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The aim of this essay is to provide an analysis of Foucault's use of the notion of revolution in the reports he wrote for "Il Corriere della Sera" during his two trips to Iran in September and November 1978. Foucault critically frames the historical and philosophical concept of revolution, in order to oppose it to the spreading revolts against the Shah, which embody the simple and negative opening of the possibility of a transformation in history. Yet is it possible to reactivate the notion of revolution in a nonrestrictive sense in order to think about the role and the possibility of political revolts and freedom today?
Reversion: lyric time(s) II
(2019)
Is a 'history' of the lyric even conceivable? What would a 'lyric' temporality look like? With a focus on Rainer Maria Rilke's decision not to translate, but rather to rewrite Dante's "Vita nova" (1293–1295) in the first of his "Duineser Elegien" (1912), the essay deploys 'reversion' (as turning back, return, coming around again), alongside 're-citation', as a keyword that can unlock the transhistorical operations of the lyric as the re-enactment of selected gestures under different circumstances.
Restrain
(2019)
The re- of 'restrain' - not the more common iterative 're-' but a mere, if semantically obscure intensifier - marks a temporal paradox: the restraint that prevents a force from reaching its 'telos' is not only a delay, but the intervention of a separate, autonomous, and anti-teleological regime of time. The article reads the biblical figure of the 'katéchon', 'the withholder', as an expression of this paradox and as symptomatic of a political-theological ambivalence essential to the foundation of Western political thought. If the 'secular order' or 'worldly government' has the function of withholding both the ultimate salvation and the final outbreak of chaos, then it sustains itself only by postponing any determination of its value or effect.
Resolution
(2019)
Many parodies operate through temporal strategies that distort the narrative proportions of their targets. This essay discusses two texts that manipulate time for parodic purposes: the contemporary animated sitcom "Bojack Horseman" and the twelfth-century romance "Ipomedon". Their shared method involves the absurd prolongation of narrative structures of resolution and satisfaction in order to reveal these structures' arbitrary nature. But this method, in turn, shows that resolution - a retrospective determination of shape and meaning - can never be avoided entirely, even if it can be deferred.
Resistance
(2019)
The term 'resistance', as it appears in the writings of Walter Benjamin, marks the attempt to think a politics that emerges out of a certain experience of history and time. This entry shows that 'Widerstand' is conceived here principally as a resistance against the course of a catastrophic history - a desire for time to cease its flow and come to a standstill.
Resistance II
(2019)
Resistance I
(2019)
In an essay on Peter Weiss, W. G. Sebald remarked that 'the grotesque deformities of our inner lives have their background and origin in collective social history'. Weiss's works explore the relationships between writing and action, aesthetics and politics. This short essay discusses some fragments of texts by Weiss, asking how subjects formed and (grotesquely) deformed by history can continue to resist or intervene to alter its course.
Repetition
(2019)
Repetition
(2019)
This article explores the creative value of the notion of 'repetition' in Michel Foucault's texts from the 1960s and early 1970s. Re-enacting Gilles Deleuze's philosophy, Foucault implicitly refers to the Freudian repetition mechanisms in order to distort and reverse them. Foucault's repetition is de-psychologized, affectively de-individualizing, and temporally erratic, using the power of a senseless repetition to create new possibilities for the future.
Repetition
(2019)
Serial texts must repeat, so that they can be recognized, but they must also change, so that they can remain interesting. Unusual temporal manipulations can emerge in such texts in order to balance these contradictory demands. This essay studies two serial texts whose need for self-extension produces a suspension of historical time: the contemporary animated sitcom "The Simpsons", and medieval romance as theorized by the twelfth-century poet Wace. I suggest that we might name this temporal constraint fiction.
Renewal
(2019)
Interruptions and discontinuity are the very essence of Aby Warburg's conception of the temporality that affects art objects. Beneath the seemingly immobilized expressive gesture, the Hamburg scholar recognizes the vitality of the "Pathosformeln" that convey the intricacy of human multi-layered temporality, made of interruptions, resumptions, inversions, regressions, stops, accelerations, and survivals (Nachleben). In this sense, Warburg's idea of 'renewal', which he developed from his well-known investigation of the Italian Renaissance, does not quite overlap with the notion of rebirth: an expressive gesture can re-emerge and be renewed in a different time without dying and being born a second time with a different form.
Rehabilitation II
(2019)
Rehabilitation I
(2019)
By distancing it from historical revival (i.e., 'Living History'), reenactment is here understood as artistic strategy as well as curatorial practice, and therefore as critical method. As artistic strategy it implies the reactivation (over time) and remediation (on different supports) of images stemming from a vast visual repertoire that artists - especially those working with time-based media (film, video, performance) - appropriate in order to give them new meanings. As curatorial practice and critical method, reenactment regards the remaking of impermanent artworks and the restaging of temporary exhibitions to possibly offer an understanding of (art) history that gives preference to a visual and performative, sometimes immersive, approach.
Recovery
(2019)
Despite the increasing incidence of eating disorders, very few films have addressed these conditions in particular. What's more, most of the US-American mainstream fiction films that deal with eating disorders tend to be built on anachronistic clichés, hardly depicting their broad array. Furthermore, the traditional narrative structure of beginning, middle, and (happy) end misrepresents the erratic temporality of eating disorder symptoms as well as the nonlinear phases of recovery and relapse.
Recitation : lyric time(s) I
(2019)
What is the time of the lyric? For Augustine, the recitation of a hymn illustrates the workings of time in the human mind; for Giorgio Agamben, the poem itself exemplifies the structure of what he defines as 'messianic time'. By focusing on Dante's sonnet 'Tanto gentile e tanto onesta pare' and looking at the double act of the recitation of the poem and the "re-citation" of prior gestures, the temporality of both the single poem and lyric discourse will come into focus.
The text considers recirculation as a process through which both visual and cultural imagery are put in motion over and over again in the current information age, especially in the context of post-Internet art. Hito Steyerl's writings and thoughts on the 'poor image', namely the low-resolution digital image bound to a perpetual wandering or 'circulationism', here serve as major reference points for the development of the argument.
Recherche II : anamnesis
(2019)
The temporal loop of Proust's "Recherche" complicates the unidirectional understanding of anamnesis in psychoanalysis, which, in turn, allows for a renewed reading of the temporality of the "Recherche", highlighting the intrinsic link between artistic 'research' and unconscious affect - at the same time origin, motif, and destination.
