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We study the impact of nonequilibrium effects on the relevant signals within a chiral fluid dynamics model including explicit propagation of the Polyakov loop. An expanding heat bath of quarks is coupled to the Langevin dynamics of the order parameter fields. The model is able to describe relaxational processes, including critical slowing down and the enhancement of soft modes near the critical point. At the first-order phase transition we observe domain formation and phase coexistence in the sigma and Polyakov loop field leading to a significant amount of clumping in the energy density. This effect gets even more pronounced if we go to systems at finite baryon density. Here the formation of high-density clusters could provide an important observable signal for upcoming experiments at FAIR and NICA.We conclude that improving our understanding of dynamical symmetry breaking is important to give realistic estimates for experimental observables connected to the QCD phase transition.
Oral presentation: 23rd World Congress of the World Society of Cardio-Thoracic Surgeons. Split, Croatia. 12-15 September 2013.
Background: In the past, questions have been raised, whether an open flexible annuloplasty band can reliably prevent recurrent mitral valve regurgitation. The purpose of this study was to evaluate the durability of mitral valve repair at midterm, using the Cosgrove-Edwards annuloplasty band in a homogenic patient cohort.
Methods: From January 2004 to December 2007, 157 consecutive patients with degenerative mitral valve disease were included in the study. All had quadrangular resection of a P2 prolapse and annuloplasty with a Cosgrove-Edwards annuloplasty band. Clinical and echocardiography follow-up was complete.
Results: There was no intraoperative or 30 day mortality. After a mean follow-up of 5.0 ± 1.9 years, survival was 94.3%. At midterm, freedom from reoperations was 98.9%, freedom from thromboembolism was 97.5% and freedom from endocarditis was 99.4%. Echocardiography follow-up showed recurrent mitral valve regurgitation higher than grade 2 in two patients. Mean ejection fraction was 60.3 ± 10.2%, left atrial diameter was 42 ± 7 mm, mean gradient was 3.2 ± 1.4 mmHg, effective orifice area was 3.3 ± 1.3cm², mitral leaflet coaptation length was 7.5 ± 1.9 mm and mitral leaflet tethering height was 6.2 ± 2.3 mm.
Conclusion: Mitral valve repair using the Cosgrove annuloplasty band for degenerative mitral valve disease provides an effective and durable form of reconstruction.
We analyze hadrochemical freeze-out in central Pb+Pb collisions at CERN SPS and LHC energies. Employing the UrQMD hybrid transport model we study the effects of the final hadron/resonance expansion phase on the hadron multiplicities established at hadronization. The bulk meson yields freeze out directly at hadronization whereas the baryon-antibaryon sector is subject to significant alterations, due to annihilation and regeneration processes. We quantify the latter changes by survival factors for each species which are applied to modify the statistical model predictions for the data. The modified SM analysis recovers the hadronization points, which coincide with the recent lattice QCD predictions of the parton-hadron transition line at finite baryochemical potential.
Recent results on baryon production in relativistic heavy ion collisions show that a revision of the chemical freeze-out conditions is necessary. Particularly, there is evidence that chemical freezeout does not occur at full chemical equilibrium. We present a method to reconstruct original hadronization conditions and show that the newly found points in the T − µB plane are in very good agreement with extrapolations of the lattice QCD critical line.
Spinodal crumbling
(2013)
Extending a previously developed two-phase equation of state, we simulate head-on relativistic lead-lead collisions with fluid dynamics, augmented with a finite-range term, and study the effects of the phase structure on the evolution of the baryon density. For collision energies that bring the bulk of the system into the mechanically unstable spinodal region of the phase diagram, the density irregularities are being amplified significantly. We also present results for the associated clump size distribution.
The physics of EPOS
(2013)
poster presentation at the 31st International Symposium on Lattice Field Theory LATTICE 2013:
We explore and compare three mixed action setups with Wilson twisted mass sea quarks and different valence quark actions: (1) Wilson twisted mass, (2) Wilson twisted mass + clover and (3) Wilson + clover. Our main goal is to reduce lattice discretization errors in mesonic spectral quantities, in particular to reduce twisted mass parity and isospin breaking.
