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During a 4-week run in October–November 2006, a pilot experiment was performed at the CERN Proton Synchrotron in preparation for the Cosmics Leaving OUtdoor Droplets (CLOUD) experiment, whose aim is to study the possible influence of cosmic rays on clouds. The purpose of the pilot experiment was firstly to carry out exploratory measurements of the effect of ionising particle radiation on aerosol formation from trace H2SO4 vapour and secondly to provide technical input for the CLOUD design. A total of 44 nucleation bursts were produced and recorded, with formation rates of particles above the 3 nm detection threshold of between 0.1 and 100 cm -3 s -1, and growth rates between 2 and 37 nm h -1. The corresponding H2O concentrations were typically around 106 cm -3 or less. The experimentally-measured formation rates and htwosofour concentrations are comparable to those found in the atmosphere, supporting the idea that sulphuric acid is involved in the nucleation of atmospheric aerosols. However, sulphuric acid alone is not able to explain the observed rapid growth rates, which suggests the presence of additional trace vapours in the aerosol chamber, whose identity is unknown. By analysing the charged fraction, a few of the aerosol bursts appear to have a contribution from ion-induced nucleation and ion-ion recombination to form neutral clusters. Some indications were also found for the accelerator beam timing and intensity to influence the aerosol particle formation rate at the highest experimental SO2 concentrations of 6 ppb, although none was found at lower concentrations. Overall, the exploratory measurements provide suggestive evidence for ion-induced nucleation or ion-ion recombination as sources of aerosol particles. However in order to quantify the conditions under which ion processes become significant, improvements are needed in controlling the experimental variables and in the reproducibility of the experiments. Finally, concerning technical aspects, the most important lessons for the CLOUD design include the stringent requirement of internal cleanliness of the aerosol chamber, as well as maintenance of extremely stable temperatures (variations below 0.1 °C)
Aging of biological systems ultimately leads to death of the individual. In humans, organ failure as the result of functional impairments after stroke, cardio-vascular disease, tumor development, neurodegeneration and other diseases are certainly crucial in bringing life to an end. But what happens in individuals with no obvious disease or disorders?
PaMTH1 is an O-methyltransferase catalysing the methylation of vicinal hydroxyl groups of polyphenols. The protein accumulates during ageing of Podospora anserina in both the cytosol and in the mitochondrial matrix. The construction and characterisation of a PaMth1 deletion strain provided additional evidence about the function of the protein in the protection against metal induced oxidative stress. Deletion of PaMth1 was found to lead to a decreased resistance against exogenous oxidative stress and to a shortened lifespan suggesting a role of PaMTH1 as a longevity assurance factor in a new molecular pathway involved in lifespan control. Key words: Podospora anserina, knock-out, reactive oxygen species, flavonoids, ageing, O-methyltransferase
In previous investigations an impact of cellular copper homeostasis on ageing of the ascomycete Podospora anserina has been demonstrated. Here we provide new data indicating that mitochondria play a major role in this process. Determination of copper in the cytosolic fraction using total reflection X-ray fluorescence spectroscopy analysis and eGfp reporter gene studies indicate an age-related increase of cytosolic copper levels. We show that components of the mitochondrial matrix (i.e. eGFP targeted to mitochondria) become released from the organelle during ageing. Decreasing the accessibility of mitochondrial copper in P. anserina via targeting a copper metallothionein to the mitochondrial matrix was found to result in a switch from a copper-dependent cytochrome-c oxidase to a copper-independent alternative oxidase type of respiration and results in lifespan extension. In addition, we demonstrate that increased copper concentrations in the culture medium lead to the appearance of senescence biomarkers in human diploid fibroblasts (HDFs). Significantly, expression of copper-regulated genes is induced during in vitro ageing in medium devoid of excess copper suggesting that cytosolic copper levels also increase during senescence of HDFs. These data suggest that the identified molecular pathway of age-dependent copper dynamics may not be restricted to P. anserina but may be conserved from lower eukaryotes to humans.
