Ruimi, Nili ; Najajreh, Yousef ; Ottmann, Oliver G. ; Mahajna, Jamal ; Ruthardt, Martin
Background: Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the 'gatekeeper' mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia.
Methods: The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.
Results: Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner.
Conclusions: Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.
Background: Hybridisation is presumed to be an important mechanism in plant speciation and a creative evolutionary force often accompanied by polyploidisation and in some cases by apomixis. The Potentilla collina group constitutes a particularly suitable model system to study these phenomena as it is morphologically extensively variable, exclusively polyploid and expresses apomixis. In the present study, the alpine taxon Potentilla alpicola has been chosen in order to study its presumed hybrid origin, identify underlying evolutionary processes and infer the discreteness or taxonomic value of hybrid forms.
Results: Combined analysis of AFLP, cpDNA sequences and ploidy level variation revealed a hybrid origin of the P. alpicola populations from South Tyrol (Italy) resulting from crosses between P. pusilla and two cytotypes of P. argentea. Hybrids were locally sympatric with at least one of the parental forms. Three lineages of different evolutionary origin comprising two ploidy levels were identified within P. alpicola. The lineages differed in parentage and the complexity of the evolutionary process. A geographically wide-spread lineage thus contrasted with locally distributed lineages of different origins. Populations of P. collina studied in addition, have been regarded rather as recent derivatives of the hexaploid P. argentea. The observation of clones within both P. alpicola and P. collina suggested a possible apomictic mode of reproduction.
Conclusions: Different hybridisation scenarios taking place on geographically small scales resulted in viable progeny presumably stabilised by apomixis. The case study of P. alpicola supports that these processes played a significant role in the creation of polymorphism in the genus Potentilla. However, multiple origin of hybrids and backcrossing are considered to produce a variety of evolutionary spontaneous forms existing aside of reproductively stabilised, established lineages.
Crawcour, Stephen ; Leibing, Eric ; Ginzburg, Denise ; Stangier, Ulrich ; Wiltink, Jörg ; Hoyer, Jürgen
Background: Cognitive-behavioral therapy (CBT) is generally known to be efficacious in the treatment of social phobia when applied in RCT's, namely when the treatment manual is based on the Clark-Wells approach. However, little is known about the efficacy of manualized treatments in routine clinical practice (Phase IV of psychotherapy research). The present study (SOPHO-PRAX) is a continuation of a large multi-centre randomized clinical trial (SOPHO-NET) and analyses the extent to which additional training practitioners in manualized procedures enhances treatment effect.
Methods: N = 36 private practitioners will be included in three treatment centres and randomly designated to either training in manualized CBT or no specific training. The treatment effects of the therapies conducted by both groups of therapists will be compared. A total of 162 patients (N = 116 completers; N = 58 per condition) will be enrolled. Liebowitz Social Anxiety Scale (LSAS) will serve as primary outcome measure. Remission from social phobia is defined as LSAS total [less than or equal to] 30 points. Data will be collected at treatment begin, after 8, 15, and 25 sessions (50 mins. each), at treatment completion, as well at 6 and 12 months post-treatment.
Discussion: The present CBT trial combines elements of randomized-controlled trials and naturalistic studies in an innovative way. It will directly inform about the incremental effects of procedures established in a controlled trial into clinical practice. Study results are relevant to health care decisions and policy. They may serve to improve quality of treatment, and shorten the timeframe between the development and widespread dissemination of effective methods, thereby reducing health cost expenditures. The results of this study will not only inform about the degree to which the new methods lead to an improvement of treatment course and outcome, but also about whether the effects of routine psychotherapeutic treatment are comparable to those of the controlled, strictly manualized treatments of the SOPHO-NET study. Trial Registration: ClinicalTrials.gov identifier: NCT01388231. This study was funded by the German Federal Ministry of Education and Research (SOPHO-NET: BMBF 01GV0607; SOPHO-PRAX: BMBF 01GV1001).
Background: Hodkin s lymphoma is one of the most frequent lymphoma in western world. Despite an overall good prognosis some patients suffer relapsing tumors which are difficult to cure. Over a long period Vitamin D has been shown to be a potential treatment for cancer. Vitamin D acts via the vitamin D receptor, a nuclear receptor, acting as an inducible transcription factor. We aimed to investigate the expression of vitamin D receptor as potential therapeutic target structure in Hodgkin s lymphoma as well as in non Hodgkin s lymphoma.
Methods: We used a panel of 193 formalin fixed tissues of lymphoma cases consisting of 55 cases of Hodgkin s lymphoma and 138 cases on several non Hodgkin s lymphoma entities.
Results: Vitamin D receptor is strongly expressed in Hodgkin s lymphoma, regardless of the subentity with an overall positivity of 80% of all Hodgkin lymphoma cases. In contrast, only about 17% of the analyzed non Hodgkin s lymphoma of B-cell origin showed positivity for vitamin D receptor. Predominant nuclear localization of vitamin D receptor in Hodgkin s lymphoma suggests activated status of the vitamin D receptor.
Conclusions: From this study, we conclude that vitamin D receptor plays a potentially important role in pathogenesis of Hodgkin s lymphoma but not in non Hodgkin s lymphoma. Further investigations of mutational status and functional studies may shed some light in functional relevance of vitamin D receptor signaling in Hodgkin s lymphoma.
