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In einer fast beiläufig formulierten Bemerkung zur Methode seiner Passagenarbeit spricht Benjamin von der "Notwendigkeit, während vieler Jahre scharf auf jedes zufällige Zitat, jede flüchtige Erwähnung eines Buches hinzuhören" (GS V, 587). Dass – wie in nicht wenigen Prosaminiaturen der Berliner Kindheit – auch für die aufwendige Zusammenstellung der Exzerpte eine ohrenfällige Metapher zur Anwendung gelangt, unterstreicht die Notwendigkeit, sich mit der Bedeutung musikalisch-akustischer Impressionen für seine Vermittlung von Traum, Mythos, Bild und Warenwelt zu befassen. Das bisherige Desinteresse an einem solchen Versuch teilt die kaum mehr überschaubare Benjamin-Exegese mit der musikologischen Literatur, deren Zurückhaltung indessen recht einfach zu erklären ist: Die aus ihrer Sicht für eine musikgeschichtliche Kontextualisierung des Dioramas oder die ästhetischen Konsequenzen des 'Chocks' in Frage kommenden Komponisten werden in der Passagenarbeit fast sämtlich übergangen. Als die intellektuellen Residuen der Hauptstadt des 19. Jahrhunderts kompilierender Flaneur und Chiffonnier ist Benjamin nur bis in die vom Boulevard Haussmann verdrängte Passage de l'Opéra gelangt, deren vom allmählichen Verfall geprägte Atmosphäre schon Aragon zu den subjektiv-surrealistischen Visionen seines Paysan de Paris inspirierte. Was sich innerhalb der Pariser Musiktheater ereignete, findet mit einer Ausnahme sein Interesse hingegen ebenso wenig, wie die Musikforschung die sich in den Bühnenwerken Aubers, Meyerbeers oder Halevys manifestierende "Verstädterung der Oper" ohne eine nennenswerte Auseinandersetzung mit dem Passagenprojekt untersuchte. Und während dessen 1935 verfasstes Exposé die Namen Offenbach und Wagner immerhin im Kontext der ironischen Utopie des Weltausstellungstaumels oder Baudelaires mit dem Gesamtkunstwerk assoziierter Flucht vor dem gesellschaftlichen Dasein der Künste8 erwähnt, fehlt der gerade für die musikalische Umsetzung der von Benjamin als zentrale Erkenntnisquelle erachteten Dialektik von "Traum" und "Erwachen" (vgl. z. B. 490–510, 579–580) unverzichtbare Hector Berlioz. Hier verbirgt sich – denkt man an Werke wie die Symphonie Fantastique, Lelio oder Harold en Italie – eine auch von der Berlioz-Literatur noch gänzlich unbeachtete Konstellation. Benjamins Einbindung eines kompositorischen Zeitgenossen in eine divergente Gedankenstränge zusammenführende Metapher oder ein "dialektisches Bild" erfordert demgegenüber eine präzise Kontextualisierung: So erscheinen in einer der mythologisierenden Eisenbahnepisoden Orpheus, Eurydike und Hermes auf dem Bahnsteig, wo eine sich aus dem aufgetürmten Gepäck formende Kofferkrypta die zum Melodram geronnene antike Urgeschichte christlich sublimiert (512).
Enhanced labeling density and whole-cell 3D dSTORM imaging by repetitive labeling of target proteins
(2018)
With continuing advances in the resolving power of super-resolution microscopy, the inefficient labeling of proteins with suitable fluorophores becomes a limiting factor. For example, the low labeling density achieved with antibodies or small molecule tags limits attempts to reveal local protein nano-architecture of cellular compartments. On the other hand, high laser intensities cause photobleaching within and nearby an imaged region, thereby further reducing labeling density and impairing multi-plane whole-cell 3D super-resolution imaging. Here, we show that both labeling density and photobleaching can be addressed by repetitive application of trisNTA-fluorophore conjugates reversibly binding to a histidine-tagged protein by a novel approach called single-epitope repetitive imaging (SERI). For single-plane super-resolution microscopy, we demonstrate that, after multiple rounds of labeling and imaging, the signal density is increased. Using the same approach of repetitive imaging, washing and re-labeling, we demonstrate whole-cell 3D super-resolution imaging compensated for photobleaching above or below the imaging plane. This proof-of-principle study demonstrates that repetitive labeling of histidine-tagged proteins provides a versatile solution to break the "labeling barrier" and to bypass photobleaching in multi-plane, whole-cell 3D experiments.