Plasticity resembling spike-timing dependent synaptic plasticity: the evidence in human cortex
(2010)
Spike-timing dependent plasticity (STDP) has been studied extensively in a variety of animal models during the past decade but whether it can be studied at the systems level of the human cortex has been a matter of debate. Only recently newly developed non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) have made it possible to induce and assess timing dependent plasticity in conscious human subjects. This review will present a critical synopsis of these experiments, which suggest that several of the principal characteristics and molecular mechanisms of TMS-induced plasticity correspond to those of STDP as studied at a cellular level. TMS combined with a second phasic stimulation modality can induce bidirectional long-lasting changes in the excitability of the stimulated cortex, whose polarity depends on the order of the associated stimulus-evoked events within a critical time window of tens of milliseconds. Pharmacological evidence suggests an NMDA receptor mediated form of synaptic plasticity. Studies in human motor cortex demonstrated that motor learning significantly modulates TMS-induced timing dependent plasticity, and, conversely, may be modulated bidirectionally by prior TMS-induced plasticity, providing circumstantial evidence that long-term potentiation-like mechanisms may be involved in motor learning. In summary, convergent evidence is being accumulated for the contention that it is now possible to induce STDP-like changes in the intact human central nervous system by means of TMS to study and interfere with synaptic plasticity in neural circuits in the context of behavior such as learning and memory. Keywords: spike-timing dependent plasticity, long-term potentiation, long-term depression, paired associative stimulation, transcranial magnetic stimulation, human, cortex, translational neuroscience
In order to quantitatively analyse the chemical and dynamical evolution of the polar vortex it has proven extremely useful to work with coordinate systems that follow the vortex flow. We propose here a two-dimensional quasi-Lagrangian coordinate system {X i, delta X i}, based on the mixing ratio of a long-lived stratospheric trace gas i, and its systematic use with i = N2O, in order to describe the structure of a well-developed Antarctic polar vortex. In the coordinate system {X i, delta X i} the mixing ratio X i is the vertical coordinate and delta X i = X i(theta) - X i vort(theta) is the meridional coordinate (X i vort(theta) being a vertical reference profile in the vortex core). The quasi-Lagrangian coordinates {X i, delta X i} persist for much longer time than standard isentropic coordinates, potential temperature theta and equivalent latitude Phi e, do not require explicit reference to geographic space, and can be derived directly from high-resolution in situ measurements. They are therefore well-suited for studying the evolution of the Antarctic polar vortex throughout the polar winter with respect to the relevant chemical and microphysical processes. By using the introduced coordinate system {X N2O, delta X N2O} we analyze the well-developed Antarctic vortex investigated during the APE-GAIA (Airborne Polar Experiment – Geophysica Aircraft in Antarctica – 1999) campaign (Carli et al., 2000). A criterion, which uses the local in-situ measurements of X i=X i(theta) and attributes the inner vortex edge to a rapid change (delta-step) in the meridional profile of the mixing ratio X i, is developed to determine the (Antarctic) inner vortex edge. In turn, we suggest that the outer vortex edge of a well-developed Antarctic vortex can be attributed to the position of a local minimum of the X H2O gradient in the polar vortex area. For a well-developed Antarctic vortex, the delta X N2O-parametrization of tracer-tracer relationships allows to distinguish the tracer inter-relationships in the vortex core, vortex boundary region and surf zone and to examine their meridional variation throughout these regions. This is illustrated by analyzing the tracer-tracer relationships X i : X N2O obtained from the in-situ data of the APE-GAIA campaign for i = CFC-11, CFC-12, H-1211 and SF6. A number of solitary anomalous points in the CFC-11 : N2O correlation, observed in the Antarctic vortex core, are interpreted in terms of small-scale cross-isentropic dispersion.
