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The paper analyses the linkages from financial developments to public finances. It maps and discusses the transmission channels to fiscal variables. These channels include asset prices, financing conditions, balance sheets of banks, non-banks and central banks and international linkages. The study argues that the fiscal effects via each and all these channels can be very serious in magnitude and can put the sustainability of public finances at risk. However, there is an only limited in-depth analysis of these channels and risks.
Im Frühjahr 2018 wurde innerhalb des vom Bundesministerium für Bildung und Forschung geförderten Projektes „QuartierMobil“ eine Haushaltsbefragung im innenstadtnahen Stadtteil Frankfurt-Bornheim durchgeführt (N = 1027). Für die Stichprobenauswahl wurden das Random-Route-Verfahren und die Last-Birthday-Methode angewendet. Der Fragebogen wurde in Abstimmung mit den Projektpartner*innen, dem Referat Mobilitäts- und Verkehrsplanung der Stadt Frankfurt sowie dem Planungsbüro Planersocietät, entwickelt. Ziel der Befragung war es, die Dynamiken und Präferenzen der Bewohnenden des Quartiers hinsichtlich ihrer Alltagsmobilität, Verkehrsmittelnutzung und Einstellungen zu Konfliktsituationen zu erhalten. Der Schwerpunkt der Befragung lag auf dem Parken im urbanen Quartier und möglichen Gestaltungsoptionen des städtischen Parkraummanagements hin zu einer nachhaltigeren Mobilität und einer Erhöhung der Aufenthalts- und Lebensqualität im Quartier.
We present a model for the autonomous and simultaneous learning of active binocular and motion vision. The model is based on the Active Efficient Coding (AEC) framework, a recent generalization of classic efficient coding theories to active perception. The model learns how to efficiently encode the incoming visual signals generated by an object moving in 3-D through sparse coding. Simultaneously, it learns how to produce eye movements that further improve the efficiency of the sensory coding. This learning is driven by an intrinsic motivation to maximize the system's coding efficiency. We test our approach on the humanoid robot iCub using simulations. The model demonstrates self-calibration of accurate object fixation and tracking of moving objects. Our results show that the model keeps improving until it hits physical constraints such as camera or motor resolution, or limits on its internal coding capacity. Furthermore, we show that the emerging sensory tuning properties are in line with results on disparity, motion, and motion-in-depth tuning in the visual cortex of mammals. The model suggests that vergence and tracking eye movements can be viewed as fundamentally having the same objective of maximizing the coding efficiency of the visual system and that they can be learned and calibrated jointly through AEC.
Fährt man in den Urlaub, weiß man eigentlich schon vorab, dass man als Reisende ob der eigenen Unwissenheit mehr bezahlt als die ortskundigen Locals. Man weiß, dass die meisten europäischen Urlaubsorte vom Tourismus leben und drückt im Stillen sein Einverständnis damit aus, indem man überhaupt reist. Gelegentlich aber zahlt man nicht nur etwas mehr, sondern wird beim Rückweg zum Flughafen von einem Taxifahrer, der kein Englisch spricht oder auch nur so tut, um die halbe Insel gefahren, obwohl man vom Beifahrersitz in sein Handy schaut und einem Google Maps einen wesentlich kürzeren Weg angezeigt hat. Man könnte sich aufregen, mit Hand und Fuß mit dem Taxifahrer schimpfen, die Türen des Wagens zuknallen und so dem eigenen Unmut Ausdruck verschaffen. Man kann aber auch ruhig bleiben, dem Taxifahrer thank you for showing us the whole island zurufen, zurückfliegen und eine Ausstellung organisieren, wie Cemile Deniz Alibas, Dominika Bednarsky, Un-Zu Ha-Nul Lee und Lena Stewens es getan haben. ...
Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia.