We derive the Polyakov-loop thermodynamic potential in the perturbative approach to pure SU(3) Yang-Mills theory. The potential expressed in terms of the Polyakov loop in the fundamental representation corresponds to that of the strong-coupling expansion, of which the relevant coefficients of the gluon energy distribution are specified by characters of the SU(3) group. At high temperature, the potential exhibits the correct asymptotic behavior, whereas at low temperature, it disfavors gluons as appropriate dynamical degrees of freedom. To quantify the Yang-Mills thermodynamics in confined phase, we introduce a hybrid approach which matches the effective gluon potential to that of glueballs, constrained by the QCD trace anomaly in terms of dilaton fields.
Exhaustive, automatic testing of dataflow (esp. mapreduce) programs has emerged as an important challenge. Past work demonstrated effective ways to generate small example data sets that exercise operators in the Pig platform, used to generate Hadoop map-reduce programs. Although such prior techniques attempt to cover all cases of operator use, in practice they often fail. Our SEDGE system addresses these completeness problems: for every dataflow operator, we produce data aiming to cover all cases that arise in the dataflow program (e.g., both passing and failing a filter). SEDGE relies on transforming the program into symbolic constraints, and solving the constraints using a symbolic reasoning engine (a powerful SMT solver), while using input data as concrete aids in the solution process. The approach resembles dynamic-symbolic (a.k.a. "concolic") execution in a conventional programming language, adapted to the unique features of the dataflow domain.
In third-party benchmarks, SEDGE achieves higher coverage than past techniques for 5 out of 20 PigMix benchmarks and 7 out of 11 SDSS benchmarks and (with equal coverage for the rest of the benchmarks). We also show that our targeting of the high-level dataflow language pays off: for complex programs, state-of-the-art dynamic-symbolic execution at the level of the generated map-reduce code (instead of the original dataflow program) requires many more test cases or achieves much lower coverage than our approach.
The study of energy and system size dependence of fluctuations of identified hadrons is one of the key goals of NA61/SHINE at the CERN SPS. Results may allow to discover the critical point (CP) of strongly interacting matter as well as to uncover properties of the onset of deconfinement (OD). Measured fluctuations are affected by numerous other effects like volume fluctuations and conservation laws. NA49 seems to observe fluctuations possibly related to the CP in collisions of medium size nuclei at the top SPS energy. However, this result will remain inconclusive until systematic data on energy and system size dependence will be available. Moreover, fluctuations in p+p as well as in Pb+Pb interactions should be better understood. In this contribution new results on multiplicity fluctuations of identified hadrons in p+p interactions at the CERN SPS energies will be presented. The NA61 data will be compared with the corresponding results on central Pb+Pb collisions of NA49 in the common acceptance region of both experiments. Furthermore, predictions of models (EPOS, UrQMD and HSD) for p+p interactions will be tested.
The QGP that might be created in ultrarelativistic heavy-ion collisions is expected to radiate thermal dilepton radiation. However, this thermal dilepton radiation interferes with dileptons originating from hadron decays. In the invariant mass region between the f and J=y peak (1GeV <= M l+l <=. 3GeV) the most substantial background of hadron decays originates from correlated DD¯ -meson decays. We evaluate this background using a Langevin simulation for charm quarks. As background medium we utilize the well-tested UrQMD-hybrid model. The required drag and diffusion coefficients are taken from a resonance approach. The decoupling of the charm quarks from the hot medium is performed at a temperature of 130MeV and as hadronization mechanism a coalescence approach is chosen. This model for charm quark interactions with the medium has already been successfully applied to the study of the medium modification and the elliptic flow at FAIR, RHIC and LHC energies. In this proceeding we present our results for the dilepton radiation from correlated D¯D decays at RHIC energy in comparison to PHENIX measurements in the invariant mass range between 1 and 3 GeV using different interaction scenarios. These results can be utilized to estimate the thermal QGP radiation.