Potentiation of glycine-gated NR1/NR3A NMDA receptors relieves Ca2+-dependent outward rectification
(2010)
Glycine has diverse functions within the mammalian central nervous system. It inhibits postsynaptic neurons via strychnine-sensitive glycine receptors (GlyRs) and enhances neuronal excitation through co-activation of N-methyl-D-aspartate (NMDA) receptors. Classical Ca2+-permeable NMDA receptors are composed of glycine-binding NR1 and glutamate-binding NR2 subunits, and hence require both glutamate and glycine for efficient activation. In contrast, recombinant receptors composed of NR1 and the glycine binding NR3A and/or NR3B subunits lack glutamate binding sites and can be activated by glycine alone. Therefore these receptors are also named “excitatory glycine receptors”. Co-application of antagonists of the NR1 glycine-binding site or of the divalent cation Zn2+ markedly enhances the glycine responses of these receptors. To gain further insight into the properties of these glycine-gated NMDA receptors, we investigated their current-voltage (I–V) dependence. Whole-cell current-voltage relations of glycine currents recorded from NR1/NR3B and NR1/NR3A/NR3B expressing oocytes were found to be linear under our recording conditions. In contrast, NR1/NR3A receptors displayed a strong outwardly rectifying I–V relation. Interestingly, the voltage-dependent inward current block was abolished in the presence of NR1 antagonists, Zn2+ or a combination of both. Further analysis revealed that Ca2+ (1.8 mM) present in our recording solutions was responsible for the voltage-dependent inhibition of ion flux through NR1/NR3A receptors. Since physiological concentrations of the divalent cation Mg2+ did not affect the I–V dependence, our data suggest that relief of the voltage-dependent Ca2+ block of NR1/NR3A receptors by Zn2+ may be important for the regulation of excitatory glycinergic transmission, according to the Mg2+-block of conventional NR1/NR2 NMDA receptors. Keywords: NMDA receptor, excitatory glycine receptor, voltage block, NR3 subunit, supralinear potentiation, Zn2+, NR1 antagonist, ligand-binding domain
Although models based on independent component analysis (ICA) have been successful in explaining various properties of sensory coding in the cortex, it remains unclear how networks of spiking neurons using realistic plasticity rules can realize such computation. Here, we propose a biologically plausible mechanism for ICA-like learning with spiking neurons. Our model combines spike-timing dependent plasticity and synaptic scaling with an intrinsic plasticity rule that regulates neuronal excitability to maximize information transmission. We show that a stochastically spiking neuron learns one independent component for inputs encoded either as rates or using spike-spike correlations. Furthermore, different independent components can be recovered, when the activity of different neurons is decorrelated by adaptive lateral inhibition.
Understanding the dynamics of recurrent neural networks is crucial for explaining how the brain processes information. In the neocortex, a range of different plasticity mechanisms are shaping recurrent networks into effective information processing circuits that learn appropriate representations for time-varying sensory stimuli. However, it has been difficult to mimic these abilities in artificial neural network models. Here we introduce SORN, a self-organizing recurrent network. It combines three distinct forms of local plasticity to learn spatio-temporal patterns in its input while maintaining its dynamics in a healthy regime suitable for learning. The SORN learns to encode information in the form of trajectories through its high-dimensional state space reminiscent of recent biological findings on cortical coding. All three forms of plasticity are shown to be essential for the network's success. Keywords: synaptic plasticity, intrinsic plasticity, recurrent neural networks, reservoir computing, time series prediction
We examined whether positive transfer of cognitive training, which so far has been observed for individual tests only, also generalizes to cognitive abilities, thereby carrying greater promise for improving everyday intellectual competence in adulthood and old age. In the COGITO Study, 101 younger and 103 older adults practiced six tests of perceptual speed (PS), three tests of working memory (WM), and three tests of episodic memory (EM) for over 100 daily 1-h sessions. Transfer assessment included multiple tests of PS, WM, EM, and reasoning. In both age groups, reliable positive transfer was found not only for individual tests but also for cognitive abilities, represented as latent factors. Furthermore, the pattern of correlations between latent change factors of practiced and latent change factors of transfer tasks indicates systematic relations at the level of broad abilities, making the interpretation of effects as resulting from unspecific increases in motivation or self-concept less likely. Keywords: cognitive training, cognitive abilities, transfer, latent factors, working memory
Disruptive behaviour disorders are reflected by a great variety of symptoms ranging from impulsive-hot tempered quarrels to purposeful and goal directed acts of cruelty. A growing body of data indicates that there are neurobiological factors that increase the risk for developing disruptive behaviour disorders. In this review, we give a broad overview of recent studies investigating physiological, neural, genetic factors, and specific neurotransmitter systems. We also discuss the impact of psychosocial risk and consider the effects of gene-environment interactions. Due to the heterogeneity of disruptive behaviour disorders, it is concluded that specific subtypes of disruptive behaviour should be considered both in terms their biological basis and in regard to specific treatment needs.