Recherche I
(2019)
Recherche, (re-)search: do I research to find something not yet found or do I re-search back to find something that has been lost? These two directionalities structure Proust's "À la recherche du temps perdu" and are reflected in its reception. But what if they only seem mutually exclusive, yet really are one and the same thing?
Preface
(2019)
What's in a prefix? How to read a prefix as short as 're-'? Does 're-' really signify? Can it point into a specific direction? Can it reverse? Can it become the shibboleth of a 'postcritical' reboot? At first glance transparent and directional, 're-' complicates the linear and teleological models commonly accepted as structuring the relations between past, present, and future, opening onto errant temporalities.
Albumin, the most abundant plasma protein, not only controls osmotic blood pressure, but also serves as a carrier for various small molecules, including pharmaceuticals. Its impact on pharmacological properties of many drugs has been extensively studied over decades. Here, we focus on its interaction with the following mobilizing agents: Granulocyte-colony stimulating factor (G-CSF) and AMD3100, where such analyses are lacking. These compounds are widely used for hematopoietic stem cell mobilization of healthy donors or patients. Using albumin-deficient (Alb−/−) mice, we studied the contribution of albumin to mobilization outcomes. Mobilization with the bicyclam CXCR4 antagonist AMD3100 was attenuated in Alb−/− mice compared to wild-type littermates. By contrast, mobilization with recombinant human G-CSF (rhG-CSF), administered twice daily over a five-day course, was significantly increased in Alb−/− mice. In terms of a mechanism, we show that rhG-CSF bioavailability in the bone marrow is significantly improved in Alb−/− mice, compared to wild-type (WT) littermates, where rhG-CSF levels dramatically drop within a few hours of the injection. These observations likely explain the favorable mobilization outcomes with split-dose versus single-dose administration of rhG-CSF to healthy donors.
We investigated the implications of string theory in the high-precision regime of quantum mechanics. In particular, we examined a quantum field theoretical propagator which was derived from string theory when compactified at the T-duality self-dual radius and which is closely related to the path integral duality. Our focus was on the hydrogen ground state energy and the 1S1/2−2S1/2 transition frequency, as they are the most precisely explored properties of the hydrogen atom. The T-duality propagator alters the photon field dynamics leading to a modified Coulomb potential. Thus, our study is complementary to investigations where the electron evolution is modified, as in studies of a minimal length in the context of the generalized uncertainty principle. The first manifestation of the T-duality propagator arises at fourth order in the fine-structure constant, including a logarithmic term. For the first time, constraints on the underlying parameter, the zero-point length, are presented. They reach down to 3.9×10−19m and are in full agreement with previous studies on black holes.
Convective shower characteristics simulated with the convection-permitting climate model COSMO-CLM
(2019)
This paper evaluates convective precipitation as simulated by the convection-permitting climate model (CPM) Consortium for Small-Scale Modeling in climate mode (COSMO-CLM) (with 2.8 km grid-spacing) over Germany in the period 2001–2015. Characteristics of simulated convective precipitation objects like lifetime, area, mean intensity, and total precipitation are compared to characteristics observed by weather radar. For this purpose, a tracking algorithm was applied to simulated and observed precipitation with 5-min temporal resolution. The total amount of convective precipitation is well simulated, with a small overestimation of 2%. However, the simulation underestimates convective activity, represented by the number of convective objects, by 33%. This underestimation is especially pronounced in the lowlands of Northern Germany, whereas the simulation matches observations well in the mountainous areas of Southern Germany. The underestimation of activity is compensated by an overestimation of the simulated lifetime of convective objects. The observed mean intensity, maximum intensity, and area of precipitation objects increase with their lifetime showing the spectrum of convective storms ranging from short-living single-cell storms to long-living organized convection like supercells or squall lines. The CPM is capable of reproducing the lifetime dependence of these characteristics but shows a weaker increase in mean intensity with lifetime resulting in an especially pronounced underestimation (up to 25%) of mean precipitation intensity of long-living, extreme events. This limitation of the CPM is not identifiable by classical evaluation techniques using rain gauges. The simulation can reproduce the general increase of the highest percentiles of cell area, total precipitation, and mean intensity with temperature but fails to reproduce the increase of lifetime. The scaling rates of mean intensity and total precipitation resemble observed rates only in parts of the temperature range. The results suggest that the evaluation of coarse-grained (e.g., hourly) precipitation fields is insufficient for revealing challenges in convection-permitting simulations.
Focused electron and ion beam-induced deposition (FEBID/FIBID) are direct-write techniques with particular advantages in three-dimensional (3D) fabrication of ferromagnetic or superconducting nanostructures. Recently, two novel precursors, HCo 3 Fe(CO) 12 and Nb(NMe 3 ) 2 (N-t-Bu), were introduced, resulting in fully metallic CoFe ferromagnetic alloys by FEBID and superconducting NbC by FIBID, respectively. In order to properly define the writing strategy for the fabrication of 3D structures using these precursors, their temperature-dependent average residence time on the substrate and growing deposit needs to be known. This is a prerequisite for employing the simulation-guided 3D computer aided design (CAD) approach to FEBID/FIBID, which was introduced recently. We fabricated a series of rectangular-shaped deposits by FEBID at different substrate temperatures between 5 ∘ C and 24 ∘ C using the precursors and extracted the activation energy for precursor desorption and the pre-exponential factor from the measured heights of the deposits using the continuum growth model of FEBID based on the reaction-diffusion equation for the adsorbed precursor.
To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.
The sources and critical enrichment processes for granite related tin ores are still not well understood. The Erzgebirge represents one of the classical regions for tin mineralization. We investigated the four largest plutons from the Western Erzgebirge (Germany) for the geochemistry of bulk rocks and autocrystic zircons and relate this information to their intrusion ages. The source rocks of the Variscan granites were identified as high-grade metamorphic rocks based on the comparison of Hf-O isotope data on zircons, the abundance of xenocrystic zircon ages as well as Nd and Hf model ages. Among these rocks, restite is the most likely candidate for later Variscan melts. Based on the evolution with time, we could reconstruct enrichment factors for tin and tungsten starting from the protoliths (575 Ma) that were later converted to high-grade metamorphic rocks (340 Ma) and served as sources for the older biotite granites (323–318 Ma) and the tin granites (315–314 Ma). This evolution involved a continuous enrichment of both tin and tungsten with an enrichment factor of ~15 for tin and ~7 for tungsten compared to the upper continental crust (UCC). Ore level concentrations (>10–100 times enrichment) were achieved only in the greisen bodies and dykes by subsequent hydrothermal processes.
CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis
(2019)
Allergic enteritis (AE) is a gastrointestinal form of food allergy. This study aimed to elucidate cellular and molecular mechanisms of AE using a murine model. To induce AE, BALB/c wild type (WT) mice received intraperitoneal sensitization with ovalbumin (an egg white allergen) plus ALUM and feeding an egg white (EW) diet. Microarray analysis showed enhanced gene expression of CC chemokine receptor (CCR) 8 and its ligand, chemokine CC motif ligand (CCL) 1 in the inflamed jejunum. Histological and FACS analysis showed that CCR8 knock out (KO) mice exhibited slightly less inflammatory features, reduced eosinophil accumulation but accelerated neutrophil accumulation in the jejunums, when compared to WT mice. The concentrations of an eosinophil chemoattractant CCL11 (eotaxin-1), but not of IL-5, were reduced in intestinal homogenates of CCR8KO mice, suggesting an indirect involvement of CCR8 in eosinophil accumulation in AE sites by inducing CCL11 expression. The potential of CCR8 antagonists to treat allergic asthma has been discussed. However, our results suggest that CCR8 blockade may promote neutrophil accumulation in the inflamed intestinal tissues, and not be a suitable therapeutic target for AE, despite the potential to reduce eosinophil accumulation. This study advances our knowledge to establish effective anti-inflammatory strategies in AE treatment.
Glioblastome (GB) sind die häufigsten bösartigen primären Hirntumore im Erwachsenenalter. Das Therapiekonzept bei Erstdiagnose besteht aus einer maximalen Tumorresektion, gefolgt von einer Strahlentherapie mit konkomitanter und anschließend adjuvanter Chemotherapie mit dem Alkylanz Temozolomid in Zyklusform. Zusätzlich zur adjuvanten Chemotherapie werden inzwischen für supratentorielle GBs auch Tumortherapiefelder empfohlen, die über elektromagnetische Wechselfelder die Tumorzellteilung hemmen sollen. Trotz multimodaler Therapiekonzepte und Fortschritte im Verständnis der GB-Biologie ist die Prognose der Patienten bei einer 5-Jahresüberlebensrate von unter 5% sehr ernüchternd. Eine mögliche Ursache für den ausbleibenden Erfolg neuer GB-Medikamente könnten die besonderen metabolischen Bedingungen des Tumormikromilieus sein. Unter diesen kann eine therapeutische zielgerichtete Inhibition bestimmter Kinasen, wie des Epidermalen Wachstumsfaktorrezeptors (EGFR) oder mammalian Target of Rapamycin (mTOR), unerwünschte Tumorzell-protektive Effekte entfalten, da bereits gezeigt werden konnte, dass sich Tumorzellen durch Suppression der mTORC1 abhängigen Signalkaskade an Energiemangelbedingungen, wie sie im Tumormikromilieu zu finden sind, anpassen, um zu überleben. Ziel dieses Projektes war es den physiologischen mTORC1-Inhibitor DNAdamage-inducible transcript 4 (DDIT4) als möglichen intrinsischen Resistenzmechanismus gegenüber Strahlen- und Chemotherapie in GBs zu untersuchen. In verschiedenen GB-Zelllinien konnte eine Induktion von DDIT4 teilweise durch Bestrahlung, Temozolomid und generell durch die im Tumormikromilieu vorherrschende Hypoxie nachgewiesen werden. Dies gelang sowohl auf transkriptioneller Ebene als auch auf Proteinniveau. Zur Beurteilung der Relevanz dieses zellulären Anpassungsmechanismus wurden Zellen mit DDIT4 Gensuppression generiert und charakterisiert. Hier zeigte sich in klonalen Überlebensanalysen eine gesteigerte Sensibilität der Zellen mit verminderter DDIT4 Expression gegenüber Temozolomid und Strahlentherapie. Darüber hinaus waren diese Zellen gegenüber Hypoxie-induziertem Zelltod sensibilisiert. Umgekehrt führte eine stabile oder Doxycyclin- induzierte DDIT4 Überexpression zu einer signifikanten Resistenz gegenüber Strahlentherapie, Temozolomid und Hypoxie-induziertem Zelltod.
Zusammenfassend beschreiben unsere Ergebnisse DDIT4 als Mediator von Therapieresistenz gegenüber den etablierten Komponenten der GBErstlinientherapie und zudem als Anpassungsmechanismus an das hypoxische Tumormikromilieu. DDIT4 stellt somit einen möglichen Angriffspunkt für eine therapeutische Inhibition beim GB dar.
Human beings are supposed to possess an approximate number system (ANS) dedicated to extracting and representing approximate numerical magnitude information as well as an object tracking system (OTS) for the rapid and accurate enumeration of small sets. It is assumed that the OTS and the ANS independently contribute to the acquisition of more elaborate numerical concepts. Chinese children have been shown to exhibit more elaborate numerical concepts than their non-Chinese peers, but it is still an open question whether similar cross-national differences exist with regard to the underlying systems, namely the ANS and the OTS. In the present study, we investigated this question by comparing Chinese and German preschool children with regard to their performance in a non-symbolic numerical magnitude comparison task (assessing the ANS) and in an enumeration task (assessing the OTS). In addition, we compared children’s counting skills. To ensure that possible between-group differences could not be explained by differences in more general performance factors, we also assessed children’s reasoning ability and processing speed. Chinese children showed a better counting performance and a more accurate performance in the non-symbolic numerical magnitude comparison task. These differences in performance could not be ascribed to differences in reasoning abilities and processing speed. In contrast, Chinese and German children did not differ significantly in the enumeration of small sets. The superior counting performance of Chinese children was thus found to be reflected in the ANS but not in the OTS.
Aquesta tesi doctoral estudia la construcció de la notícia sobre esdeveniments del procés polític català en els mitjans de comunicació escrits alemanys. El període d’anàlisi s’estèn del 2010 al 2015, quan el procés ha passat de la societat civil a l’agenda política catalana i s’ha internacionalitzat. En aquest context, l’opinió publicada alemanya es considera un referent.
La tesi analitza dotze fets clau a partir d’una doble metodologia, quantitativa i qualitativa. Es duu a terme una anàlisi d’Agenda i de Frames, també s’aplica una Anàlisi del Discurs i es complementa la recerca amb entrevistes a periodistes i polítics. La metodologia ha estat provada i validada per set analistes germanòfons.
Els resultats de la recerca, exposats a més en quaranta-nou taules i figures, mostren l’establiment de l’agenda i els enquadraments dels temes i actors del procés català, la relació entre discurs, poder i legitimació, així com la construcció de l’opinió publicada alemanya.