A complete, well-preserved record of the Cenomanian/Turonian (C/T) Oceanic Anoxic Event 2 (OAE-2) was recovered from Demerara Rise in the southern North Atlantic Ocean (ODP site 1260). Across this interval, we determined changes in the stable carbon isotopic composition of sulfur-bound phytane (δ13Cphytane), a biomarker for photosynthetic algae. The δ13Cphytane record shows a positive excursion at the onset of the OAE-2 interval, with an unusually large amplitude (~7‰) compared to existing C/T proto-North Atlantic δ13Cphytane records (3–6‰). Overall, the amplitude of the excursion of δ13Cphytane decreases with latitude. Using reconstructed sea surface temperature (SST) gradients for the proto-North Atlantic, we investigated environmental factors influencing the latitudinal δ13Cphytane gradient. The observed gradient is best explained by high productivity at DSDP Site 367 and Tarfaya basin before OAE-2, which changed in overall high productivity throughout the proto-North Atlantic during OAE-2. During OAE-2, productivity at site 1260 and 603B was thus more comparable to the mid-latitude sites. Using these constraints as well as the SST and δ13Cphytane-records from Site 1260, we subsequently reconstructed pCO2 levels across the OAE-2 interval. Accordingly, pCO2 decreased from ca. 1750 to 900 ppm during OAE-2, consistent with enhanced organic matter burial resulting in lowering pCO2. Whereas the onset of OAE-2 coincided with increased pCO2, in line with a volcanic trigger for this event, the observed cooling within OAE-2 probably resulted from CO2 sequestration in black shales outcompeting CO2 input into the atmosphere. Together these results show that the ice-free Cretaceous world was sensitive to changes in pCO2 related to perturbations of the global carbon cycle.
The development of a non- destructive measurement method for ion beam parameters has been treated in various projects. Although results are promising, the high complexity of beam dynamics has made it impossible to implement a real time process control up to now. In this paper we will propose analysing methods based on the dynamics of Cellular Nonlinear Networks (CNN) that can be implemented on pixel parallel CNN based architectures and yield satisfying results even at low resolutions.
At nonzero temperature, it is expected that QCD undergoes a phase transition to a deconfined, chirally symmetric phase, the Quark-Gluon Plasma (QGP). I review what we expect theoretically about this possible transition, and what we have learned from heavy ion experiments at RHIC. I argue that while there are unambiguous signals for qualitatively new behavior at RHIC, versus experiments at lower energies, that in detail, no simple theoretical model can explain all salient features of the data.
Bekele, Selemon ; Braghin, Fabio ; Chajecki, Zbigniew ; Chung, Paul ; Cramer, John G. ; Csörgo, Tamás ; Eggers, Hans ; Gavin, Sean ; Grassi, Frédérique ; Hama, Yogiro ; Kisiel, Adam ; Ko, Che-Ming ; Koide, Tomoi ; Krein, Gastão ; Lacey, Roy Alphanso ; Lednický, Richard ; Lisa, Michael A. ; Metzger, Wesley ; Miśkowiec, Dariusz Czesław ; Morita, Kenji ; Padula, Sandra S. ; Pratt, Scott ; Qian, Wei-Liang ; Simak, Vladislav ; Sinyukov, Yuri ; Šumbera, Michal ; Tavares, Bernardo M. ; Verde, Giuseppe ; Zschiesche, Detlef
After five years of running at RHIC, and on the eve of the LHC heavy-ion program, we highlight the status of femtoscopic measurements. We emphasize the role interferometry plays in addressing fundamental questions about the state of matter created in such collisions, and present an enumerated list of measurements, analyses and calculations that are needed to advance the field in the coming years.
The title co-crystal, C9H9NO2·C6H6O2, is composed of one 2,6-diacetylpyridine molecule and one resorcinol molecule as the asymmetric unit. In the 2,6-diacetylpyridine molecule, the two carbonyl groups are antiperiplanar to the pyridine N atom. In the crystal, the 2,6-diacetylpyridine and resorcinol molecules are connected by two O-H...O hydrogen bonds, forming planar chains of alternating components running along [120].
The title compound, C23H32Cl2N2O2, a potential chiral ligand for coordination chemistry, was prepared by a two-step reaction. The molecule is located on a crystallographic centre of inversion. As a result, the methyl group bonded to the methylene group is disordered over two equally occupied positions, sharing the same site as the H atom of the chiral C atom. As a further consequence of the crystallographic centrosymmetry, the 1,2-diaminopropane unit adopts an antiperiplanar conformation and the two benzene rings are coplanar. The central chain is in an all-trans arrangement. An intramolecular O-H...N hydrogen bond makes an S(6) ring motif. A C-H...[pi] interaction links the molecules into one-dimensional chains along the [001] direction.
Chelidamic acid (4-hydroxypyridine-2,6-dicarboxylic acid) and 2,6-diaminopyridine react to form the title salt, C5H8N3+·C7H4NO5-; there are two formula units in the asymmetric unit. The pyridine N atom of 2,6-diaminopyridine is protonated whereas chelidamic acid is deprotonated at both carboxylate groups but protonated at the N atom; the reaction involves intra- and intermolecular proton transfer. In the crystal, each 2,6-diaminopyridinium cation participates in five strong N-H...O hydrogen bonds (including one bifurcated hydrogen bond). The crystal structure also features strong O-H...O hydrogen bonds between the chelidamate anions, leading to chains along the a axis.
The crystal structure of the title compound, Na[(C6F5)BH3], is composed of discrete anions and cations. The sodium cations are surrounded by four anions with three short Na...B [2.848 (8), 2.842 (7) and 2.868 (8) Å] and two short Na...F contacts [2.348 (5) and 2.392 (5) Å], forming a three-dimensional network. The anion is the first structural example of a pentafluorophenyl ring carrying a BH3 group.
Leistenschneider, Armin ; Aumann, Thomas ; Boretzky, Konstanze ; Canto, Luiz Felipe ; Carlson, Brett Vern ; Cortina, Dolores ; Datta Pramanik, Ushasi ; Elze, Thomas W. ; Emling, Hans ; Geissel, Hans ; Grünschloss, Alexander ; Helariutta, Kerttuli ; Hellström, Margareta ; Hussein, Mahir S. ; Ilievski, Stamenko ; Kratz, Jens-Volker ; Kulessa, Reinhard ; Khiem, Le Hong ; Lubkiewicz, Edvard ; Münzenberg, Gottfried ; Palit, Rudrayoti ; Reiter, Peter ; Scheidenberger, Christoph ; Schmidt, Karl-Heinz ; Simon, Haik ; Sümmerer, Klaus ; Wajda, Eugeniusz ; Walús, Wladek
Abrasion-ablation models and the empirical EPAX parametrization of projectile fragmentation are described. Their cross section predictions are compared to recent data of the fragmentation of secondary beams of neutron-rich, unstable 19,20,21O isotopes at beam energies near 600 MeV/nucleon as well as data for stable 17,18O beams.