Die Arbeit untersucht die Herstellung und ökonomische Umsetzung von "ethnischem Anderssein" in sog. Kultur-Kochkursen in Frankfurt am Main. In den beforschten Kultur-Kochkursen vermitteln ethnisch markierte KochkursleiterInnen "ihre Küche und Kultur" einem (multikulturalistisch) interessiertem Publikum. Die Arbeit fokussiert auf die performative Herstellung, Umsetzung und Repräsentation von (vermarktbarem) ethnischen Andersseins durch die KochkursleiterInnen in der Kochkurssituation und überprüft die Annahme, dass Ethnizität primär durch (Selbst-)Othering – die Betonung von unüberbrückbarer, essentieller kultureller Differenz – vermarktet wird. Die Befunde, welche auf Internetrecherchen, teilnehmenden Beobachtungen und narrativen Interviews basieren, zeigen, dass die organisierenden Institutionen die Kulturkochkurse zwar mit dem Verweis auf Authentizität, Tradition und Andersartigkeit bewerben, die Kultur-KochkursleiterInnen selbst in der Kochkurssituation allerdings kein kulturalistisches, exotisierendes und Differenz betonendes Ethnizitätskonzept perfomieren, sondern vielmehr Dynamik, Vielfalt und Vermischungen artikulieren, praktizieren und stark positiv konnotieren.
Leben bedeutet eine fortdauernde Anpassung an Umweltbedingungen durch ein hoch entwickeltes Informationsverarbeitungssystem. Diese Anpassung wird durch das neuroendokrine und autonome Nervensystem gewährleistet. Eine tages- und jahreszeitliche Organisation des neuroendokrinen und autonomen Systems findet durch das Photoneuroendokrine System (PNS) statt. Erst in jüngster Zeit konnte gezeigt werden, dass neben peptidergen Substanzen auch lipiderge Signalmoleküle des Endocannabinoidsystems eine essentielle Rolle bei der interzelluären Kommunikation spielen. Hierbei zählen Anandamid (AEA) und 2-Arachidonoylglycerol (2-AG) zu den umfassend erforschten Endocannabinoiden. ...
Diese Arbeit untersuchte die Epidemiologie und den Einfluss verschiedener Faktoren (Grunderkrankung, empirische Therapie, Schweregrad der Sepsis und Erreger mit Resistenz) auf das Überleben von Patienten mit Septikämien. Die häufigsten Grunderkrankungen dieses Kollektivs waren Leukämien (33%), solide Neoplasien (14%) sowie kardiale Vorerkrankungen (14%). Knapp die Hälfte der Patienten erwarb die Septikämie im Krankenhaus (47%). ...
Tubular carbonate concretions of up to 1 m in length and perpendicular to bedding, occur abundantly in the Upper Pliensbachian (upper Amaltheus margaritatus Zone, Gibbosus Subzone) in outcrops (Fontaneilles section) in the vicinity of Rivière-sûr-Tarn, southern France. Stable isotope analyses of these concretions show negative delta 13C values that decrease from the rim to the center from - 18.8‰ to - 25.7‰ (V-PDB), but normal marine delta 18 O values (- 1.8‰). Carbon isotope analyses of Late Pliensbachian bulk carbonate (matrix) samples from the Fontaneilles section show clearly decreasing C-isotope values across the A. margaritatus Zone, from +1‰ to - 3‰ (V-PDB). Isotope analyses of coeval belemnite rostra do not document such a negative C-isotope trend with values remaining stable around +2‰ (V-PDB). Computer tomographic (CT) scanning of the tubular concretions show multiple canals that are lined or filled entirely with pyrite. Previously, the formation of these concretions with one, two, or more central tubes, has been ascribed to the activity of an enigmatic organism, possibly with annelid or arthropod affinities, known asTisoa siphonalis. Our results suggest tisoan structures are abiogenic. Based on our geochemical analyses and sedimentological observations we suggest that these concretions formed as a combination of the anaerobic oxidation of methane (AOM) and sulfate reduction within the sediment. Fluids rich in methane and/or hydrocarbons likely altered local bulk rock carbon isotope records, but did not affect the global carbon cycle. Interestingly, Tisoa siphonalis has been described from many locations in the Grands Causses Basin in southern France, and from northern France and Luxemburg, always occurring at the same stratigraphic level. Upper Pliensbachian authigenic carbonates thus possibly cover an area of many thousand square kilometers. Greatly reduced sedimentation rates are needed to explain the stabilization of the sulfate-methane transition zone in the sedimentary column in order for the tubular concretions to form. Late Pliensbachian cooling, reducing run-off, and/or the influx of colder water and more vigorous circulation could be responsible for a halt in sedimentation. At the same time (thermogenic) methane may have destabilized during a major phase of Late Pliensbachian sea level fall. As such Tisoa siphonalis is more than a geological curiosity, and its further study could prove pivotal in understanding Early Jurassic paleoenvironmental change.