Causes of maladaptation
(2019)
Evolutionary biologists tend to approach the study of the natural world within a framework of adaptation, inspired perhaps by the power of natural selection to produce fitness advantages that drive population persistence and biological diversity. In contrast, evolution has rarely been studied through the lens of adaptation's complement, maladaptation. This contrast is surprising because maladaptation is a prevalent feature of evolution: population trait values are rarely distributed optimally; local populations often have lower fitness than imported ones; populations decline; and local and global extinctions are common. Yet we lack a general framework for understanding maladaptation; for instance in terms of distribution, severity, and dynamics. Similar uncertainties apply to the causes of maladaptation. We suggest that incorporating maladaptation‐based perspectives into evolutionary biology would facilitate better understanding of the natural world. Approaches within a maladaptation framework might be especially profitable in applied evolution contexts – where reductions in fitness are common. Toward advancing a more balanced study of evolution, here we present a conceptual framework describing causes of maladaptation. As the introductory article for a Special Feature on maladaptation, we also summarize the studies in this Issue, highlighting the causes of maladaptation in each study. We hope that our framework and the papers in this Special Issue will help catalyze the study of maladaptation in applied evolution, supporting greater understanding of evolutionary dynamics in our rapidly changing world.
Multitasking is ubiquitous in our everyday life. Accordingly, situations in which two or more tasks need to be handled concurrently or in close temporal succession have been studied intensely. Different paradigms have been developed in that context (Koch et al., 2018). Over the last decades, the psychological refractory period (PRP) paradigm has dominated dual-task research, because it allows quantitative predictions of reaction time increases coupled to stimulus onset asynchrony. Part of the success of this paradigm is grounded in the fact that most of the studies are run under strict experimental control with very elementary tasks, mostly characterized by a definite start and ending. However, it remains unclear whether these limited settings sufficiently reflect the range of eventualities we find in real life. Rather, there is accumulating evidence that important factors modulating multitask performance are not sufficiently captured by the PRP approach. Here we focus on evidence that motor responses that involve continuous interaction with the environment may engage processes that alter the coordination of concurrently performed tasks in fundamental ways. ...
Among the causality assessment methods used for the diagnosis of drug-induced liver injury (DILI), Roussel Uclaf Causality Assessment Method (RUCAM) remains the most widely used not only for individual cases but also for prospective and retrospective studies worldwide. This first place is justified by the characteristics of the method such as precise definition and classification of the liver injury, which determines the right scale in the scoring system, precise definition of the seven criteria, and the validation approach based on cases with positive rechallenge. RUCAM is used not only for any types of drugs but also for herbal medicines causing herb-induced liver injury, (HILI) and dietary supplements. In 2016, the updated RUCAM provided further specifications of criteria and instructions to improve interobserver variability. Although this method was criticized for criteria such as the age and alcohol consumption, recent consensus meeting of experts has recognized their value and recommended their incorporation into any method. While early studies searching for DILI in large databases especially in electronic medical records were based on codes of diseases or natural language without causality assessment, the recommendation is now to include RUCAM in the search for DILI/HILI. There are still studies on DILI detection or the identification of biomarkers that take into consideration the cases assessed as “possible,” although it is well known that these cases reduce the strength of the association between the cases and the offending compound or the new biomarker to be validated. Attempts to build electronic RUCAM or automatized application of this method were successful despite some weaknesses to be corrected. In the future, more reflections are needed on an expert system to standardize the exclusion of alternative causes according to the clinical context. Education and training on RUCAM should be encouraged to improve the results of the studies and the day-to-day work in pharmacovigilance departments in companies or in regulatory agencies. It is also expected to improve RUCAM with biomarkers or other criteria provided that the validation process replaces expert opinion by robust standards such as those used for the original method.
The lysosomal polypeptide transporter TAPL belongs to the superfamily of ATP-binding cassette transporters. TAPL forms a homodimeric transport complex, which translocates oligo- and polypeptides into the lumen of lysosomes driven by ATP hydrolysis. Although the structure and the function of ABC transporters were intensively studied in the past, details about the single steps of the transport cycle are still elusive. Therefore, we analyzed the coupling of peptide binding, transport and ATP hydrolysis for different substrate sizes. Although longer and shorter peptides bind with the same affinity and are transported with identical Km values, they differ significantly in their transport rates. This difference can be attributed to a higher activation energy for the longer peptide. TAPL shows a basal ATPase activity, which is inhibited in the presence of longer peptides. Uncoupling between ATP hydrolysis and peptide transport increases with peptide length. Remarkably, also the type of nucleotide determines the uncoupling. While GTP is hydrolyzed as good as ATP, peptide transport is significantly reduced. In conclusion, TAPL does not differentiate between transport substrates in the binding process but during the following steps in the transport cycle, whereas, on the other hand, not only the coupling efficiency but also the activation energy varies depending on the size of peptide substrate.