I discuss the physics of non-Abelian plasmas which are locally anisotropic in momentum space. Such momentum-space anisotropies are generated by the rapid longitudinal expansion of the matter created in the first 1 fm/c of an ultrarelativistic heavy ion collision. In contrast to locally isotropic plasmas anisotropic plasmas have a spectrum of soft unstable modes which are characterized by exponential growth of transverse chromo-magnetic/-electric fields at short times. This instability is the QCD analogue of the Weibel instability of QED. Parametrically the chromo-Weibel instability provides the fastest method for generation of soft background fields and dominates the short-time dynamics of the system. The existence of the chromo-Weibel instability has been proven using diagrammatic methods, transport theory, and numerical solution of classical Yang-Mills fields. I review the results obtained from each of these methods and discuss the numerical techniques which are being used to determine the late-time behavior of plasmas subject to a chromo-Weibel instability.
Podlech, Oliver ; Harter, Patrick Nikolaus ; Mittelbronn, Michel Guy André ; Pöschel, Simone ; Naumann, Ulrike
In Europe, commercially available extracts from the white-berry mistletoe (Viscum album L.) are widely used as a complementary cancer therapy. Mistletoe lectins have been identified as main active components and exhibit cytotoxic effects as well as immunomodulatory activity. Since it is still not elucidated in detail how mistle toe extracts such as ISCADOR communicate their effects, we analyzed the mechanisms that might be responsible for their antitumoral function on a molecular and functional level. ISCADOR-treated glioblastoma (GBM) cells down-regulate central genes involved in glioblastoma progression and malignancy such as the cytokine TGF-β and matrix-metalloproteinases. Using in vitro glioblastoma/immune cell co-cultivation assays as well as measurement of cell migration and invasion, we could demonstrate that in glioblastoma cells, lectin-rich ISCADOR M and ISCADOR Q significantly enforce NK-cell-mediated GBM cell lysis. Beside its immune stimulatory effect, ISCADOR reduces the migratory and invasive potential of glioblastoma cells. In a syngeneic as well as in a xenograft glioblastoma mouse model, both pretreatment of tumor cells and intratumoral therapy of subcutaneously growing glioblastoma cells with ISCADOR Q showed delayed tumor growth. In conclusion, ISCADOR Q, showing multiple positive effects in the treatment of glioblastoma, may be a candidate for concomitant treatment of this cancer.
The TATA Box Binding Protein (TBP) is a 20 kD protein that is essential and universally conserved in eucarya and archaea. Especially among archaea, organisms can be found that live below 0°C as well as organisms that grow above 100°C. The archaeal TBPs show a high sequence identity and a similar structure consisting of α-helices and β-sheets that are arranged in a saddle-shape 2-symmetric fold. In previous studies, we have characterized the thermal stability of thermophilic and mesophilic archaeal TBPs by infrared spectroscopy and showed the correlation between the transition temperature (Tm) and the optimal growth temperature (OGT) of the respective donor organism. In this study, a “new” mutant TBP has been constructed, produced, purified and analyzed for a deeper understanding of the molecular mechanisms of thermoadaptation. The β-sheet part of the mutant consists of the TBP from Methanothermobacter thermoautotrophicus (OGT 65°C, MtTBP65) whose α-helices have been exchanged by those of Methanosarcina mazei (OGT 37°C, MmTBP37). The Hybrid-TBP irreversibly aggregates after thermal unfolding just like MmTBP37 and MtTBP65, but the Tm lies between that of MmTBP37 and MtTBP65 indicating that the interaction between the α-helical and β-sheet part of the TBP is crucial for the thermal stability. The temperature stability is probably encoded in the variable α-helices that interact with the highly conserved and DNA binding β-sheets.
The estimation model PhytoCalc allows a non-destructive quantification of dry weight and nutrient pools of understorey plants in forests by using the relationship between species biomass, cover and mean shoot length. The model has been validated with independent samples in several German forest types and can be a useful tool in forest monitoring. However, in open areas within forests (e.g. clearcuts), the current model version underestimates biomass and produces unreliable nutrient pool estimations. Thus, tissue density, as approximated by leaf dry matter content (LDMC), is systematically higher under high light compared to low light conditions. We demonstrate that the ratio of LDMC under clearcut conditions to LDMC under forest conditions can be used to adjust the PhytoCalc model to clearcut conditions. We investigated the LDMC ratio of five exemplary species commonly occurring on clearcuts. Integrating the square of the ratio as a correction factor improved estimates of biomass to more than 70% fit between observations and predictions. Results also suggest this ratio can be used to correct nutrient concentrations modelled in PhytoCalc, which tend to be overestimated in clearcuts. As morphological groups of plant species exhibit significantly different ratios, we advise using group-specific correction factors for clearcut adjustments in the future.
The key cognitive impairments of children with attention deficit/-hyperactivity disorder (ADHD) include executive control functions such as inhibitory control, task-switching, and working memory (WM). In this training study we examined whether task-switching training leads to improvements in these functions. Twenty children with combined type ADHD and stable methylphenidate medication performed a single-task and a task-switching training in a crossover training design. The children were randomly assigned to one of two groups. One group started with the single-task training and then performed the task-switching training and the other group vice versa. The effectiveness of the task-switching training was measured as performance improvements (relative to the single-task training) on a structurally similar but new switching task and on other executive control tasks measuring inhibitory control and verbal WM as well as on fluid intelligence (reasoning). The children in both groups showed improvements in task-switching, that is, a reduction of switching costs, but not in performing the single-tasks across four training sessions. Moreover, the task-switching training lead to selective enhancements in task-switching performance, that is, the reduction of task-switching costs was found to be larger after task-switching than after single-task training. Similar selective improvements were observed for inhibitory control and verbal WM, but not for reasoning. Results of this study suggest that task-switching training is an effective cognitive intervention that helps to enhance executive control functioning in children with ADHD.