As microscopic transport models usually have difficulties to deal with in-medium effects in heavy-ion collisions, we present an alternative approach that uses coarse-grained output from transport calculations with the UrQMD model to determine thermal dilepton emission rates. A four-dimensional space-time grid is set up to extract local baryon and energy densities, respectively temperature and baryon chemical potential. The lepton pair emission is then calculated for each cell of the grid using thermal equilibrium rates. In the current investigation we inlcude the medium-modified r spectral function by Eletsky et al., as well as contributions from the QGP and four-pion interactions for high collision energies. First dielectron invariant mass spectra for Au+Au collisions at 1.25 AGeV and for dimuons from In+In at 158 AGeV are shown. At 1.25 AGeV a clear enhancement of the total dilepton yield as compared to a pure transport result is observed. In the latter case, we compare our outcome with the NA60 dimuon excess data. Here a good agreement is achieved, but the yield in the low-mass tail is underestimated. In general the results show that the coarse-graining approach gives reasonable results and can cover a broad collision-energy range.
We report on the event-by-event multiplicity fluctuations of identified particles in central Pb+Pb collisions measured by the NA49 experiment at the CERN SPS. Employing a novel approach we unfolded the moments of the unknown multiplicity distributions of protons (p), kaons (K), pions (π) and electrons. Using these moments we reconstructed an excitation function of the fluctuation measure νdyn[A;B], with A and B denoting different particle types. Specifically, we reconstructed νdyn for the [p, π], [p, K] and [K, π] pairs. The energy dependence of νdyn is in agreement with previously published NA49 results on the related measure σdyn. Moreover, for [K; p] and [K;p] pairs, we discovered a dependence of the fluctuation measure νdyn on the phase space coverage (acceptance). Interestingly for the [p,π] case no significant acceptance dependence was observed. These observations provide a likely explanation of the reported differences between measurements of NA49 and those of STAR in central Au+Au collisions.
The paper takes a deeper look at participation rates in cMOOCs. To get a better insight into the behavior of learners in MOOCs, studiumdigitale has developed a tool which helps to analyze the contribution of participants in the so called cMOOCs. These are MOOCs which are fostering the active participation of learners in various tools and which are based on the concept of connectivism [1]. After an approach at each part of the definition of MOOCs and the discussion of the different categories of this quite new phenomena a deeper look will be taken into the analysis of two cMOOCs, OPCO11 and OPCO12 which took place 2011 and 2012 [2].
When studying real world complex networks, one rarely has full access to all their components. As an example, the central nervous system of the human consists of 1011 neurons which are each connected to thousands of other neurons. Of these 100 billion neurons, at most a few hundred can be recorded in parallel. Thus observations are hampered by immense subsampling. While subsampling does not affect the observables of single neuron activity, it can heavily distort observables which characterize interactions between pairs or groups of neurons. Without a precise understanding how subsampling affects these observables, inference on neural network dynamics from subsampled neural data remains limited.
We systematically studied subsampling effects in three self-organized critical (SOC) models, since this class of models can reproduce the spatio-temporal activity of spontaneous activity observed in vivo. The models differed in their topology and in their precise interaction rules. The first model consisted of locally connected integrate- and fire units, thereby resembling cortical activity propagation mechanisms. The second model had the same interaction rules but random connectivity. The third model had local connectivity but different activity propagation rules. As a measure of network dynamics, we characterized the spatio-temporal waves of activity, called avalanches. Avalanches are characteristic for SOC models and neural tissue. Avalanche measures A (e.g. size, duration, shape) were calculated for the fully sampled and the subsampled models. To mimic subsampling in the models, we considered the activity of a subset of units only, discarding the activity of all the other units.
