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According to the inflationary theory of cosmology, most elementary particles in the current universe were created during a period of reheating after inflation. In this work we self-consistently couple the Einstein-inflaton equations to a strongly coupled quantum field theory (QFT) as described by holography. We show that this leads to an inflating universe, a reheating phase and finally a universe dominated by the QFT in thermal equilibrium.
We use holography to study the dynamics of a strongly-coupled gauge theory in four-dimensional de Sitter space with Hubble rate H. The gauge theory is non-conformal with a characteristic mass scale M. We solve Einstein’s equations numerically and determine the time evolution of homogeneous gauge theory states. If their initial energy density is high compared with H4 then the early-time evolution is well described by viscous hydrodynamics with a non-zero bulk viscosity. At late times the dynamics is always far from equilibrium. The asymptotic late-time state preserves the full de Sitter symmetry group and its dual geometry is a domain-wall in AdS5. The approach to this state is characterised by an emergent relation of the form P = w E that is different from the equilibrium equation of state in flat space. The constant w does not depend on the initial conditions but only on H/M and is negative if the ratio H/M is close to unity. The event and the apparent horizons of the late-time solution do not coincide with one another, reflecting its non-equilibrium nature. In between them lies an “entanglement horizon” that cannot be penetrated by extremal surfaces anchored at the boundary, which we use to compute the entanglement entropy of boundary regions. If the entangling region equals the observable universe then the extremal surface coincides with a bulk cosmological horizon that just touches the event horizon, while for larger regions the extremal surface probes behind the event horizon.
We present the first holographic simulations of non-equilibrium steady state formation in strongly coupled N=4 SYM theory in 3+1 dimensions. We initially join together two thermal baths at different temperatures and chemical potentials and compare the subsequent evolution of the combined system to analytic solutions of the corresponding Riemann problem and to numeric solutions of ideal and viscous hydrodynamics. The time evolution of the energy density that we obtain holographically is consistent with the combination of a shock and a rarefaction wave: A shock wave moves towards the cold bath, and a smooth broadening wave towards the hot bath. Between the two waves emerges a steady state with constant temperature and flow velocity, both of which are accurately described by a shock+rarefaction wave solution of the Riemann problem. In the steady state region, a smooth crossover develops between two regions of different charge density. This is reminiscent of a contact discontinuity in the Riemann problem. We also obtain results for the entanglement entropy of regions crossed by shock and rarefaction waves and find both of them to closely follow the evolution of the energy density.
We present the first holographic simulations of non-equilibrium steady state formation in strongly coupled N=4 SYM theory in 3+1 dimensions. We initially join together two thermal baths at different temperatures and chemical potentials and compare the subsequent evolution of the combined system to analytic solutions of the corresponding Riemann problem and to numeric solutions of ideal and viscous hydrodynamics. The time evolution of the energy density that we obtain holographically is consistent with the combination of a shock and a rarefaction wave: A shock wave moves towards the cold bath, and a smooth broader wave towards the hot bath. Between the two waves emerges a steady state with constant temperature and flow velocity, both of which are accurately described by a shock+rarefaction wave solution of the Riemann problem. In the steady state region develops a smooth crossover between two regions of different charge densities that diffuses on a timescale proportional to t√ and is reminiscent of a contact discontinuity in the Riemann problem. We also obtain results for the entanglement entropy of regions crossed by shock and rarefaction waves and find both of them to closely follow the evolution of the energy density.
Background: Despite known clinical benefits, guideline-recommended heart rate (HR) control is not achieved for a significant proportion of patients with HF with reduced ejection fraction. The wearable cardioverter-defibrillator (WCD) provides continuous HR monitoring and alerts that could aid medication titration.
Objective: This study sought to evaluate sex differences in achieving guideline-recommended HR control during a period of WCD use.
Methods: Data from patients fitted with a WCD from 2015 to 2018 were obtained from the manufacturer’s database (ZOLL). The proportion of patients with adequate nighttime resting HR control at the beginning of use (BOU) and at the end of use (EOU) were compared by sex. Adequate HR control was defined as having a nighttime median HR <70 beats/min.