The magnetic compass of a migratory bird, the European robin (Erithacus rubecula), was shown to be lateralized in favour of the right eye/left brain hemisphere. However, this seems to be a property of the avian magnetic compass that is not present from the beginning, but develops only as the birds grow older. During first migration in autumn, juvenile robins can orient by their magnetic compass with their right as well as with their left eye. In the following spring, however, the magnetic compass is already lateralized, but this lateralization is still flexible: it could be removed by covering the right eye for 6 h. During the following autumn migration, the lateralization becomes more strongly fixed, with a 6 h occlusion of the right eye no longer having an effect. This change from a bilateral to a lateralized magnetic compass appears to be a maturation process, the first such case known so far in birds. Because both eyes mediate identical information about the geomagnetic field, brain asymmetry for the magnetic compass could increase efficiency by setting the other hemisphere free for other processes.
Background: The genome of the carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii, Order: Dasyuromorphia), was sequenced in the hopes of finding a cure for or gaining a better understanding of the contagious devil facial tumor disease that is threatening the species’ survival. To better understand the Tasmanian devil genome, we screened it for transposable elements and investigated the dynamics of short interspersed element (SINE) retroposons.
Results: The temporal history of Tasmanian devil SINEs, elucidated using a transposition in transposition analysis, indicates that WSINE1, a CORE-SINE present in around 200,000 copies, is the most recently active element. Moreover, we discovered a new subtype of WSINE1 (WSINE1b) that comprises at least 90% of all Tasmanian devil WSINE1s. The frequencies of WSINE1 subtypes differ in the genomes of two of the other Australian marsupial orders. A co-segregation analysis indicated that at least 66 subfamilies of WSINE1 evolved during the evolution of Dasyuromorphia. Using a substitution rate derived from WSINE1 insertions, the ages of the subfamilies were estimated and correlated with a newly established phylogeny of Dasyuromorphia. Phylogenetic analyses and divergence time estimates of mitochondrial genome data indicate a rapid radiation of the Tasmanian devil and the closest relative the quolls (Dasyurus) around 14 million years ago.
Conclusions: The radiation and abundance of CORE-SINEs in marsupial genomes indicates that they may be a major player in the evolution of marsupials. It is evident that the early phases of evolution of the carnivorous marsupial order Dasyuromorphia was characterized by a burst of SINE activity. A correlation between a speciation event and a major burst of retroposon activity is for the first time shown in a marsupial genome.
Extraction of network topology from multi-electrode recordings : is there a small-world effect?
(2011)
The simultaneous recording of the activity of many neurons poses challenges for multivariate data analysis. Here, we propose a general scheme of reconstruction of the functional network from spike train recordings. Effective, causal interactions are estimated by fitting generalized linear models on the neural responses, incorporating effects of the neurons’ self-history, of input from other neurons in the recorded network and of modulation by an external stimulus. The coupling terms arising from synaptic input can be transformed by thresholding into a binary connectivity matrix which is directed. Each link between two neurons represents a causal influence from one neuron to the other, given the observation of all other neurons from the population. The resulting graph is analyzed with respect to small-world and scale-free properties using quantitative measures for directed networks. Such graph-theoretic analyses have been performed on many complex dynamic networks, including the connectivity structure between different brain areas. Only few studies have attempted to look at the structure of cortical neural networks on the level of individual neurons. Here, using multi-electrode recordings from the visual system of the awake monkey, we find that cortical networks lack scale-free behavior, but show a small, but significant small-world structure. Assuming a simple distance-dependent probabilistic wiring between neurons, we find that this connectivity structure can account for all of the networks’ observed small-world-ness. Moreover, for multi-electrode recordings the sampling of neurons is not uniform across the population. We show that the small-world-ness obtained by such a localized sub-sampling overestimates the strength of the true small-world structure of the network. This bias is likely to be present in all previous experiments based on multi-electrode recordings.
Hollert, Henner ; Filser, Juliane ; Häußling, Roger ; Hein, Michaela ; Matthies, Michael ; Oehlmann, Jörg ; Ratte, Hans-Toni ; Roß-Nickoll, Martina ; Schäffer, Andreas ; Scheringer, Martin ; Schiwy, Andreas Herbert
In den vergangenen Jahren gab es verschiedene Initiativen, die auf die unzureichende Fördersituation der Schadstoffbezogenen Umweltwissenschaften in der Bundesrepublik Deutschland aufmerksam gemacht haben. Um eine objektive Analyse über die Fördersituation der Ökotoxikologie und Umweltchemie in Deutschland zu erhalten, wurde eine anonyme Online-Befragung ausgearbeitet. Mit Unterstützung der Society of Environmental Toxicology and Chemistry (SETAC) – German Language Branch und der Gesellschaft Deutscher Chemiker (GDCh) – Fachgruppe für Umweltchemie und Ökotoxikologie wurde eine Einladung zur Teilnahme an der Befragung an alle Mitglieder dieser beiden maßgeblichen Verbände der Ökotoxikologie und Umweltchemie im deutschsprachigen Raum versendet. Nur leitende Mitarbeiter aus den Bereichen Forschung, Behörden und Industrie sollten an der Befragung teilnehmen. Die Befragung gliedert sich in eine Sektion zur sozioökonomischen Charakterisierung der Teilnehmer, eine zur Förderung der Forschung durch die DFG und eine zur Förderung durch andere Geldgeber. Insgesamt haben 71 Wissenschaftler und Wissenschaftlerinnen in leitenden Positionen aus verschiedenen Sparten an der Befragung teilgenommen. Die Ergebnisse zeigen, dass die Teilnehmer als sehr leistungsstark eingestuft werden können. 48,5 % der Befragten hatten bereits einen Antrag bei der DFG gestellt. Ein Drittel der Befragten gaben an, eine Förderung durch die DFG erhalten zu haben. 64 % sind mit der Förderung Schadstoffbezogener Umweltwissenschaften durch die DFG nicht zufrieden, nur 7 % sind zufrieden. Es zeigte sich, dass die Anträge insgesamt sehr heterogen auf verschiedene Fachbereiche der DFG verteilt sind. Geowissenschaften, Wasserforschung und Chemie nehmen die ersten Ränge ein, vor Biologie und Ökologie. Im Gegensatz dazu gaben 91,2 % der Befragten an, dass Sie bereits Drittmittelanträge bei anderen Förderinstitutionen (außer der DFG) gestellt haben, und 83,6 % wurden bereits entsprechende Drittmittelanträge bewilligt. 62,3 % der Befragten sind der Meinung, dass sich die Fördersituation für die Schadstoffbezogenen Umweltwissenschaften in den letzten Jahren insgesamt verschlechtert oder sogar deutlich verschlechtert hat. Der überwiegende Anteil der Befragten (60,9 %) ist mit der Fördersituation durch Drittmittelgeber unzufrieden, nur 10,9 % sind damit zufrieden. Auf die Frage „Ist die Forschungsförderung im europäischen Ausland insgesamt besser als in Deutschland?“ antworteten 30 % mit „ja“, 9 % mit „nein“ und 61 % mit „ich weiß nicht“. Zusammenfassend ergab die Befragung, dass die Fördersituation der Ökotoxikologie und Umweltchemie in Deutschland insgesamt als steigerungsbedürftig, bei der DFG jedoch als problematisch zu bewerten ist. Die auffällige Unterrepräsentation der DFG im Vergleich zu anderen Drittmittelgebern verdeutlicht, dass die wichtigste Förderinstitution Deutschlands den Bedürfnissen der Schadstoffbezogenen Umweltwissenschaften nicht hinreichend Rechnung trägt. Insbesondere die Antworten auf die offenen Fragen bezüglich Verbesserungsmöglichkeiten der Forschungsförderung sollten als Grundlage für einen offenen Dialog der Schadstoffbezogenen Umweltforschung mit den Drittmittelgebern DFG, BMBF und DBU bzw. den entsprechenden Institutionen in CH und A genutzt werden.