Under subsampling the avalanche measures A depended on three main factors: First, A depended on the interaction rules of the model and its topology, thus each model showed its own characteristic subsampling effects on A. Second, A depended on the number of sampled sites n. With small and intermediate n, the true A¬ could not be recovered in any of the models. Third, A depended on the distance d between sampled sites. With small d, A was overestimated, while with large d, A was underestimated.
Since under subsampling, the observables depended on the model's topology and interaction mechanisms, we propose that systematic subsampling can be exploited to compare models with neural data: When changing the number and the distance between electrodes in neural tissue and sampled units in a model analogously, the observables in a correct model should behave the same as in the neural tissue. Thereby, incorrect models can easily be discarded. Thus, systematic subsampling offers a promising and unique approach to model selection, even if brain activity was far from being fully sampled.
Neuronal dynamics differs between wakefulness and sleep stages, so does the cognitive state. In contrast, a single attractor state, called self-organized critical (SOC), has been proposed to govern human brain dynamics for its optimal information coding and processing capabilities. Here we address two open questions: First, does the human brain always operate in this computationally optimal state, even during deep sleep? Second, previous evidence for SOC was based on activity within single brain areas, however, the interaction between brain areas may be organized differently. Here we asked whether the interaction between brain areas is SOC. ...
Network or graph theory has become a popular tool to represent and analyze large-scale interaction patterns in the brain. To derive a functional network representation from experimentally recorded neural time series one has to identify the structure of the interactions between these time series. In neuroscience, this is often done by pairwise bivariate analysis because a fully multivariate treatment is typically not possible due to limited data and excessive computational cost. Furthermore, a true multivariate analysis would consist of the analysis of the combined effects, including information theoretic synergies and redundancies, of all possible subsets of network components. Since the number of these subsets is the power set of the network components, this leads to a combinatorial explosion (i.e. a problem that is computationally intractable). In contrast, a pairwise bivariate analysis of interactions is typically feasible but introduces the possibility of false detection of spurious interactions between network components, especially due to cascade and common drive effects. These spurious connections in a network representation may introduce a bias to subsequently computed graph theoretical measures (e.g. clustering coefficient or centrality) as these measures depend on the reliability of the graph representation from which they are computed. Strictly speaking, graph theoretical measures are meaningful only if the underlying graph structure can be guaranteed to consist of one type of connections only, i.e. connections in the graph are guaranteed to be non-spurious. ...
Using a partonic transport model we investigate the evolution of conical structures in ultrarelativistic matter. Using two different source terms and varying the transport properties of the matter we study the formation of Mach Cones. Furthermore, in an additional study we extract the two-particle correlations from the numerical calculations and compare them to an analytical approximation. The influence of the viscosity to the shape of Mach Cones and the corresponding two-particle correlations is studied by adjusting the cross section of the medium.
Poster presentation: 28th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC)
Significant progress has been made over the last decade towards realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells, and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also continuously expanding cytotoxic cell lines such as NK-92 are being considered for adoptive cancer immunotherapy. High cytotoxicity of NK-92 has previously been shown against malignant cells of hematologic origin in preclinical studies, and general safety of infusion of NK-92 cells has been established in phase I clinical trials. To enhance their therapeutic utility, we genetically modified NK-92 cells to express chimeric antigen receptors (CAR) specific for tumor-associated surface antigens. Such CAR were composed of a tumor-specific scFv antibody fragment fused via hinge and transmembrane domains to intracellular signaling moieties such as CD3 zeta chain, or composite fusion molecules also containing a costimulatory protein domain in addition to CD3 zeta. For development towards clinical applications, here a codon-optimized second generation CAR was constructed that consists of an ErbB2-specific scFv antibody domain fused via a linker to a composite CD28-CD3 zeta signaling domain. GMP-compliant protocols for vector production, lentiviral transduction and expansion of a genetically modified NK-92 single cell clone (NK-92/5.28.z) were established. Functional analysis of NK-92/5.28.z cells revealed high and stable CAR expression, selective cytotoxicity against ErbB2-expressing but otherwise NK-resistant tumor cells of different origins in vitro, as well as homing to ErbB2-expressing tumors in vivo. Furthermore, antigen specificity and selective cytotoxicity of these cells were retained in vivo, resulting in antitumoral activity against subcutaneous and intracranial glioblastoma xenografts in NSG mice. Ongoing work now focuses on the development of these cells for adoptive immunotherapy of ErbB2-positive glioblastoma.