Results: A total of 21,440 women and a comparative sample of 17,328 men (median 90 [IQR 59–116] days of WCD wear) were included in the final dataset. Among patients who did not receive a shock, over half had insufficient HR control at BOU (59% of women, 53% of men). Although the proportion of patients with resting HR ≥70 beats/min improved by EOU, 43% of women and 36% of men did not achieve guideline-recommended HR control.
Conclusion: A significant proportion of women and men did not achieve adequate HR control during a period of medical therapy optimization. Compared with men, a greater proportion of women receiving WCD shocks had insufficiently controlled HR in the week preceding ventricular tachyarrhythmia/ventricular fibrillation and 43% of nonshocked women, compared with 36% of men, did not reach adequate HR control during the study period. The WCD can be utilized as a remote monitoring tool to record HR and inform adequate uptitration of beta-blockers, with particular focus on reducing the treatment gap in women.
Background: Data on the arrhythmic burden of women at risk for sudden cardiac death are limited, especially in patients using the wearable cardioverter-defibrillator (WCD).
Objective: We aimed to characterize WCD compliance, atrial and ventricular arrhythmic burden, and WCD outcomes by sex in patients enrolled in the Prospective Registry of Patients Using the Wearable Cardioverter Defibrillator (WEARIT-II U.S. Registry).
Methods: In the WEARIT-II Registry, we stratified 2000 patients by sex into women (n = 598) and men (n = 1402). WCD wear time, ventricular and atrial arrhythmic events during WCD use, and implantable cardioverter-defibrillator (ICD) implantation rates at the end of WCD use were evaluated.
Results: The mean WCD wear time was similar in women and men (94 days vs 90 days; P = .145), with longer daily use in women (21.4 h/d vs 20.7 h/d; P = .001). Burden of ventricular tachycardia or ventricular fibrillation was higher in women, with 30 events per 100 patient-years compared with 18 events per 100 patient-years in men (P = .017), with similar findings for treated and non-treated ventricular tachycardia/ventricular fibrillation. Recurrent atrial arrhythmias/sustained ventricular tachycardia was also more frequent in women than in men (167 events per 100 patient-years vs 73 events per 100 patient-years; P = .042). However, ICD implantation rate at the end of WCD use was similar in both women and men (41% vs 39%; P = .448).
Conclusion: In the WEARIT-II Registry, we have shown a higher burden of ventricular and atrial arrhythmic events in women than in men. ICD implantation rates at the end of WCD use were similar. Our findings warrant monitoring women at risk for sudden cardiac death who have a high burden of atrial and ventricular arrhythmias while using the WCD.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals with convolutional neural networks to achieve high single-molecule accuracy and outperforms other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals with convolutional neural networks to achieve high single-molecule accuracy and outperforms other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals with convolutional neural networks to achieve high single-molecule accuracy and outperforms other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
Buch des Monats Oktober 2022
(2022)
Kurzvorstellung der folgenden Publikation:
Mann, William Benson: Das Leben und das Bekenntniß sowie die schauderhaften Verbrechen des Anton Probst, des Mörders der Familie Deering : nebst einer wahrheitsgetreuen Geschichte vieler der scheußlichsten und geheimnißvollsten Morde, die hier und in anderen Ländern begangen wurden. - 12 Illustrationen. - Philadelphia : Verlag von Barclay & Co., 1866. - Seiten 39 - 109.
Der Beitrag sucht Georg Christoph Lichtenbergs Position im Sprachdenken der zweiten Hälfte des 18. Jahrhunderts zu bestimmen. Diese ist durch eine Kombination von anthropologischen und technisch-pragmatischen, sprachhandwerklichen Überlegungen zur "Wörterfertigung" geprägt, bei der Fragen von Lexik und Nomenklatur im Vordergrund stehen. Zu den Leitkriterien des guten Stils gehören Lichtenberg zufolge Wahrheit und Genauigkeit sowie Natürlichkeit und Individualisierung.
Der Beitrag untersucht den Gebrauch des Tonbegriffs im ästhetischen und poetologischen Diskurs des mittleren und späten 18. Jahrhunderts. Ausgangspunkt dafür ist eine Verhältnisbestimmung der Termini Schreibart, Stil und Ton, aus der die gattungspoetologische Bedeutung des Tons hervorgeht. Entgegen dem seit der romantischen Ästhetik dominanten Verständnis verbindet die Dichtungstheorie des 18. Jahrhunderts (Friedrich Gottlieb Klopstock, Johann Joachim Eschenburg, Johann Jakob Engel, Johann Christoph Adelung) mit dem Begriff nicht nur die klangliche Dimension von Literatur, sondern auch eine affektive Grundierung von Gattungsformen und ein Konzept für die Beschreibung von gattungshybriden Texten.