Background: Abnormalities of 11q23 involving the MLL gene are found in approximately 10% of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia. Methods: Cytogenetics, fluorescence in situ hybridization (FISH), molecular studies (RT-PCR and LDI-PCR), and bioinformatic sequence analysis were used to characterize the CT45A2 gene as novel MLL fusion partner in pediatric acute leukemia. Results: Fluorescence in situ hybridization of the patient G-banded metaphases demonstrated a cryptic insertion of 11q23 in Xq26.3 involving the MLL gene. Breakpoint fusion analysis revealed that a DNA fragment of 653 kb from 11q23, containing MLL exons 1-9 in addition to 16 other 11q23 genes, was inserted into the upstream region of the CT45A2 gene located at Xq26.3. In addition, a deletion at Xq26.3 encompassing the 3' region of the DDX26B gene (exons 9-16) and the entire CT45A1 gene was identified. RNA analysis revealed the presence of a novel MLL-CT45A2 fusion transcript in which the first 9 exons of the MLL gene were fused in-frame to exon 2 of the CT45A2 gene, resulting in a spliced MLL fusion transcript with an intact open reading frame. The resulting chimeric transcript predicts a fusion protein where the N-terminus of MLL is fused to the entire open reading frame of CT45A2. Finally, we demonstrate that all breakpoint regions are rich in long repetitive motifs, namely LINE/L1 and SINE/Alu sequences, but all breakpoints were exclusively identified outside these repetitive DNA sequences. Conclusion: We have identified CT45A2 as a novel spliced MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia, as a result of a cryptic insertion of 11q23 in Xq26.3. Since CT45A2 is the first Cancer/Testis antigen family gene found fused with MLL in acute leukemia, future studies addressing its biologic relevance for leukemogenesis are warranted.
Background: The enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and its (over)expression has been linked to several human malignancies. Here, we studied a possible association between EZH2 expression and prognosis in patients with renal cell carcinoma (RCC). Methods: EZH2 protein expression in RCC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing RCC tumor tissue and corresponding normal tissue samples of 520 patients. For immunohistochemical assessment of EZH2 expression, nuclear staining quantity was evaluated using a semiquantitative score. The effect of EZH2 expression on cancer specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. Results: During follow-up, 147 patients (28%) had died of their disease, median follow-up of patients still alive was 6.0 years (range 0 - 16.1 years). EZH2 nuclear staining was present in tumor cores of 411 (79%) patients. A multivariate Cox regression analysis revealed that high nuclear EZH2 expression was an independent predictor of poor CSS (>25-50% vs. 0%: HR 2.72, p = 0.025) in patients suffering from non-metastatic RCC. Apart from high nuclear EZH2 expression, tumor stage and Fuhrman's grading emerged as significant prognostic markers. In metastatic disease, nuclear EZH2 expression and histopathological subtype were independent predictive parameters of poor CSS (EZH2: 1-5%: HR 2.63, p = 0.043, >5-25%: HR 3.35, p = 0.013, >25%-50%: HR 4.92, p = 0.003, all compared to 0%: HR 0.36, p = 0.025, respectively). Conclusions: This study defines EZH2 as a powerful independent unfavourable prognostic marker of CSS in patients with metastatic and non-metastatic RCC.
The editorial board of Aging reviews research papers published in 2009,which they believe have or will have a significant impact on aging research.Among many others, the topics include genes that accelerate aging or incontrast promote longevity in model organisms, DNA damage responsesand telomeres, molecular mechanisms of life span extension by calorierestriction and pharmacologic interventions into aging. The emergingmessage in 2009 is that aging is not random but determined by agenetically-regulated longevity network and can be decelerated bothgenetically and pharmacologically.
Im Koalitionsvertrag von Rot-Grün heißt es am Ende einer Präambel zur „Schule der Zukunft“: „Die Diskussion darüber, wie das Schulsystem ausgestaltet werden soll, ist in Nordrhein-Westfalen sehr kontrovers und polarisiert geführt worden. Wir wollen versuchen, mit allen Fraktionen und allen beteiligten Akteurinnen und Akteuren einen Konsens in der Schulpolitik zu erzielen.“ (Koalitionsvertrag zwischen der NRWSPD und Bündnis 90/Die Grünen NRW, Juli 2010, S.7) Wie stehen die Chancen für einen solchen Konsens?