Accurate labeling of endogenous proteins for advanced light microscopy in living cells remains challenging. Nanobodies have been widely used for antigen labeling, visualization of subcellular protein localization and interactions. To facilitate an expanded application, we present a scalable and high-throughput strategy to simultaneously target multiple endogenous proteins in living cells with micro- to nanometer resolution. For intracellular protein labeling, we advanced nanobodies by site-specific and stoichiometric attachment of bright organic fluorophores. Their fast and fine-tuned intracellular transfer by microfluidic cell squeezing enabled high-throughput delivery with less than 10% dead cells. This strategy allowed for the dual-color imaging of distinct endogenous cellular structures, and culminated in super-resolution imaging of native protein networks in genetically non-modified living cells. The simultaneous delivery of multiple engineered nanobodies does not only offer exciting prospects for multiplexed imaging of endogenous protein, but also holds potential for visualizing native cellular structures with unprecedented accuracy.
Background: There is absence of specific biomarkers and an incomplete understanding of the pathophysiology of exudative age-related macular degeneration (AMD).
Methods and findings: Eighty-eight vitreous samples (73 from patients with treatment naïve AMD and 15 control samples from patients with idiopathic floaters) were analyzed with capillary electrophoresis coupled to mass spectrometry in this retrospective case series to define potential candidate protein markers of AMD. Nineteen proteins were found to be upregulated in vitreous of AMD patients. Most of the proteins were plasma derived and involved in biological (ion) transport, acute phase inflammatory reaction, and blood coagulation. A number of proteins have not been previously associated to AMD including alpha-1-antitrypsin, fibrinogen alpha chain and prostaglandin H2-D isomerase. Alpha-1-antitrypsin was validated in vitreous of an independent set of AMD patients using Western blot analysis. Further systems biology analysis of the data indicated that the observed proteomic changes may reflect upregulation of immune response and complement activity.
Conclusions: Proteome analysis of vitreous samples from patients with AMD, which underwent an intravitreal combination therapy including a core vitrectomy, steroids and bevacizumab, revealed apparent AMD-specific proteomic changes. The identified AMD-associated proteins provide some insight into the pathophysiological changes associated with AMD.
Molecular and cellular research modalities for the study of liver pathologies have been tremendously improved over the recent decades. Advanced technologies offer novel opportunities to establish cell isolation techniques with excellent purity, paving the path for 2D and 3D microscopy and high-throughput assays (e.g., bulk or single-cell RNA sequencing). The use of stem cell and organoid research will help to decipher the pathophysiology of liver diseases and the interaction between various parenchymal and non-parenchymal liver cells. Furthermore, sophisticated animal models of liver disease allow for the in vivo assessment of fibrogenesis, portal hypertension and hepatocellular carcinoma (HCC) and for the preclinical testing of therapeutic strategies. The purpose of this review is to portray in detail novel in vitro and in vivo methods for the study of liver cell biology that had been presented at the workshop of the 8th meeting of the European Club for Liver Cell Biology (ECLCB-8) in October of 2018 in Bonn, Germany.