In this work we provided additional insights into our understanding of bulk QCD matter through the study of the transport coeffcients which govern the non-equilibrium microscopical processes of statistical ensembles. Specically, we focused on the low energy regime corresponding to the hadron gas, as the properties of this region of the phase diagram are still relatively unknown, and existing calculations for the transport coeffcients are either scarce, contradictory, or somewhat limited in scope; this thesis' main goal was thus to shed some light on this by providing new independent calculations of these quantities.
We subsequently presented two formalisms which can be used to calculate transport coeffcients. The first one (which also was the main tool we used in the following chapters to produce our results) relies on the development of so-called Green-Kubo formulas, which relate non-equilibrium dissipative fluctuations with transport coeffcients; notably, the off-diagonal components of the energy-momentum tensor are shown to be related to the shear viscosity, its diagonal components to the bulk viscosity and fluctuations in the electric current can be related to the electric conductivity. We additionally introduced two new conductivities, namely the baryon-electric and strange electric conductivities, which we dubbed, together with the already known electric one, the "cross-conductivity", which encodes information about how electric fluctuations are correlated to changes in electric, baryonic or strange currents, or vice-versa. The second way of calculating transport coeffcient which we discussed consists in linearizing the collision term of the Boltzmann equation through the Chapman-Enskog formalism. While in principle providing direct semi-analytical results for the transport coeffcients, this approach is complicated to implement when more than a few species are considered, and as such was then mostly used as a tool to calibrate our Green-Kubo calculations.
The hadron gas model that we used for all calculations, namely the transport approach SMASH, was then presented. The main features of the model were explained, such as the collision criterion, the considered degrees of freedom and the specific way in which they microscopically interact with each other. It was verified that SMASH does reproduce analytical results of the Boltzmann equation in an expanding universe scenario, thus showing the equivalence of this transport approach and the associated kinetic theory results. A special care was taken to detail the ways in which a state of thermal and chemical equilibrium (which is necessary for Green-Kubo relations to be valid) can be reached and described using SMASH.
...
Ziel dieser Arbeit war es, eine vergleichende Bewertung der Erkennbarkeit der apikalen Aufhellung in den dreidimensionalen DVT-Aufnahmen und den konventionellen Panoramaschichtaufnahmen im Oberkiefer unter den folgenden Gesichtspunkten vorzunehmen:
Werden die apikalen Aufhellungen sowohl bei zwei- als auch bei dreidimensionalen Aufnahmen gleichermaßen erkannt?
Spielt die Stärke der Kompakta eine Rolle in der radiologischen Diagnose einer apikalen Aufhellung?
Zu diesem Zweck wurden 351 Patienten aus der Datenbank einer privaten Praxis in Stuttgart ausgewählt. Davon erfüllten 199 Patienten die Einschlusskriterien. Es wurden insgesamt 2223 Zähne durch den Untersucher ausgewertet. Es konnten 144 apikale Aufhellungen mittels der DVT diagnostiziert werden, wovon lediglich 23 (15,9 %) mittels der OPT erkannt wurden. Die Ergebnisse dieser Studie zeigen insgesamt einen signifikanten Unterschied zwischen den DVT- und den OPG-Befunden hinsichtlich der Sichtbarkeit der apikalen Aufhellungen im Oberkiefer. Andere Parameter wie die Tiefe, die Breite und die Länge der apikalen Aufhellungen wurden ebenfalls untersucht. Die Messungen erfolgten mittels der Software i-CatVision 2008 für die DVT-Aufnahmen und mittels DBSWIN von Dürr Dental für die OPG- Aufnahmen. Es ergab sich daraus, dass die apikalen Läsionen, die im OPG und in der DVT sichtbar waren, signifikant größere Breiten hatten als die, die nur in der DVT sichtbar waren. Es zeigte sich hierbei ein signifikanter Unterschied (U- Test, p =0,018). Dies weist daraufhin, dass insbesondere schmale apikale Läsionen nicht sicher in OPG-Aufnahmen diagnostiziert werden, während sie in der DVT nachweisbar sind. Des Weiteren wurde in der Studie die Kompaktadicke gemessen. Es bestand kein signifikanter Zusammenhang zwischen der Sichtbarkeit der apikalen Aufhellung und der Kompaktadicke. Zusammenfassend lässt sich anhand der Ergebnisse der vorliegenden Arbeit feststellen, dass die Kompaktadicke keine Rolle bei der Sichtbarkeit der apikalen Läsionen spielt und dass die OPT im Nachweis apikaler Läsionen der DVT eindeutig unterlegen ist. Es wurden dadurch nur 19 % der apikalen 64 Aufhellungen diagnostiziert und damit ist eine Unterdiagnose sehr wahrscheinlich.
Schlussfolgernd scheint die DVT ein zuverlässiges diagnostisches Mittel bezüglich des Erkennens der apikalen Läsionen zu sein. Mehrere Studien bezeichnen die DVT als Goldstandard und ziehen sie für die Diagnose der apikalen Aufhellungen den konventionellen Röntgenbildern vor. Dieses Vorgehen widerspricht jedoch dem Bestreben nach einer möglichst geringen Strahlenexposition gemäß dem ALARA-Prinzips. Damit bleibt die DVT derzeit eine Ergänzung zur konventionellen Bildgebung.
Der VEGF-neutralisierende Antikörper Bevacizumab ist ein wichtiger Bestandteil der modernen Tumortherapie. Auch in der Glioblastom Therapie wird Bevacizumab eingesetzt, da in klinischen Studien eine Verlängerung des progressionsfreien Überlebens beobachtet wurde. Leider entwickeln sich schnell Resistenzen und das Gesamtüberleben konnte durch Bevacizumab in der Erstlinientherapie von Glioblastomen nicht verlängert werden.
Die genaue Wirkungsweise von Bevacizumab und somit auch die Resistenzentwicklung sind nur teilweise bekannt. Es wird vermutet, dass es durch Gefäßveränderungen zu einer Mangelsituation und zu Hypoxie kommt. Einige Studien deuten darauf hin, dass es neben der Wiedererlangung einer VEGF-unabhängigen Gefäßversorgung auch zu Resistenz gegen das durch Bevacizumab hervorgerufene, von Sauerstoffmangel gekennzeichnete Mikromilieu kommt. So konnte gezeigt werden, dass Bevacizumab-resistente Tumoren einen stark glykolytischen, sauerstoff-unabhängigen Zellmetabolismus aufweisen und vermehrt Laktat produzieren. Darüber hinaus wurde in Folge der Bevacizumab-Behandlung eine Fehlfunktion von Mitochondrien beobachtet. Unklar ist noch, ob die beschriebenen metabolischen Veränderungen ein Epiphänomen der Nährstoffmangelsituation sind oder ob sie kausal mit der Resistenzentwicklung in Zusammenhang stehen.