Background: The rationale for gathering information from plants procuring nitrogen through symbiotic interactions controlled by a common genetic program for a sustainable biofuel production is the high energy demanding application of synthetic nitrogen fertilizers. We curated sequence information publicly available for the biofuel plant sugarcane, performed an analysis of the common SYM pathway known to control symbiosis in other plants, and provide results, sequences and literature links as an online database.
Methods: Sugarcane sequences and informations were downloaded from the nucEST database, cleaned and trimmed with seqclean, assembled with TGICL plus translating mapping method, and annotated. The annotation is based on BLAST searches against a local formatted plant Uniprot90 generated with CD-HIT for functional assignment, rpsBLAST to CDD database for conserved domain analysis, and BLAST search to sorghum's for Gene Ontology (GO) assignment. Gene expression was normalized according the Unigene standard, presented as ESTs/100 kb. Protein sequences known in the SYM pathway were used as queries to search the SymGRASS sequence database. Additionally, antimicrobial peptides described in the PhytAMP database served as queries to retrieve and generate expression profiles of these defense genes in the libraries compared to the libraries obtained under symbiotic interactions.
Results: We describe the SymGRASS, a database of sugarcane orthologous genes involved in arbuscular mycorrhiza (AM) and root nodule (RN) symbiosis. The database aggregates knowledge about sequences, tissues, organ, developmental stages and experimental conditions, and provides annotation and level of gene expression for sugarcane transcripts and SYM orthologous genes in sugarcane through a web interface. Several candidate genes were found for all nodes in the pathway, and interestingly a set of symbiosis specific genes was found.
Conclusions: The knowledge integrated in SymGRASS may guide studies on molecular, cellular and physiological mechanisms by which sugarcane controls the establishment and efficiency of endophytic associations. We believe that the candidate sequences for the SYM pathway together with the pool of exclusively expressed tentative consensus (TC) sequences are crucial for the design of molecular studies to unravel the mechanisms controlling the establishment of symbioses in sugarcane, ultimately serving as a basis for the improvement of grass crops.
The Compressed Baryonic Matter (CBM) experiment [1] is a fixed target heavy-ion experiment that will operate at the international Facility for Antiproton and Ion Research (FAIR) [2] now under construction in Darmstadt, Germany. The experiment intends to study rare probes, which are emitted from heavy ion collisions with a beam energy of 4 to 45 AGeV. A focus is laid to the short lived open charm particles and to particles decaying into di-lepton pairs. Handling the up to 107 Au+Au collisions/s required for generating those probes with sufficient statistics, as much as reaching the required sensitivity for observing them, forms a major challenge for the silicon detectors of the experiment. We present the concept and the development status of two central detectors of CBM, the CMOS pixel based micro vertex detector (MVD) and the micro-strip detector based silicon tracking system (STS).
22nd International Workshop on Vertex Detectors, 15-20 September 2013 Lake Starnberg, Germany
While the existence of a strongly interacting state of matter, known as “quark-gluon plasma” (QGP), has been established in heavy ion collision experiments in the past decade, the task remains to map out the transition from the hadronic matter to the QGP. This is done by measuring the dependence of key observables (such as particle suppression and elliptic flow) on the collision energy of the heavy ions. This procedure, known as "beam energy scan", has been most recently performed at the Relativistic Heavy Ion Collider (RHIC).
Utilizing a Boltzmann+hydrodynamics hybrid model, we study the collision energy dependence of initial state eccentricities and the final state elliptic and triangular flow. This approach is well suited to investigate the relative importance of hydrodynamics and hadron transport at different collision energies.