Exercise is a treatment option in peripheral artery disease (PAD) patients to improve their clinical trajectory, at least in part induced by collateral growth. The ligation of the femoral artery (FAL) in mice is an established model to induce arteriogenesis. We intended to develop an animal model to stimulate collateral growth in mice through exercise. The training intensity assessment consisted of comparing two different training regimens in C57BL/6 mice, a treadmill implementing forced exercise and a free-to-access voluntary running wheel. The mice in the latter group covered a much greater distance than the former pre- and postoperatively. C57BL/6 mice and hypercholesterolemic ApoE-deficient (ApoE-/-) mice were subjected to FAL and had either access to a running wheel or were kept in motion-restricting cages (control) and hind limb perfusion was measured pre- and postoperatively at various times. Perfusion recovery in C57BL/6 mice was similar between the groups. In contrast, ApoE-/- mice showed significant differences between training and control 7 d postoperatively with a significant increase in pericollateral macrophages while the collateral diameter did not differ between training and control groups 21 d after surgery. ApoE-/- mice with running wheel training is a suitable model to simulate exercise induced collateral growth in PAD. This experimental set-up may provide a model for investigating molecular training effects.
Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm.
Evaluation of INSTAND e.V.’s external quality assessment for C-reactive protein and procalcitonin
(2019)
Background: The purpose of this paper was to analyze the general diagnostic strength and performance of in vitro diagnostics for C-reactive protein and procalcitonin based on the results of external quality assessment schemes (EQAs).
Methods: We analyzed qualitative and quantitative data on both markers collected by the Society for Promotion Quality Assurance in Medical Laboratories (INSTAND e.V.) from 20 EQAs. The C-reactive protein evaluation was method-specific and the procalcitonin evaluation manufacturer-specific (pseudonymized). Coefficients of variation were determined in order to evaluate interlaboratory comparability and the performance of individual laboratories during the analyzed period was examined.
Results: Overall most of our participants were able to correctly distinguish the positive from the negative samples, but we occasionally observed also false-positive results for the immunological detection of C-reactive protein. For the semi-quantitative results of C-reactive protein we observed an overall median difference below 5% except for dry chemistry methods (≤ 21%). For procalcitonin two manufacturer collectives showed a good comparability, while one manufacturer detected up to 42% higher results. The coefficients of variation are promising for both analytes even though they surpass the manufacturer’s indication for some collectives. The performance of individual laboratories during the analyzed period was more stable for C-reactive protein than for procalcitonin.
Conclusion: In-vitro diagnostic testing for C-reactive protein and procalcitonin showed promising results in our EQAs but still further improvements are needed. We recommend stepping up research on reference measurement methods for both parameters to possibly enhancing the accuracy and diagnostic strength of such assays.
kurz und kn@pp news : Nr. 46
(2019)
Mit selbstbewusster Haltung wendet sich der gutaussehende John Taylor in seinem Porträt von William L. Denune und Richard Cooper dem Betrachter zu. Dass der englische Arzt ein gepriesener Okulist und versierter Mann von Welt war, wird in dem Kupferstich zum einen mittels der Inschriften des Sockels unter seinem Porträt betont, die ihn als den Augenarzt des Königs von Großbritannien und als Mitglied mehrerer medizinischer Universitäten betiteln, zum anderen durch die Zurschaustellung seiner wissenschaftlichen Abhandlungen. Sein Biograph George Coats, selbst ein englischer Augenarzt, beschreibt ihn als einen klugen und eleganten Mann, ausgestattet mit einer charismatischen Ausstrahlung, welche jenen imponierte, die außerstande waren, die prahlerische Oberfläche zu durchschauen, unter der s ich ein verlogener, unverfrorener Quacksalber verbarg. Die meisten von Taylors Zeitgenossen kritisierten seine wissenschaftlichen Schriften und Praktiken und er selbst gestand einmal, dass Hunderte von Patienten an den Folgen seiner Operationen erblindeten. Wie konnte es dazu kommen, dass dieser offensichtliche Scharlatan zum Hofokulisten von König George II. ernannt wurde und prominente Persönlichkeiten wie Edward Gibbon sowie Johann Sebastian Bach behandelte? ...