Mitochondria form a dynamic tubular reticulum within eukaryotic cells. Currently, quantitative understanding of its morphological characteristics is largely absent, despite major progress in deciphering the molecular fission and fusion machineries shaping its structure. Here we address the principles of formation and the large-scale organization of the cell-wide network of mitochondria. On the basis of experimentally determined structural features we establish the tip-to-tip and tip-to-side fission and fusion events as dominant reactions in the motility of this organelle. Subsequently, we introduce a graph-based model of the chondriome able to encompass its inherent variability in a single framework. Using both mean-field deterministic and explicit stochastic mathematical methods we establish a relationship between the chondriome structural network characteristics and underlying kinetic rate parameters. The computational analysis indicates that mitochondrial networks exhibit a percolation threshold. Intrinsic morphological instability of the mitochondrial reticulum resulting from its vicinity to the percolation transition is proposed as a novel mechanism that can be utilized by cells for optimizing their functional competence via dynamic remodeling of the chondriome. The detailed size distribution of the network components predicted by the dynamic graph representation introduces a relationship between chondriome characteristics and cell function. It forms a basis for understanding the architecture of mitochondria as a cell-wide but inhomogeneous organelle. Analysis of the reticulum adaptive configuration offers a direct clarification for its impact on numerous physiological processes strongly dependent on mitochondrial dynamics and organization, such as efficiency of cellular metabolism, tissue differentiation and aging.
Molecular biology of hearing
(2012)
The inner ear is our most sensitive sensory organ and can be subdivided into three functional units: organ of Corti, stria vascularis and spiral ganglion. The appropriate stimulus for the organ of hearing is sound, which travels through the external auditory canal to the middle ear where it is transmitted to the inner ear. The inner ear houses the hair cells, the sensory cells of hearing. The inner hair cells are capable of mechanotransduction, the transformation of mechanical force into an electrical signal, which is the basic principle of hearing. The stria vascularis generates the endocochlear potential and maintains the ionic homeostasis of the endolymph. The dendrites of the spiral ganglion form synaptic contacts with the hair cells. The spiral ganglion is composed of neurons that transmit the electrical signals from the cochlea to the central nervous system. In recent years there has been significant progress in research on the molecular basis of hearing. An increasing number of genes and proteins related to hearing are being identified and characterized. The growing knowledge of these genes contributes not only to greater appreciation of the mechanism of hearing but also to a deeper understanding of the molecular basis of hereditary hearing loss. This basic research is a prerequisite for the development of molecular diagnostics and novel therapies for hearing loss.
wo assumptions underlie current models of the geographical ranges of perennial plant species: 1. current ranges are in equilibrium with the prevailing climate, and 2. changes are attributable to changes in macroclimatic factors, including tolerance of winter cold, the duration of the growing season, and water stress during the growing season, rather than to biotic interactions. These assumptions allow model parameters to be estimated from current species ranges. Deterioration of growing conditions due to climate change, e.g. more severe drought, will cause local extinction. However, for many plant species, the predicted climate change of higher minimum temperatures and longer growing seasons means, improved growing conditions. Biogeographical models may under some circumstances predict that a species will become locally extinct, despite improved growing conditions, because they are based on an assumption of equilibrium and this forces the species range to match the species-specific macroclimatic thresholds. We argue that such model predictions should be rejected unless there is evidence either that competition influences the position of the range margins or that a certain physiological mechanism associated with the apparent improvement in growing conditions negatively affects the species performance. We illustrate how a process-based vegetation model can be used to ascertain whether such a physiological cause exists. To avoid potential modelling errors of this type, we propose a method that constrains the scenario predictions of the envelope models by changing the geographical distribution of the dominant plant functional type. Consistent modelling results are very important for evaluating how changes in species areas affect local functional trait diversity and hence ecosystem functioning and resilience, and for inferring the implications for conservation management in the face of climate change.
Beutel, Manfred ; Leuzinger-Bohleber, Marianne ; Rüger, Bernhard ; Bahrke, Ulrich ; Negele, Alexa ; Haselbacher, Antje ; Fiedler, Georg ; Keller, Wolfram ; Hautzinger, Martin
Background: Despite limited effectiveness of short-term psychotherapy for chronic depression, there is a lack of trials of long-term psychotherapy. Our study is the first to determine the effectiveness of controlled long-term psychodynamic and cognitive-behavioral (CBT) treatments and to assess the effects of preferential vs. randomized assessment.