Two generic mechanisms for emergence of direction selectivity coexist in recurrent neural networks
(2013)
Poster presentation: Twenty Second Annual Computational Neuroscience Meeting: CNS*2013. Paris, France. 13-18 July 2013.
In the mammalian visual cortex, the time-averaged response of many neurons is maximal for stimuli moving in a particular direction. Such a direction selective response is not found in LGN, upstream of the visual processing pathway, suggesting that cortical networks play a strong role in the generation of direction selectivity. Here we investigate the mechanisms for the emergence of direction selectivity in the recurrent networks of nonlinear firing rate neurons in layer 4 of V1 receiving the input from LGN. In the model the LGN inputs are characterized by different receptive field positions, and their relative temporal phase shifts are reversed for the stimuli moving in the opposite direction. We propose that two distinct mechanisms result in the neuronal direction selective response in these recurrent networks. The first one is a result of nonlinear feed-forward summation of several time-shifted inputs. The second mechanism is based on the competition between neurons for firing in a winner-take-all regime. Both mechanisms rely on inhibitory interactions in the connectivity matrix of lateral connections, but the second one involves inhibitory loops. Typically, the first mechanism results in lower selectivity values than the second, but the time-course of acquiring direction selective response is faster for the first mechanism. Importantly, the two mechanisms have different input frequency tuning. The first mechanism, based on the nonlinear summation, result in a relatively narrow tuning curve around the preferred frequency of the stimulus in the case of the moving grating. In contrast, the direction selectivity arising from the second mechanism depends only weakly on the input frequency, i.e. has a broader tuning curve. These differences allow us to provide the recipe for identifying in experiment which of the two mechanisms is used by a given direction selective neuron. We then analyze how the statistics of the connections in the random recurrent networks affect the relative contributions from these two mechanisms and determine the distributions of the direction selectivity values. We identify the motifs in the connectivity matrix, which are required for each mechanism and show that the minimal conditions for both mechanisms are met in a very broad set of random recurrent networks with sufficiently strong inhibitory connections. Thus, we propose that these mechanisms coexist in generic recurrent networks with inhibition. Our results may account for the recent experimental observations that direction selectivity is present in dark-reared mice and ferrets [1,2]. It can also explain the emergence of direction selectivity in species lacking a spatially organized direction selectivity map.
[Tagungsbericht] Making finance sustainable: Ten years equator principles – success or letdown?
(2013)
In 2003, a number of banks adopted the Equator Principles (EPs), a voluntary Code of Conduct based on the International Finance Corporation’s (IFC) performance standards, to ensure the ecological and social sustainability of project finance. These so called Equator Principles Financial Institutions (EPFI) commit to requiring their borrowers to adopt sustainable management plans of environmental and social risks associated with their projects. The Principles apply to the project finance business segment of the banks and cover projects with a total cost of US $10 million or more. While for long developing countries relied on World Bank and other public assistance to finance infrastructure projects there has occurred a shift in recent years to private funding. The NGOs have been frustrated by this shift of project finance as they had spent their resources to exercise pressure on the public financial institutions to incorporate environmental and social standards in their project finance activities. However, after a shift of NGO pressure to private financial institutions the latter adopted the EPs for fear of reputational risks. NGOs had laid down their own more ambitious ideas about sustainable finance in the Collevecchio Declaration on Financial Institutions and Sustainability. Legally speaking, the EPs are a self-regulatory soft law instrument. However, it has a hard law dimension as the Equator Banks require their borrowers to comply with the EPs through covenants in the loan contracts that may trigger a default in a case of violation. ...