Im Sinne einer Musikhistorie als "Plural von Zusammenhängen" (H. Blumenberg), deren sich überkreuzende Fäden der narrativen Bündelung durch Hörer und Chronisten bedürfen, erweist sich Schönbergs "Überlebender aus Warschau" als ein Scharnierstück der von politischen Verwerfungen durchsetzten Musikgeschichte des 20. Jahrhunderts. Die Einbeziehung des die Dignität kultureller und religiöser Selbstbehauptung symbolisierenden Glaubensbekenntnisses setzt kompositionsgeschichtlich einerseits eine national-religiöse Tradition fort, denkt man etwa an die Schlüsselstellung, die das Zitat von Luthers Choral "Ein feste Burg" in nicht wenigen Werken des 19. Jahrhunderts einnimmt. Andererseits resultiert auch die Wirkung des 'Survivor' - wie Reinhold Brinkmann im Zeichen der um und nach 1968 leidenschaftlich ausgetragenen Diskussion der politischen Aussagekraft musikalischer Werke betonte - aus der Aktivierung des politischen Textinhalts durch eine dezidiert musikalische Konzeption: Die dem "Shema Yisrael" vorausgehende musikalische Steigerung lässt sich als kompositorisches Modell bereits im apotheotisch angelegten Schluss von Schönbergs 'Gurreliedern' ("Erwacht, erwacht ihr Blumen zur Wonne") nachweisen. Auf dynamischer Ebene ist diese Klimax der Takte 72-80, die es buchstäblich darauf anlegt, den Hörer zu überwältigen, durch das anziehende Tempo (von Viertel=60 bis Viertel=160) und ein Crescendo zum dreifachen Forte, rhythmisch durch die aus der Erzählerstimme in das Orchester überspringenden triolischen Figuren, sowie tonal durch ein chromatisches Wechselspiel zwischen den vier Ausprägungen des übermäßigen Dreiklangs und der dadurch ebenfalls erforderlichen Transposition der Reihenformen bestimmt. Schönbergs ideelle Besinnung auf die Religion stützt sich kompositorisch somit ein Stück weit gerade auf ihr säkularisiertes Gegenstück - jene musikalischen Überhöhungen, die das Zeitalter der "Weltanschauungsmusik" in Form einer bisweilen hypertrophen Kunstreligion zelebrierte. Die Erinnerung des "Überlebenden" wird so auf den "grandiose moment" des musikalischen Widerstands konzentriert, während Schönberg eine gleichwertige Einbeziehung des Erzählertexts in das motivisch- tonale Gefüge der Komposition dezidiert ausschließt. Trotz dieser historischen Verortung steht der von Adorno als "autonome Gestaltung der zur Hölle gesteigerten Heteronomie" beargwöhnte 'Survivor' zugleich aber nicht nur ideengeschichtlich, sondern durchaus auch kompositionstechnisch - wie hier an Kompositionen von Schönbergs (posthumem) Schwiegersohn Luigi Nono gezeigt werden soll - mit avancierten Beispielen einer 'musique engagée' der 1960er Jahre in Verbindung.
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
Background & Aims: Phosphodiesterase‐5 inhibitors (PDE‐5‐I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side‐effects have been reported. Non‐selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE‐5‐I with NSBB and its impact on PH and ED in experimental cirrhosis.
Methods: ED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile‐duct‐ligation or carbon‐tetrachloride intoxication in rats. Corpus cavernosum pressure – a surrogate of ED ‐, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE‐5 signalling were analysed using PCR and western Blot.
Results: ED in humans was related to severity of liver disease and to NSBB treatment. PDE‐5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side‐effects.
Conclusions: ED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE‐5‐I and NSBB improves ED and PH in experimental cirrhosis.
Background & Aims: Acute‐on‐chronic liver failure (ACLF) is characterized by high short‐term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis.
Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL‐33 receptor (sIL‐33R). Patients were divided according to CI (<3.2; 3.2‐4.2; >4.2 L/min/m2) in hypo‐ (n = 84), normo‐ (n = 69) and hyperdynamic group (n = 55). After a median follow‐up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P = .011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL‐6 was an independent predictor of fatal ACLF development.
Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.
Background and Aims: Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH. Methods: Groups of 12-week-old ApoE-/- mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD). After 3 weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100 mg/kg body weight) or vehicle (0.5% carmellose) every day, 5 days/week for a further 4 weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed. Results: IFM-514 inhibited IL-1β production in mice challenged with 20 mg/kg lipopolysaccharide, and in mouse and human inflammatory cells in vitro. IFM-514 inhibited hepatic inflammation in the in vivo non-alcoholic steatohepatitis model assessed by H&E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious in vivo in MDC-fed ApoE-/- mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed ApoE-/- mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached. Conclusion: Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.