Methods/design: Patients are assigned to treatment according to their preference or randomized (if they have no clear preference). Up to 80 sessions of psychodynamic or psychoanalytically oriented treatments (PAT) or up to 60 sessions of CBT are offered during the first year in the study. After the first year, PAT can be continued according to the ‘naturalistic’ usual method of treating such patients within the system of German health care (normally from 240 up to 300 sessions over two to three years). CBT therapists may extend their treatment up to 80 sessions, but focus mainly maintenance and relapse prevention. We plan to recruit a total of 240 patients (60 per arm). A total of 11 assessments are conducted throughout treatment and up to three years after initiation of treatment. The primary outcome measures are the Quick Inventory of Depressive Symptoms (QIDS, independent clinician rating) and the Beck Depression Inventory (BDI) after the first year.
Discussion: We combine a naturalistic approach with randomized controlled trials(RCTs)to investigate how effectively chronic depression can be treated on an outpatient basis by the two forms of treatment reimbursed in the German healthcare system and we will determine the effects of treatment preference vs. randomization.
Staphylococcus aureus proteins Sbi and Efb recruit human plasmin to degrade complement C3 and C3b
(2012)
Koch, Tina K. ; Reuter, Michael ; Barthel, Diana ; Böhm, Sascha ; Elsen, Jean van den ; Kraiczy, Peter ; Zipfel, Peter F. ; Skerka, Christine
Upon host infection, the human pathogenic microbe Staphylococcus aureus (S. aureus) immediately faces innate immune reactions such as the activated complement system. Here, a novel innate immune evasion strategy of S. aureus is described. The staphylococcal proteins surface immunoglobulin-binding protein (Sbi) and extracellular fibrinogen-binding protein (Efb) bind C3/C3b simultaneously with plasminogen. Bound plasminogen is converted by bacterial activator staphylokinase or by host-specific urokinase-type plasminogen activator to plasmin, which in turn leads to degradation of complement C3 and C3b. Efb and to a lesser extend Sbi enhance plasmin cleavage of C3/C3b, an effect which is explained by a conformational change in C3/C3b induced by Sbi and Efb. Furthermore, bound plasmin also degrades C3a, which exerts anaphylatoxic and antimicrobial activities. Thus, S. aureus Sbi and Efb comprise platforms to recruit plasmin(ogen) together with C3 and its activation product C3b for efficient degradation of these complement components in the local microbial environment and to protect S. aureus from host innate immune reactions.
Saccade-related modulations of neuronal excitability support synchrony of visually elicited spikes
(2011)
During natural vision, primates perform frequent saccadic eye movements, allowing only a narrow time window for processing the visual information at each location. Individual neurons may contribute only with a few spikes to the visual processing during each fixation, suggesting precise spike timing as a relevant mechanism for information processing. We recently found in V1 of monkeys freely viewing natural images, that fixation-related spike synchronization occurs at the early phase of the rate response after fixation-onset, suggesting a specific role of the first response spikes in V1. Here, we show that there are strong local field potential (LFP) modulations locked to the onset of saccades, which continue into the successive fixation periods. Visually induced spikes, in particular the first spikes after the onset of a fixation, are locked to a specific epoch of the LFP modulation. We suggest that the modulation of neural excitability, which is reflected by the saccade-related LFP changes, serves as a corollary signal enabling precise timing of spikes in V1 and thereby providing a mechanism for spike synchronization.
Uhlhaas, Peter J. ; Pipa, Gordon ; Lima, Bruss ; Melloni, Lucia ; Neuenschwander, Sergio ; Nikolić, Danko ; Singer, Wolf
Following the discovery of context-dependent synchronization of oscillatory neuronal responses in the visual system, the role of neural synchrony in cortical networks has been expanded to provide a general mechanism for the coordination of distributed neural activity patterns. In the current paper, we present an update of the status of this hypothesis through summarizing recent results from our laboratory that suggest important new insights regarding the mechanisms, function and relevance of this phenomenon. In the first part, we present recent results derived from animal experiments and mathematical simulations that provide novel explanations and mechanisms for zero and nero-zero phase lag synchronization. In the second part, we shall discuss the role of neural synchrony for expectancy during perceptual organization and its role in conscious experience. This will be followed by evidence that indicates that in addition to supporting conscious cognition, neural synchrony is abnormal in major brain disorders, such as schizophrenia and autism spectrum disorders. We conclude this paper with suggestions for further research as well as with critical issues that need to be addressed in future studies.
In binocular rivalry, presentation of different images to the separate eyes leads to conscious perception alternating between the two possible interpretations every few seconds. During perceptual transitions, a stimulus emerging into dominance can spread in a wave-like manner across the visual field. These traveling waves of rivalry dominance have been successfully related to the cortical magnification properties and functional activity of early visual areas, including the primary visual cortex (V1). Curiously however, these traveling waves undergo a delay when passing from one hemifield to another. In the current study, we used diffusion tensor imaging (DTI) to investigate whether the strength of interhemispheric connections between the left and right visual cortex might be related to the delay of traveling waves across hemifields. We measured the delay in traveling wave times (ΔTWT) in 19 participants and repeated this test 6 weeks later to evaluate the reliability of our behavioral measures. We found large interindividual variability but also good test–retest reliability for individual measures of ΔTWT. Using DTI in connection with fiber tractography, we identified parts of the corpus callosum connecting functionally defined visual areas V1–V3. We found that individual differences in ΔTWT was reliably predicted by the diffusion properties of transcallosal fibers connecting left and right V1, but observed no such effect for neighboring transcallosal visual fibers connecting V2 and V3. Our results demonstrate that the anatomical characteristics of topographically specific transcallosal connections predict the individual delay of interhemispheric traveling waves, providing further evidence that V1 is an important site for neural processes underlying binocular rivalry.