In der vorliegenden Arbeit sollte deshalb geprüft werden, ob die metabolische Umstellung hin zu einem glykolytischen, anaeroben Phänotyp eine hinreichende Bedingung zur Entwicklung einer Hypoxie- und Bevacizumabresistenz darstellt.
Hierzu wurden Glioblastomzellen (LNT229) derart verändert, dass sie keine oxidative Phosphorylierung durchführen konnten und rein auf die glykolytische Energiegewinnung angewiesen waren (rho0-Zellen). Diese Veränderung führte in-vitro zu einer Hypoxieresistenz der Zellen. Außerdem waren rho0-Zellen empfindlicher gegenüber Glukoseentzug und einer Behandlung mit dem Glykolyse-Inhibitor 2-Deoxyglucose (2DG). Des Weiteren waren im Mausmodell intrakranielle rho0-Tumorxenografts resistent gegenüber Bevacizumab. Diese Resistenz konnte durch zusätzliche Therapie mit 2DG wieder aufgehoben werden.
Somit konnte in der vorliegenden Arbeit gezeigt werden, dass die Hemmung der oxidativen Phosphorylierung zu einem glykolytischen Phänotyp führt, der hinreichend ist, um eine Hypoxieresistenz und in Folge dessen eine Bevacizumabresistenz in Glioblastomzellen zu verursachen. Dies lässt einen kausalen Zusammenhang zwischen bereits in anderen Studien beschriebenen metabolischen Veränderungen und einer Bevacizumabresistenz in Tumoren vermuten. Der zelluläre Glukosestoffwechsel ist damit ein vielversprechender therapeutischer Angriffspunkt zur Vermeidung und Überwindung einer Bevacizumabresistenz.
Das Strukturgleichungsmodell (SEM) wird in den Sozial- und Verhaltenswissenschaften oft verwendet, um die Beziehung zwischen latenten Variablen zu modellieren. In der Analyse dieser Modelle spielt die Bewertung der Modellgüte eine wesentliche Rolle, wobei geprüft werden soll, ob das untersuchte Modell (Zielmodell) zu den erhobenen Daten passt. Dafür werden verschiedene inferenzstatistische und deskriptive Gütemaße verwendet. In nichtlinearen SEM, in denen nichtlineare Effekte, wie beispielsweise Interaktionseffekte, modelliert werden, gibt es bisher allerdings keine Verfahren, um die Modellgüte ausreichend prüfen zu können. Insbesondere der χexp2-Test ist für verschiedene nichtlineare SEM nicht geeignet (vgl. Klein & Schermelleh-Engel, 2010; Mooijaart & Satorra, 2009).
In dieser Arbeit werden zwei unterschiedliche nichtlineare SEM betrachtet. Das erste dieser Modelle wird für die Analyse von Interaktions- und quadratischen Effekten verwendet (quadratisches SEM, QSEM). Das zweite Modell ist das Heterogene Wachstumskurvenmodell (HGM; Klein & Muthén, 2006). In diesem Modell wird das latente Wachstumskurvenmodell (LGM), mit dem individuelle Wachstumsverläufe modelliert werden können, um eine heterogene Varianzkomponente des Slope-Faktors erweitert. Diese Heterogenität des Slope-Faktors ist abhängig von den Ausgangswerten und Kovariaten.
Ziel dieser Arbeit war es, die Bewertung der Modellgüte für das QSEM und das HGM zu verbessern. Für das QSEM und das HGM wurde jeweils ein globaler Modelltest entwickelt („Quasi-Likelihood-Ratio-Test“; QLRT). Darüber hinaus wurden Differenztests für diese Art der Modelle diskutiert. Außerdem wurde für beide Modelle je ein Gütemaß bereitgestellt, um fehlende Nichtlinearität, wie fehlende nichtlineare Terme bzw. fehlende Heterogenität der Slope-Varianzen, aufdecken zu können (der Homoscedastic Fit Index, HFI, für das QSEM und der hhet-Test für das HGM).
Die Entwicklung der neuen Gütemaße ist im Wesentlichen von der verwendeten Schätzmethode abhängig. Für beide Modelle, das QSEM und das HGM, wurde in dieser Arbeit die Quasi-Maximum-Likelihood-Methode (Quasi-ML-Methode; Wedderburn, 1974) ausgewählt, mit der für beide betrachteten Modelle geeignete Schätzungen erzielt werden können (Klein & Muthén, 2006, 2007). Die Quasi-ML-Methode ist vergleichbar mit der Maximum-Likelihood-Methode, berücksichtigt allerdings Fehlspezifikationen der LogLikelihood-Funktion, wie beispielsweise kleinere Abweichungen von der angenommenen Verteilung. Für das QSEM wurde im Rahmen der Entwicklung der Modelltests eine zur Schätzung von QSEM entwickelte Quasi-ML-Methode (QML-Methode; Klein & Muthén, 2007) vereinfacht zu der „simplified QML“-Methode (sQML-Methode; Büchner & Klein, 2019). Für die sQML-Methode ist es erheblich einfacher als für die QML-Methode einen globalen Modelltest zu entwickeln. In einer Simulationsstudie konnte gezeigt werden, dass die sQML-Methode ähnlich gute Schätzeigenschaften wie die QML-Methode aufweist.
Die Idee der neuen globalen Modelltests für das QSEM und das HGM besteht darin, statt des für das lineare SEM verwendeten χexp2-Tests, der ein Likelihood-Quotienten-Test („Likelihood Ratio Test“, LRT) ist, einen Quasi-LRT (QLRT) zu verwenden, der auf der Quasi-ML-Methode basiert (Büchner & Klein, 2019; Büchner, Klein & Irmer, 2019). Wie für den χexp2-Test soll das Zielmodell mit einem unbeschränkten Vergleichsmodell verglichen werden. Ist der Unterschied zwischen den Modellen groß, wird darauf geschlossen, dass das Zielmodell nicht gut zu den Daten passt. Die Schwierigkeit bei der Entwicklung solcher QLRT liegt dabei in der Definition eines Vergleichsmodells. Die hier verwendete Idee für solche Vergleichsmodelle besteht darin, wie im χexp2-Test, die Beschränkungen durch das Zielmodell im Vergleichsmodell aufzuheben. Eine weitere Herausforderung ist die Bestimmung der asymptotischen Verteilung der QLRT-Statistiken, die nicht, wie viele LRT-Statistiken, asymptotisch χexp2-verteilt sind. Deshalb wurde die korrekte asymptotische Verteilung dieser Teststatistiken bestimmt, die das Ermitteln von p-Werten ermöglicht.