Background. Extracts from Viscum album L. (VE) are used in the complementary cancer therapy in Europe for decades. VE contain several compounds like the mistletoe lectins (MLs) 1-3 and viscotoxins and also several minor ingredients. Since mistletoe lectin 1 (ML-1) has been described as the main component of VE harboring antitumor activity, purified native or recombinant ML-1 has been recently used in clinical trials. MLs stimulate the immune system, induce cytotoxicity, are able to modify the expression of cancer-associated genes, and influence the proliferation and motility of tumor cells.
Objective. In this study our goal was to determine anticancer effects of the VE ISCADOR Qu, of recombinant ML-1 (Aviscumine), and of native ML-1 in the treatment of glioblastoma (GBM), the most common and highly malignant brain tumor in adults. Additionally we were interested whether these drugs, used in combination with a temozolomide-(TMZ)-based radio-chemotherapy, provide synergistic effects.
Methods. Cell culture assays, ex vivo murine hippocampal brain slice cultures, human GBM cryosections, and a xenograft orthotopic glioblastoma mouse model were used.
Results. In cells, the expression of the ML receptor CD75s, which is also expressed in GBM specimen, but not in normal brain, correlates with the drug-induced cytotoxicity. In GBM cells, the drugs induce cell death in a concentration-dependent manner and reduce cell growth by inducing cell cycle arrest in the G2/M phase. The cell cycle arrest was paralleled by modifications in the expression of cell cycle regulating genes. ML containing drugs, if combined with glioma standard therapy, provide synergistic and additive anticancer effects. Despite not reaching statistical significance, a single intratumoral application of Aviscumine prolonged the median survival of GBM mice longer than tumor irradiation. Moreover, intratumorally applied Aviscumine prolonged the survival of GBM-bearing mice if used in combination with irradiation and TMZ for further 6.5 days compared to the radio-chemotherapy.
Conclusion. Our results suggest that an adjuvant treatment of glioma patients with ML-containing drugs might be beneficial.
Diagnosing and treating acute severe and recurrent antivenom-related anaphylaxis (ARA) is challenging and reported experience is limited. Herein, we describe our experience of severe ARA in patients with neurotoxic snakebite envenoming in Nepal. Patients were enrolled in a randomised, double-blind trial of high vs. low dose antivenom, given by intravenous (IV) push, followed by infusion. Training in ARA management emphasised stopping antivenom and giving intramuscular (IM) adrenaline, IV hydrocortisone, and IV chlorphenamine at the first sign/s of ARA. Later, IV adrenaline infusion (IVAI) was introduced for patients with antecedent ARA requiring additional antivenom infusions. Preantivenom subcutaneous adrenaline (SCAd) was introduced in the second study year (2012). Of 155 envenomed patients who received ≥ 1 antivenom dose, 13 (8.4%), three children (aged 5−11 years) and 10 adults (18−52 years), developed clinical features consistent with severe ARA, including six with overlapping signs of severe envenoming. Four and nine patients received low and high dose antivenom, respectively, and six had received SCAd. Principal signs of severe ARA were dyspnoea alone (n=5 patients), dyspnoea with wheezing (n=3), hypotension (n=3), shock (n=3), restlessness (n=3), respiratory/cardiorespiratory arrest (n=7), and early (n=1) and late laryngeal oedema (n=1); rash was associated with severe ARA in 10 patients. Four patients were given IVAI. Of the 8 (5.1%) deaths, three occurred in transit to hospital. Severe ARA was common and recurrent and had overlapping signs with severe neurotoxic envenoming. Optimising the management of ARA at different healthy system levels needs more research. This trial is registered with NCT01284855.