Neuronal mechanisms underlying beta/gamma oscillations (20-80 Hz) are not completely understood. Here, we show that in vivo beta/gamma oscillations in the cat visual cortex sometimes exhibit remarkably stable frequency even when inputs fluctuate dramatically. Enhanced frequency stability is associated with stronger oscillations measured in individual units and larger power in the local field potential. Simulations of neuronal circuitry demonstrate that membrane properties of inhibitory interneurons strongly determine the characteristics of emergent oscillations. Exploration of networks containing either integrator or resonator inhibitory interneurons revealed that: (i) Resonance, as opposed to integration, promotes robust oscillations with large power and stable frequency via a mechanism called RING (Resonance INduced Gamma); resonance favors synchronization by reducing phase delays between interneurons and imposes bounds on oscillation cycle duration; (ii) Stability of frequency and robustness of the oscillation also depend on the relative timing of excitatory and inhibitory volleys within the oscillation cycle; (iii) RING can reproduce characteristics of both Pyramidal INterneuron Gamma (PING) and INterneuron Gamma (ING), transcending such classifications; (iv) In RING, robust gamma oscillations are promoted by slow but are impaired by fast inputs. Results suggest that interneuronal membrane resonance can be an important ingredient for generation of robust gamma oscillations having stable frequency.
The cerebral cortex presents itself as a distributed dynamical system with the characteristics of a small world network. The neuronal correlates of cognitive and executive processes often appear to consist of the coordinated activity of large assemblies of widely distributed neurons. These features require mechanisms for the selective routing of signals across densely interconnected networks, the flexible and context dependent binding of neuronal groups into functionally coherent assemblies and the task and attention dependent integration of subsystems. In order to implement these mechanisms, it is proposed that neuronal responses should convey two orthogonal messages in parallel. They should indicate (1) the presence of the feature to which they are tuned and (2) with which other neurons (specific target cells or members of a coherent assembly) they are communicating. The first message is encoded in the discharge frequency of the neurons (rate code) and it is proposed that the second message is contained in the precise timing relationships between individual spikes of distributed neurons (temporal code). It is further proposed that these precise timing relations are established either by the timing of external events (stimulus locking) or by internal timing mechanisms. The latter are assumed to consist of an oscillatory modulation of neuronal responses in different frequency bands that cover a broad frequency range from <2 Hz (delta) to >40 Hz (gamma) and ripples. These oscillations limit the communication of cells to short temporal windows whereby the duration of these windows decreases with oscillation frequency. Thus, by varying the phase relationship between oscillating groups, networks of functionally cooperating neurons can be flexibly configurated within hard wired networks. Moreover, by synchronizing the spikes emitted by neuronal populations, the saliency of their responses can be enhanced due to the coincidence sensitivity of receiving neurons in very much the same way as can be achieved by increasing the discharge rate. Experimental evidence will be reviewed in support of the coexistence of rate and temporal codes. Evidence will also be provided that disturbances of temporal coding mechanisms are likely to be one of the pathophysiological mechanisms in schizophrenia.
Reconocimiento versus ethos
(2012)
El filósofo mexicano Bolívar Echeverría distingue cuatro ethe de la modernidad capitalista, entre ellos: el realista, hoy dominante, es el de la claridad; el barroco, es el de contradicciones, de doblesentidos. Según la teoría hegeliana del reconocimiento (Honneth/Habermas), la convivencia racional entre culturas sólo es posible dentro del ethos realista. Se parte del a priori dudoso de la posibilidad del reconocimiento dentro de la sociedad burguesa (entendiendo al racismo como algo accidental y no estructural). El ethos barroco, que existe en América Latina, implica la posibilidad de convivir con el otro sin reconocerlo en términos hegelianos, abriendo vías al mestizaje cultural. La falta de claridad de este ethos es la base de cierta convivencia intercultural bajo su actual imposibilidad estructural.
Müllenbach, Roman ; Weber, Susanne N. ; Krawczyk, Marcin ; Zimmer, Vincent ; Sarrazin, Christoph ; Lammert, Frank ; Grünhage, Frank
Background: The human ATP-binding cassette, subfamily B, member 11 (ABCB11) gene encodes the bile salt export pump, which is exclusively expressed at the canalicular membrane of hepatocytes. A frequent variant in the coding region, c.1331 T > C, leading to the amino acid exchange p.V444A, has been associated with altered serum bile salt levels in healthy individuals and predisposes homozygous carriers of the [C] allele for obstetric cholestasis. Recently, elevated bile salt levels were shown to be significantly associated with rates and risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon-alpha2 and ribavirin, suggesting a potential role for bile salt levels in HCV treatment outcomes and in the fibrogenic evolution of HCV-related liver disease. The aim of this study was to investigate a possible association of ABCB11 c.1331 T > C with hepatitis C virus (HCV) infection and fibrosis stages as assessed by non-invasive transient elastography in a German cohort of patients.
Methods: ABCB11 c.1331 T > C genotype was determined by allelic discrimination assay in 649 HCV infected cases and 413 controls. Overall, 444 cases were staged for fibrotic progression by measurement of liver stiffness.
Results: Homo- or heterozygous presence of the frequent [C] allele was associated with HCV positivity (OR = 1.41, CI = 1.02 - 1.95, p = 0.037). No association was detectable between the ABCB11 c.1331 T > C genotype and increased liver stiffness.
Conclusions: Our data confirm that homozygous presence of the major [C] allele of ABCB11 c.1331 T > C is a genetic susceptibility factor for HCV infection, but not for liver fibrosis.
Bygum, Anette ; Aygören-Pürsün, Emel ; Caballero, Teresa ; Beusterien, Kathleen ; Gholizadeh, Shadi ; Musingarimi, Patience ; Wait, Suzanne ; Boysen, Henrik B.
Background: Hereditary angioedema (HAE) is a rare but serious disease marked by swelling attacks in the extremities, face, trunk, airway, or abdominal areas that can be spontaneous or the result of trauma and other triggers. It can be life-threatening due to the risk of asphyxiation. While there have been major advancements in our understanding of the immunogenetics of HAE, there are significant gaps in the literature regarding understanding of the humanistic and economic impact of the disease, particularly in Europe. The purpose of the HAE Burden of Illness Study-Europe (HAE-BOIS-Europe), the development and methodology of which is described here, is to better understand the management and impact of HAE from the patient perspective in Europe.
Methods/Design: This is a cross-sectional study in which retrospective data were also collected being conducted in Denmark, Germany and Spain. The study is open to patients ages 12 and older with a diagnosis of HAE-I or HAE-II. Data collection includes: (i) a survey on individuals’ health care resource use, direct and indirect medical costs, impact on work and school, treatment satisfaction, and emotional functioning (via the Hospital Anxiety and Depression Scale); and (ii) one-on-one interviews to collect detailed descriptive data and patient testimonials on the impact of HAE on patients’ health-related quality of life.