Globale Modelltests sind zwar geeignet, wichtige Aussagen zur Passung des Modells zu machen, ermöglichen aber keine direkte Aussage über den Vergleich zweier konkurrierender Modelle. Ein solcher Modellvergleich ist aber wichtig, um ein möglichst sparsames Modell zu erhalten. Zum Vergleich ineinander geschachtelter Modelle werden häufig Differenztests verwendet. Diese werden auch in der Arbeit mit dem QSEM und dem HGM empfohlen. Allerdings ist zu beachten, dass die Teststatistiken für mit der Quasi-MLMethode geschätzten Modelle nicht χexp2-verteilt sind. Im Rahmen dieser Arbeit wurde eine korrekte asymptotische Verteilung angegeben. Im Speziellen wurde der Differenztest für den Vergleich zwischen einem HGM und einem LGM vorgestellt, mit dem getestet wird, ob die im HGM modellierten heterogenen Slope-Varianzen notwendig sind.
Ein weiteres Ziel bestand darin, fehlende Nichtlinearität, die nicht in einem Modell berücksichtigt ist, aufzudecken. Dafür wurde ein Test für Regressionsmodelle, der hhet-Test (Klein, Gerhard, Büchner, Diestel & Schermelleh-Engel, 2016), angepasst. Für das SEM wurde dieser Test zu einem Fit-Index, dem HFI (Gerhard, Büchner, Klein & SchermellehEngel, 2017), weiterentwickelt und darin die Verteilung der Residuen der abhängigen Variable bewertet. Der HFI deckt dabei Veränderungen in der Verteilung auf, die durch fehlende nichtlineare Terme verursacht sind. Für das LGM wird der hhet-Test verwendet, um fehlende heterogene Entwicklungsverläufe aufzudecken. Es wird die Verteilung der mit dem LGM standardisierten beobachteten Variablen geprüft.
Für alle vorgeschlagenen Gütemaße wurden Simulationsstudien durchgeführt, um ihre Eignung für die Bewertung des QSEMs bzw. des HGMs zu prüfen. Die α-Fehler-Raten waren meistens nahe an dem erstrebten 5%-Niveau. Für den QLRT für das QSEM bei kleinen Stichproben und für den HFI bei komplexeren Modellen waren sie allerdings erhöht. Darüber hinaus zeigten die Tests insgesamt eine gute Teststärke für das Aufdecken von Fehlspezifikationen. Wie in allen statistischen Tests muss dafür die Stichprobengröße ausreichend groß sein. Die praktische Anwendbarkeit der beiden QLRTs, des hhet-Tests und des Differenztests für das HGM wurde anhand von empirischen Beispielen aufgezeigt.
Background: Approximately every third surgical patient is anemic. The most common form, iron deficiency anemia, results from persisting iron‐deficient erythropoiesis (IDE). Zinc protoporphyrin (ZnPP) is a promising parameter for diagnosing IDE, hitherto requiring blood drawing and laboratory workup.
Study design and methods: Noninvasive ZnPP (ZnPP‐NI) measurements are compared to ZnPP reference determination of the ZnPP/heme ratio by high‐performance liquid chromatography (ZnPP‐HPLC) and the analytical performance in detecting IDE is evaluated against traditional iron status parameters (ferritin, transferrin saturation [TSAT], soluble transferrin receptor–ferritin index [sTfR‐F], soluble transferrin receptor [sTfR]), likewise measured in blood. The study was conducted at the University Hospitals of Frankfurt and Zurich.
Results: Limits of agreement between ZnPP‐NI and ZnPP‐HPLC measurements for 584 cardiac and noncardiac surgical patients equaled 19.7 μmol/mol heme (95% confidence interval, 18.0–21.3; acceptance criteria, 23.2 μmol/mol heme; absolute bias, 0 μmol/mol heme). Analytical performance for detecting IDE (inferred from area under the curve receiver operating characteristics) of parameters measured in blood was: ZnPP‐HPLC (0.95), sTfR (0.92), sTfR‐F (0.89), TSAT (0.87), and ferritin (0.67). Noninvasively measured ZnPP‐NI yielded results of 0.90.
Conclusion: ZnPP‐NI appears well suited for an initial IDE screening, informing on the state of erythropoiesis at the point of care without blood drawing and laboratory analysis. Comparison with a multiparameter IDE test revealed that ZnPP‐NI values of 40 μmol/mol heme or less allows exclusion of IDE, whereas for 65 μmol/mol heme or greater, IDE is very likely if other causes of increased values are excluded. In these cases (77% of our patients) ZnPP‐NI may suffice for a diagnosis, while values in between require analyses of additional iron status parameters.
Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless, ex vivo activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained in vivo. NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with ex vivo activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.
Charge states and energy loss of heavy ions after passing an inductively coupled plasma target
(2019)
In various kinds of fields such as accelerator physics, warm dense matter, high energy density physics, and inertial confinement fusion, heavy ions beam-plasma interaction plays an important role, and abundant investigations have been and are being carried out. Taking advantage of a good level of understanding on the interaction between a swift heavy ions beam and a hydrogen gas discharge plasma, an engineering application of a spherical theta-pinch device as a plasma stripper for FAIR (facility for antiproton and ion research) and a scientific application of a swift heavy ions beam as a novel plasma diagnostic tool are proposed and investigated.
The spherical theta-pinch device is manufactured, improved, and comprehensively tested for its application as a plasma stripper. The device is mainly composed of an evacuated glass vessel that can be filled with gas (for example: hydrogen) and a LRC circuit including a capacitors bank and a set of coils. Discharging the device at an initial hydrogen pressure in the glass vessel and an operation voltage for the capacitors bank, a circuit current oscillates in the LRC circuit. The oscillating circuit current in the set of coils induces a corresponding alternating magnetic field inside the glass vessel to ignite and maintain a hydrogen plasma.