According to a popular stereotype, women are better at multitasking than men, but empirical evidence for gender differences in multitasking performance is mixed. Previous work has focused on specific aspects of multitasking or has not considered gender differences in abilities contributing to multitasking performance. We therefore tested gender differences (N = 96, 50% female) in sequential (i.e., task switching) and concurrent (i.e., dual tasking) multitasking, while controlling for possible gender differences in working memory, processing speed, spatial abilities, and fluid intelligence. Applying two standard experimental paradigms allowed us to test multitasking abilities across five different empirical indices (i.e., performance costs) for both reaction time (RT) and accuracy measures, respectively. Multitasking resulted in substantial performance costs across all experimental conditions without a single significant gender difference in any of these ten measures, even when controlling for gender differences in underlying cognitive abilities. Thus, our results do not confirm the widespread stereotype that women are better at multitasking than men at least in the popular sequential and concurrent multitasking settings used in the present study.
Die vorliegende Dissertation untersucht die Nichtgleichgewichtsdynamik von relativistischen Schwerionenkollisionen ausgehend von der anfänglichen Produktion von Teilchen durch den Zerfall von Strings, der Bildung eines Quark-Gluon-Plasmas (QGP), dessen kinetische und chemische Äquilibrierung als Funktion der Zeit sowie seine Transporteigenschaften im Gleichgewicht bei endlicher Temperatur und endlichem chemischen Potential. Ein Verständnis der frühen Phase der Schwerionenkollisionen ist insbesondere von großen Interesse, da letztere eine Verbindung zwischen den ersten Nukleon-Nukleon Kollisionen und der Quark-Gluon-Plasma Phase herstellen, die zu einem späteren Zeitpunkt ein gewisses Maß an Thermalisierung zeigt. Allerdings können nur Nichtgleichgewichts-Theorien eine Verbindung zwischen dem anfänglichen QGP und seiner - zumindest partiellen - Thermalisierung herstellen. Um die Dynamik eines stark wechselwirkenden Mediums wie des Quark-Gluon-Plasmas zu beschreiben, reichen übliche Transportgleichungen (basierend auf der Boltzmann-Gleichung) nicht aus und es müssen komplexere Theorien, die auch für stark korrelierte Medien geeignet sind, angewendet werden. Hier kommen hydrodynamische Simulationen oder Transportrechnungen - basierend auf verallgemeinerten Transportgleichungen - zum Einsatz. Solche verallgemeinerte Transportgleichungen, wie die Kadanoff-Baym-Gleichungen, ergeben sich aus der quantenmechanischen Nichtgleichgewichts-Vielteilchentheorie, in der Green’s- Funktionen in Minkowski Raum-Zeit die interessierenden Größen sind, um die Dynamik des betrachteten Mediums zu beschreiben. Mit geeigneten Näherungen kann man so kinetische Transportgleichungen erhalten, die eine einheitliche Behandlung von stabilen und instabilen Teilchen auch außerhalb des Gleichgewichts ermöglichen. Diese Bestandteile bilden die Basis des Transportmodells Parton-Hadron-String Dynamics (PHSD), welches daher ein geeignetes ’Instrument’ ist um die verschiedenen Phasen einer Schwerionenkollision zu analysieren, egal ob die verschiedenen Formen der Materie im Gleichgewicht sind oder nicht.
In dieser Arbeit wird zunächst die Quantenchromodynamik (QCD) vorgestellt und erklärt, wie diese Theorie im Laufe der Jahre entwickelt wurde um ein wichtiger Bestandteil des Standardmodells der Teilchenphysik zu werden. Wir werden weiterhin die verbleibenden Herausforderungen in unserem Verständnis der QCD vorstellen, die sich primär auf das Phasendiagramm der stark wechselwirkenden Materie konzentrieren.