Discussion: The present manuscript describes the development and plans for implementing a multi-country European study with the aim of characterizing the humanistic and economic burden of HAE from the patient perspective. This study will help raise awareness of HAE as a rare but debilitating condition with wide-ranging impacts.
Brügger, Dirk Steffen ; Kemming, Gregor I. ; Jacob, Matthias ; Meisner, Franz Georg ; Wojtczyk, Christoph J. ; Packert, Kristian ; Keipert, Peter E. ; Faithfull, N. Simon ; Habler, Oliver ; Becker, Bernhard F. ; Rehm, Markus
Introduction: Metabolic acidosis during hemorrhagic shock is common and conventionally considered to be due to hyperlactatemia. There is increasing awareness, however, that other nonlactate, unmeasured anions contribute to this type of acidosis.
Methods: Eleven anesthetized dogs were hemorrhaged to a mean arterial pressure of 45 mm Hg and were kept at this level until a metabolic oxygen debt of 120 mLO2/kg body weight had evolved. Blood pH, partial pressure of carbon dioxide, and concentrations of sodium, potassium, magnesium, calcium, chloride, lactate, albumin, and phosphate were measured at baseline, in shock, and during 3 hours post-therapy. Strong ion difference and the amount of weak plasma acid were calculated. To detect the presence of unmeasured anions, anion gap and strong ion gap were determined. Capillary electrophoresis was used to identify potential contributors to unmeasured anions.
Results: During induction of shock, pH decreased significantly from 7.41 to 7.19. The transient increase in lactate concentration from 1.5 to 5.5 mEq/L during shock was not sufficient to explain the transient increases in anion gap (+11.0 mEq/L) and strong ion gap (+7.1 mEq/L), suggesting that substantial amounts of unmeasured anions must have been generated. Capillary electrophoresis revealed increases in serum concentration of acetate (2.2 mEq/L), citrate (2.2 mEq/L), alpha-ketoglutarate (35.3 microEq/L), fumarate (6.2 microEq/L), sulfate (0.1 mEq/L), and urate (55.9 microEq/L) after shock induction.
Conclusion: Large amounts of unmeasured anions were generated after hemorrhage in this highly standardized model of hemorrhagic shock. Capillary electrophoresis suggested that the hitherto unmeasured anions citrate and acetate, but not sulfate, contributed significantly to the changes in strong ion gap associated with induction of shock.
Dohrmann, Frank ; Fröhlich, Ingo ; Galatyuk, Tetyana ; Holzmann, Romain ; Kählitz, Philipp K. ; Kämpfer, Burkhard ; Morinière, Emilie ; Pachmayer, Yvonne C. ; Ramstein, Béatrice ; Salabura, Piotr ; Stroth, Joachim ; Trebacz, Radoslaw ; Wiele, Jacques van de ; Wüstenfeld, Jörn
We have developed a versatile software package for the simulation of di-electron production in pp and dp collisions at moderate beam kinetic energies (1-2GeV). Particular attention has been paid to incorporate different descriptions of the Dalitz decay Δ rightarrow Ne + e - via a common interface. In addition, suitable parameterizations for the virtual bremsstrahlung process NN rightarrow NNe + e - based on one-boson exchange models have been implemented. Such simulation tools with high flexibility of the framework are important for the interpretation of the di-electron data taken with the HADES spectrometer and demonstrates the wide applicability within the field of nuclear and hadronic physics.
The aim of this study was to investigate the frequency and effects of peer-victimization on mental health problems among adolescents. Parental and school support were assumed as protective factors that might interact with one another in acting as buffers for adolescents against the risk of peer-victimization. Besides these protective factors, age and gender were additionally considered as moderating factors. The Social and Health Assessment survey was conducted among 986 students aged 11-18 years in order to assess peer-victimization, risk and protective factors and mental health problems. For mental health problems, the Strengths and Difficulties Questionnaire (SDQ) was used. Effects of peer-victimization on mental health problems were additionally compared with normative SDQ data in order to obtain information about clinically relevant psychopathology in our study sample. Results of this study show that peer-victimization carries a serious risk for mental health problems in adolescents. School support is effective in both male and female adolescents by acting as a buffer against the effect of victimization, and school support gains increasing importance in more senior students. Parental support seems to be protective against maladjustment, especially in peer-victimized girls entering secondary school. Since the effect of peer-victimization can be reduced by parental and school support, educational interventions are of great importance in cases of peer-victimization.
Research indicates that autism is the extreme end of a continuously distributed trait. The Social Responsiveness Scale (SRS) and the Social and Communication Disorders Checklist (SCDC) aim to assess autistic traits. The objective of this study was to compare their clinical validity. The SRS showed sensitivities of .74 to .80 and specificities of .69 to 1.00 for autism. Sensitivities were .85 to .90 and specificities .28 to.82 for the SCDC. Correlations with the ADI-R, ADOS and SCQ were higher for the SRS than for the SCDC. The SCDC seems superior to the SRS to screen for unspecific social and communicative deficits including autism. The SRS appears more suitable than the SCDC in clinical settings and for specific autism screening.
Bölte, Sven ; Schlitt, Sabine ; Gapp, Volker ; Hainz, Daniela ; Schirman, Shella ; Poustka, Fritz ; Weber, Bernhard ; Freitag, Christine M. ; Ciaramidaro, Angela ; Walter, Henrik
Autism spectrum disorders (ASD) have been associated with sensory hypersensitivity. A recent study reported visual acuity (VA) in ASD in the region reported for birds of prey. The validity of the results was subsequently doubted. This study examined VA in 34 individuals with ASD, 16 with schizophrenia (SCH), and 26 typically developing (TYP). Participants with ASD did not show higher VA than those with SCH and TYP. There were no substantial correlations of VA with clinical severity in ASD or SCH. This study could not confirm the eagle-eyed acuity hypothesis of ASD, or find evidence for a connection of VA and clinical phenotypes. Research needs to further address the origins and circumstances associated with altered sensory or perceptual processing in ASD.