Based on the built setup of circuit and plasma diagnostics, the measurements of circuit current, plasma light emission, plasma shape, and hydrogen Balmer series are carried out. The recorded signals of the circuit current and the plasma light emission of many consecutively repetitive discharges overlap perfectly, which indicate a very good reproducibility of the parameters of the LRC circuit during discharge and the generated plasma. From the measured circuit current, a real energy transfer efficiency is calculated by our proposed new model, which shows its overall tendency varying with the hydrogen pressure and the operation voltage, including the maximum value of 25% occurring at an initial hydrogen pressure of around 25 Pa and a maximum operation voltage of 14 kV. So, the discharge at an initial hydrogen pressure of 20 Pa and an operation voltage of 14 ...
Elucidating the immune evasion mechanisms of borrelia mayonii, the causative agent of lyme disease
(2019)
Borrelia (B.) mayonii sp. nov. has recently been reported as a novel human pathogenic spirochete causing Lyme disease (LD) in North America. Previous data reveal a higher spirochaetemia in the blood compared to patients infected by LD spirochetes belonging to the B. burgdorferi sensu lato complex, suggesting that this novel genospecies must exploit strategies to overcome innate immunity, in particular complement. To elucidate the molecular mechanisms of immune evasion, we utilized various methodologies to phenotypically characterize B. mayonii and to identify determinants involved in the interaction with complement. Employing serum bactericidal assays, we demonstrated that B. mayonii resists complement-mediated killing. To further elucidate the role of the key regulators of the alternative pathway (AP), factor H (FH), and FH-like protein 1 (FHL-1) in immune evasion of B. mayonii, serum adsorption experiments were conducted. The data revealed that viable spirochetes recruit both regulators from human serum and FH retained its factor I-mediated C3b-inactivating activity when bound to the bacterial cells. In addition, two prominent FH-binding proteins of approximately 30 and 18 kDa were detected in B. mayonii strain MN14-1420. Bioinformatics identified a gene, exhibiting 60% identity at the DNA level to the cspA encoding gene of B. burgdorferi. Following PCR amplification, the gene product was produced as a His-tagged protein. The CspA-orthologous protein of B. mayonii interacted with FH and FHL-1, and both bound regulators promoted inactivation of C3b in the presence of factor I. Additionally, the CspA ortholog counteracted complement activation by inhibiting the alternative and terminal but not the classical and Lectin pathways, respectively. Increasing concentrations of CspA of B. mayonii also strongly affected C9 polymerization, terminating the formation of the membrane attack complex. To assess the role of CspA of B. mayonii in facilitating serum resistance, a gain-of-function strain was generated, harboring a shuttle vector allowing expression of the CspA encoding gene under its native promotor. Spirochetes producing the native protein on the cell surface overcame complement-mediated killing, indicating that CspA facilitates serum resistance of B. mayonii. In conclusion, here we describe the molecular mechanism utilized by B. mayonii to resists complement-mediated killing by capturing human immune regulators.
Background: The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age.
Material/Methods: Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years).
Results: Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus.
Conclusions: Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV diseas.
We study the Wigner function for massive spin-1/2 fermions in electromagnetic fields. The Wigner function is analytically solved in five cases when electromagnetic fields are constants. For a general space-time dependent field configuration, we use the method of semi-classical expansion and solved the Wigner function at linear order in the Planck's constant. At the same order, we obtained a generalized Boltzmann equation for particle distribution, and a generalized BMT equation for spin polarization. Using the Wigner function, we calculated some physical quantities in a thermal equilibrium system.
Nina Kühnle wendet sich in ihrer Untersuchung in erster Linie sozialgeschichtlichen Fragestellungen zu. Im Eingangskapitel wirft sie die zentrale Ausgangsfrage ihrer Arbeit auf: Handelt es sich bei der sog. "Ehrbarkeit" in Württemberg tatsächlich um eine "ständegeschichtlich einzigartige Sondergruppe" unter den städtischen Oberschichten in Deutschland (8), die man in dieser Form tatsächlich nur in Württemberg antrifft? Und handelt es sich bei dieser "Ehrbarkeit" um einen halbwegs abgrenzbaren stadtbürgerlichen Stand, der sich von den Patriziaten anderer, zumal süddeutscher Städtelandschaften in signifikanter Weise unterscheidet? Eben dies war die mittlerweile allerdings überholte These des württembergischen Landeshistorikers Hansmartin Decker-Hauff: Ihm zufolge bildete die württembergische Ehrbarkeit einen ganz spezifischen Stand, der sich dadurch ausgezeichnet habe, dass bei ihm allein die ausgeübten Ämter und Funktionen die Standeszugehörigkeit begründet hätten. In der eingehenden Auseinandersetzung mit dieser These zeigt die Verf. sodann deren Schwachstellen auf (12–17), wobei sie an die Kritik von Gabriele Haug-Moritz anknüpft, die in ihrer Monographie über die württembergische Ehrbarkeit von Decker-Hauffs Konzept nicht mehr viel übrig gelassen hat: Die Ehrbarkeit bestand nicht – das dürfte mittlerweile feststehen – aus der Gruppe der Amtsinhaber; letztere kamen vielmehr zu Amt und Würden, weil sie aus der Ehrbarkeit stammten (17). "Ehrbarkeit" ergab sich demzufolge nicht aus einem Amt, sondern umgekehrt aus der Zugehörigkeit zu einer bestimmten Gesellschaftsschicht. Angesichts dessen spricht die Verf. in ihrer Arbeit auch nicht von "der Ehrbarkeit", sondern von "städtischen Führungsgruppen" oder der "Stadtelite" (26f.), hier im Anschluss an die neuere Sozialgeschichte, die bekanntlich seit geraumer Zeit eine besondere Vorliebe für das Wort "Elite" entwickelt hat. ...
Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite therapeutic progress, prognosis in high-risk NB is poor and innovative therapies are urgently needed. Therefore, we addressed the potential cytotoxic capacity of interleukin (IL)-activated natural killer (NK) cells compared to cytokine-induced killer (CIK) cells for the treatment of NB. NK cells were isolated from peripheral blood mononuclear cells (PBMCs) by indirect CD56-enrichment or CD3/CD19-depletion and expanded with different cytokine combinations, such as IL-2, IL-15, and/or IL-21 under feeder-cell free conditions. CIK cells were generated from PBMCs by ex vivo stimulation with interferon-γ, IL-2, OKT-3, and IL-15. Comparative analysis of expansion rate, purity, phenotype and cytotoxicity was performed. CD56-enriched NK cells showed a median expansion rate of 4.3-fold with up to 99% NK cell content. The cell product after CD3/CD19-depletion consisted of a median 43.5% NK cells that expanded significantly faster reaching also 99% of NK cell purity. After 10–12 days of expansion, both NK cell preparations showed a significantly higher median cytotoxic capacity against NB cells relative to CIK cells. Remarkably, these NK cells were also capable of efficiently killing NB spheroidal 3D culture in long-term cytotoxicity assays. Further optimization using a novel NK cell culture medium and a prolonged culturing procedure after CD3/CD19-depletion for up to 15 days enhanced the expansion rate up to 24.4-fold by maintaining the cytotoxic potential. Addition of an IL-21 boost prior to harvesting significantly increased the cytotoxicity. The final cell product consisted for the major part of CD16−, NCR-expressing, poly-functional NK cells with regard to cytokine production, CD107a degranulation and antitumor capacity. In summary, our study revealed that NK cells have a significantly higher cytotoxic potential to combat NB than CIK cell products, especially following the synergistic use of IL-15 and IL-21 for NK cell activation. Therefore, the use of IL-15+IL-21 expanded NK cells generated from CD3/CD19-depleted apheresis products seems to be highly promising as an immunotherapy in combination with haploidentical stem cell transplantation (SCT) for high-risk NB patients.
Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients.
Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5–2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF).
Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating “full-blown” systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes.
Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.
MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal gene regulation in the tumor microenvironment (TME). In the TME, both tumor and stroma cells cross-communicate via diverse factors including miRs, which are taking central stage as a therapeutic target of anti-tumor therapy. One of the immune escape strategies adopted by tumor cells is to release miRs as a Trojan horse to hijack circulating or tumor-localized monocytes/macrophages to tune them for pro-tumoral functions. On the other hand, macrophage-derived miRs exert anti-tumor functions. The transfer of miRs from host to recipient cells depends on the supramolecular structure and composition of miR carriers, which determine the distinct uptake mechanism by recipient cells. In this review, we provide a recent update on the miR-mediated crosstalk between tumor cells and macrophages and their mode of uptake in the TME.
EDTA is commonly used as an efficient chelator of metal ion enzyme cofactors. It is highly soluble, optically inactive and does not interfere with most chemicals used in standard buffers making EDTA a common choice to generate metal-free conditions for biochemical and biophysical investigations. However, the controversy in the literature on metal-free enzyme activities achieved using EDTA or by other means called our attention to a putative effect of EDTA beyond chelation. Here, we show that EDTA competes for the nucleotide binding site of the nucleotide hydrolase dUTPase by developing an interaction network within the active site similar to that of the substrate. To achieve these findings, we applied kinetics and molecular docking techniques using two different dUTPases. Furthermore, we directly measured the binding of EDTA to dUTPases and to two other dNTPases, the Taq polymerase and MutT using isothermal titration calorimetry. EDTA binding proved to be exothermic and mainly enthalpy driven with a submicromolar dissociation constant considerably lower than that of the enzyme:substrate or the Mg:EDTA complexes. Control proteins, including an ATPase, did not interact with EDTA. Our findings indicate that EDTA may act as a selective inhibitor against dNTP hydrolyzing enzymes and urge the rethinking of the utilization of EDTA in enzymatic experiments.
Yellow fever virus (YFV) represents a re-emerging zoonotic pathogen, transmitted by mosquito vectors to humans from primate reservoirs. Sporadic outbreaks of YFV occur in endemic tropical regions, causing a viral hemorrhagic fever (VHF) associated with high mortality rates. Despite a highly effective vaccine, no antiviral treatments currently exist. Therefore, YFV represents a neglected tropical disease and is chronically understudied, with many aspects of YFV biology incompletely defined including host range, host–virus interactions and correlates of host immunity and pathogenicity. In this article, we review the current state of YFV research, focusing on the viral lifecycle, host responses to infection, species tropism and the success and associated limitations of the YFV-17D vaccine. In addition, we highlight the current lack of available treatments and use publicly available sequence and structural data to assess global patterns of YFV sequence diversity and identify potential drug targets. Finally, we discuss how technological advances, including real-time epidemiological monitoring of outbreaks using next-generation sequencing and CRISPR/Cas9 modification of vector species, could be utilized in future battles against this re-emerging pathogen which continues to cause devastating disease.
As the prognosis of invasive aspergillosis remains unacceptably poor in patients undergoing hematopoietic stem cell transplantation (HSCT), there is a growing interest in the adoptive transfer of antifungal effector cells, such as Natural Killer (NK) cells. Because immunosuppressive agents are required in most HSCT recipients, knowledge of the impact of these compounds on the antifungal activity of NK cells is a prerequisite for clinical trials. We, therefore, assessed the effect of methylprednisolone (mPRED), cyclosporin A (CsA) and mycophenolic acid (MPA) at different concentrations on proliferation, apoptosis/necrosis, and the direct and indirect anti-Aspergillus activity of human NK cells. Methylprednisolone decreased proliferation and increased apoptosis of NK cells in a significant manner. After seven days, a reduction of viable NK cells was seen for all three immunosuppressants, which was significant for MPA only. Cyclosporin A significantly inhibited the direct hyphal damage by NK cells in a dose-dependent manner. None of the immunosuppressive compounds had a major impact on the measured levels of interferon-γ, granulocyte-macrophage colony-stimulating factor and RANTES (regulated on activation, normal T cell expressed and secreted; CCL5). Our data demonstrate that commonly used immunosuppressive compounds have distinct effects on proliferation, viability and antifungal activity of human NK cells, which should be considered in designing studies on the use of NK cells for adoptive antifungal immunotherapy.
Objective: Many cancer patients complain about cognitive dysfunction. While cognitive deficits have been attributed to the side effects of chemotherapy, there is evidence for impairment at disease onset, prior to cancer-directed therapy. Further debated issues concern the relationship between self-reported complaints and objective test performance and the role of psychological distress.
Method: We assessed performance on neuropsychological tests of attention and memory and obtained estimates of subjective distress and quality of life in 27 breast cancer patients and 20 healthy controls. Testing in patients took place shortly after the initial diagnosis, but prior to subsequent therapy.
Results: While patients showed elevated distress, cognitive performance differed on a few subtests only. Patients showed slower processing speed and poorer verbal memory than controls. Objective and self-reported cognitive function were unrelated, and psychological distress correlated more strongly with subjective complaints than with neuropsychological test performance.
Conclusion: This study provides further evidence of limited cognitive deficits in cancer patients prior to the onset of adjuvant therapy. Self-reported cognitive deficits seem more closely related to psychological distress than to objective test performance.