This work presents an effective model for strongly interacting matter and the QCD equation of state (EoS). The model includes both hadron and quark degrees of freedom and takes into account the transition of chiral symmetry restoration as well as the deconfinement phase transition. At low temperatures T and baryonic densities ρB a hadron resonance gas is described using a SU(3)-flavor sigma-omega model and a quark phase is introduced in analogy to PNJL models for higher T and ρB. In this way, the correct asymptotic degrees of freedom are used in a wide range of T and ρB. Here, results of this model concerning the chiral and deconfinement phase transitions and thermodynamic model properties are presented. Large hadron resonance multiplicities in the transition region emphasize the importance of heavy-mass resonance states in this region and their impact on the chiral transition behavior. The resulting phase diagram of QCD matter at small chemical potentials is in line with latest lattice QCD and thermal model results.
Cytoprotective functions of amyloid precursor protein family members in stress signaling and aging
(2013)
Poster presentation: Molecular Neurodegeneration: Basic biology and disease pathways Cannes, France. 10-12 September 2013.
Background: The amyloid precursor protein (APP) is processed via two different metabolic pathways: the amyloidogenic and the non-amyloidogenic pathway, the latter of which leading to generation of the secreted N-terminal APP fragment sAPPα [1]. Previous studies from our group suggest that sAPPα exerts potent neuroprotective effects and inhibits stress-triggered cell death via modulation of gene expression, as well as by antagonizing different types of neurotoxic stress [2]. It was also observed that the biochemical processing of APP is downregulated during aging which in turn reduced the secretion of sAPPα [3]. Based on these observations, we have studied the potential physiological function of sAPPα/APP and APLPs (APP like proteins) on the regulation of age-associated, stress induced signaling pathways, apoptosis and senescence.
Materials and methods: SH-SY5Y, PC12, IMR90 cells were used as cellular models. Depletion of APP, APLP1 (APP like protein 1) and APLP2 (APP like protein 2) in SH-SY5Y cells was achieved by stable lentiviral knockdown. To analyze the protective function of sAPPα, we have used conditioned supernatants of wild type APP overexpressing HEK cells and recombinant His-tagged sAPPα purified from yeast. The cells were treated with sAPPα prior to the addition of different stress stimuli (MG132, epoxomicin, UV, H2O2) after which cell death, gene expression and senescence were analyzed by MTT assays, caspase activity assays, Western blots and X-Gal staining respectively.
Results: Our data show that sAPPα can antagonize premature senescence induced by repetitive short term induction of proteasomal stress in IMR-90 cells and apoptosis triggered by prolonged proteasomal stress and other death stimuli in PC12, SH-SY5Y and IMR90 cells which was accompanied by a sAPPα-dependent inhibition of the JNK stress signaling pathway. In contrast, no significant changes in cell viability and apoptosis were observed when APP knockdown cells were pretreated with sAPPα.
Conclusions: Our observations suggest that sAPPα can antagonize both apoptosis and cellular senescence and requires expression of holo-APP to mediate its cytoprotective effects. They also support the notion that the physiological function of APP is linked to modulation of neuronal and brain aging.
Background: After induction of DNA double strand breaks (DSBs), the DNA damage response (DDR) is activated. One of the earliest events in DDR is the phosphorylation of serine 139 on the histone variant H2AX (gH2AX) catalyzed by phosphatidylinositol 3-kinases-related kinases. Despite being extensively studied, H2AX distribution[1] across the genome and gH2AX spreading around DSBs sites[2] in the context of different chromatin compaction states or transcription are yet to be fully elucidated.
Materials and methods: gH2AX was induced in human hepatocellular carcinoma cells (HepG2) by exposure to 10 Gy X-rays (250 kV, 16 mA). Samples were incubated 0.5, 3 or 24 hours post irradiation to investigate early, intermediate and late stages of DDR, respectively. Chromatin immunoprecipitation was performed to select H2AX, H3 and gH2AX-enriched chromatin fractions. Chromatin-associated DNA was then sequenced by Illumina ChIP-Seq platform. HepG2 gene expression and histone modification (H3K36me3, H3K9me3) ChIP-Seq profiles were retrieved from Gene Expression Omnibus (accession numbers GSE30240 and GSE26386, respectively).