Im zweiten Kapitel untersuchen wir die Nichtgleichgewichts-Feldtheorie und die damit verbundenen Techniken - wie die Keldysh-Kontur - zur Beschreibung der Green’schen Funktionen als wesentlichen Freiheitsgrade. Wir leiten die Evolutionsgleichung für die Green’schen Funktionen her, d. h. die Kadanoff Baym-Gleichungen am Beispiel einer skalaren Feldtheorie.
Im nächsten Kapitel wird das Transportmodell Parton-Hadron-String Dynamics (PHSD), welches die Anwendung der verallgemeinerten Transportgleichungen zur Beschreibung relativistischer Schwerionenkollisionen darstellt, vorgestellt.
Wir beginnen im Kapitel 4 mit der Untersuchung der Nichtgleichgewichtseigenschaften des Quark-Gluon-Plasmas, welches bei relativistischen Schwerionenkollisionen erzeugt wird. Zu diesem Zweck vergleichen wir die Quark-Gluon-Plasmaentwicklung aus dem PHSD mit einem viskosen hydrodynamischen Modell, bei dem ein lokales kinetisches und chemisches Gleichgewicht angenommen wird.
Im Kapitel 5 konzentrieren wir uns auf das frühe Vorgleichgewichtsstadium ultra-relativistischer Schwerionenkollisionen und insbesondere auf die Freiheitsgrade der QGP-Phase in diesem Stadium. Wir untersuchen die Auswirkungen eines QGP, welches anfänglich entweder aus einem System aus massiven Gluonen (Szenario I) oder alternativ aus Quarks und Antiquarks (Szenario II) besteht. Das nächste Kapitel wird ebenfalls die Produktion von Teilchen im Frühstadium von Schwerionenkollisionen behandeln, jedoch bei niedrigeren Kollisionsenergien. Hier wird eine mikroskopische Beschreibung des K+/pi+-Verhältnisses im Vordergrund stehen, d. h. die Erklärung des Maximums in diesem Verhältnis bei etwa 30 A GeV ("Horn") in zentralen Au+Au (oder Pb+Pb) Kollisionen. Insbesonders werden wir die Modifikation des String-Fragmentierungsprozesses (über den Schwinger-Mechanismus) in einer Umgebung mit hoher hadronischer Dichte aufgrund der teilweisen Wiederherstellung der chiralen Symmetrie untersuchen.
In Kapitel 7 erweitern wir das Parton-Hadron-String Dynamics (PHSD)-Transportmodell im partonischen Sektor, indem wir explizit die totalen und differentiellen partonischen Streuungsquerschnitte als Funktion der Temperatur T und des baryochemischen Potentials μB berechnen auf der Basis der effektiven Propagatoren und Kopplungen des Dynamical QuasiParticle Models (DQPM), welches auch die generelle Zeitentwicklung der partonischen Freiheitsgrade beschreibt. Wir finden nur eine sehr bescheidene Änderung von n/s mit dem baryonchemischen Potential μB in Abhängigkeit von der skalierten Temperatur T/Tc(μB). Dies gilt auch für eine Vielzahl von hadronischen Observablen aus zentralen A+A Kollisionen im Energiebereich von 5 GeV < vsNN < 200 GeV bei der Implementierung der differentiellen Querschnitte in das PHSD-Modell. Da wir in Schwerionen-Observablen nur kleine Spuren einer μB-Abhängigkeit finden - obwohl die effektiven Partonenmassen und Kollisionsbreiten sowie deren Partonenquerschnitte eindeutig von μB abhängen - impliziert dies, dass man eine beträchtliche Partonendichte und ein großes Raum-Zeit-QGP-Volumen zur Untersuchung der Dynamik in der partonischen Phase benötigt. Diese Bedingungen sind nur bei hohen Kollisionsenergien erfüllt, bei denen μB jedoch eher niedrig ist. Wenn andererseits die Kollisionsenergie verringert und somit μB erhöht wird, wird die hadronische Phase dominant und dementsprechend wird es zunehmend schwieriger, Signale aus der Partonendynamik auf der Basis von "Bulk"-Observablen zu extrahieren.