Results: First, we combined G/C usage, gene content, gene expression or histone modification profiles (H3K36me3, H3K9me3) to define genomic compartments characterized by different chromatin compaction states or transcriptional activity. Next, we investigated H3, H2AX and gH2AX distributions in such defined compartments before and after exposure to ionizing radiation (IR) to study DNA repair kinetics during DDR. Our sequencing results indicate that H2AX distribution followed H3 occupancy and, thus, the nucleosome pattern. The highest H2AX and H3 enrichment was observed in transcriptionally active compartments (euchromatin) while the lowest was found in low G/C and gene-poor compartments (heterochromatin). Under physiological conditions, the body of highly and moderately transcribed genes was devoid of gH2AX, despite presenting high H2AX levels. gH2AX accumulation was observed in 5’ or 3’ flanking regions, instead. The same genes showed a prompt gH2AX accumulation during the early stage of DDR which then decreased over time as DDR proceeded.
Finally, during the late stage of DDR the residual gH2AX signal was entirely retained in heterochromatic compartments. At this stage, euchromatic compartments were completely devoid of gH2AX despite presenting high levels of non-phosphorylated H2AX.
Conclusions: We show that gH2AX distribution ultimately depends on H2AX occupancy, the latter following H3 occupancy and, thus, nucleosome pattern. Both H2AX and H3 levels were higher in actively transcribed compartments. However, gH2AX levels were remarkably low over the body of actively transcribed genes suggesting that transcription levels antagonize gH2AX spreading. Moreover, repair processes did not take place uniformly across the genome; rather, DNA repair was affected by genomic location and transcriptional activity. We propose that higher H2AX density in euchromaticcompartments results in high relative gH2AXconcentration soon after the activation of DDR, thus favoring the recruitment of the DNA repair machinery to those compartments. When the damage is repaired and gH2AX is removed, its residual fraction is retained in the heterochromatic compartments which are then targeted and repaired at later times.
Oral presentation: 23rd World Congress of the World Society of Cardio-Thoracic Surgeons. Split, Croatia. 12-15 September 2013.
Background: Partial upper sternotomy (PUS) is established less invasive approach for single and double valve surgery. Reports of aortic surgery performed through PUS are rare.
Methods: The records of 52 patients undergoing primary elective surgery on the proximal aorta through PUS between 2005 and 2011 were reviewed. Patients mean age was 57 years, 35% were in NYHA Class III or IV, 59% had recent cardiac decompensation, and 17% had pulmonary hypertension. The PUS was taken down to the 4th left intercostal space in 44 patients (85%).
Results: No conversion to full sternotomy was necessary. The aortic cross-clamp, cardiopulmonary bypass and operative times averaged 136 ± 20 min., 186 ± 36 min. and 327 ± 83 min., respectively. In eight patients, the right axillary artery was cannulated for establishing cardiopulmonary bypass; the others were cannulated centrally. All patients except one received a procedure on the ascending aorta, either replacement in 30 (58%) or reduction aortoplasty in 21 (40%). Aortic root replacement was additionally performed in 31 patients (60%), including David in 20 (38%) and Ross procedure in 6 (11.5%). The aortic arch was replaced either partially in 5 (10%) or totally in 3 (6%) patients, in moderate hypothermia employing antegrade cerebral perfusion. Additional procedures, included mitral valve repair in 15 (29%) patients and coronary grafting. Ventilation time, intensive care unit and hospital stay averaged 17 ± 12 hours, 2 ± 1, and 11 ± 9 days. Chest drainage was 470 ± 380 ml/24 hours. Permanent neurologic deficit did not occur. Wound dehiscence was observed in a single patient (2%). Thirty-day and hospital mortality were not observed.
Conclusions: Less invasive surgery on the aortic root, ascending aorta and aortic arch can be performed safely and reproducibly. Potential benefits include a minimized risk of wound dehiscence and reduced postoperative bleeding. The PUS does not compromise the quality of the operation.