Am Nachdruck, wie er bei Johann Christoph Gottsched, Johann Jacob Bodmer, Johann Jacob Breitinger, Johann Georg Sulzer und Johann Gottfried Herder diskutiert wird, lässt sich exemplarisch beobachten, wie eine Gruppe von rhetorischen Verfahren zur Kennzeichnung von nationalen Kollektivstilen ausgebaut wird. Eine wichtige Voraussetzung für die Ausweitung des Nachdrucks von einer Stilfigur zu einem 'nachdrücklichen Stil', so die hier verfolgte These, ist der über physikalische Leitvorstellungen von Druck, Stoß und Wurf geleistete metaphorische Anschluss an ästhetische Kraftvorstellungen.
Der Begriff des 'körnigen Stils' steht in der Sprach- und Literaturkritik des 18. Jahrhunderts für eine kurze und gehaltvolle, oft auch als 'nachdrücklich' beschriebene Schreibart. Im Literaturstreit zwischen Johann Christoph Gottsched und den 'Schweizern' erlangte er zugleich programmatische und polemische Bedeutung. Im Zentrum des Aufsatzes steht die für das 'Körnige' konstitutive Konstellation von Kürze, Kraft und Konkretion. Ausgehend von Theodor W. Adornos stilsoziologischer Beobachtung, dass der lakonische Stil in Briefen des 18. Jahrhunderts Ausdruck bürgerlicher Notdurft sei, zeige ich an Texten von Johann Christoph Adelung, Johann Jacob Breitinger, Gottfried Wilhelm Leibniz und Johann Gottfried Herder, dass das Stilideal des Körnigen im 18. Jahrhundert mit dem Streben nach einer Erneuerung und Bereicherung der deutschen Schriftsprache einherging. Zum Kapital, aus dem diese neue Sprache sich speisen sollte, gehörte das ausdifferenzierte Vokabular des Handwerks und des Handels. Der zeitgenössischen Theorie zufolge stellte der körnige Stil also weniger die Notdurft als den Reichtum und die Sprachmächtigkeit des Bürgertums zur Schau.
In seinem Frühwerk "Über die neuere deutsche Literatur" arbeitet der junge Johann Gottfried Herder an der Herausbildung einer neuen Prosa. Durch kommentiertes Zitieren aus den "Briefen, die neueste Literatur betreffend" entwirft er das Ideal einer 'biegsamen' und 'behaglichen' ungebundenen Schreibweise, die sich ganz wesentlich in Stilversuchen manifestiert - in beschriebenen, kritisierten und zitierten sowie denjenigen des Verfassers selbst.
Beispiel und Regel im 18. Jahrhundert : ein Blick in Christian Ludwigs zweisprachige Wörterbücher
(2024)
Zweisprachige Wörterbücher des 18. Jahrhunderts sind eine wichtige Quelle für die Analyse impliziter stilistischer Urteile. Sie wurden einerseits, insbesondere in der zweiten Jahrhunderthälfte, von den präskriptiven Regeln der großen monolingualen Wörterbücher und Grammatiken beeinflusst, andererseits hatten sie die Aufgabe, Fremdsprachenlernern deskriptiv Gebrauchsmuster an Beispielen vorzuführen. Der Beitrag zeichnet nach, wie sich die Autoren dieser doppelten Herausforderung stellten und wie das entstehende präskriptive Regelsystem vor dem Hintergrund der Stilpluralisierung im 18. Jahrhundert zu interpretieren ist.
In seiner "Poétique française" (1763) und seinen "Eléments de littérature" (1787) entwickelt der französische Dichter und Theoretiker Jean-François Marmontel Ansichten zum Stil, die von der traditionellen Regelpoetik geprägt sind, allmählich aber einen Übergang zur Individualstilpoetik andeuten. Während er diese verschiedenen Paradigmen durch den Geschmacksbegriff noch zu vereinen sucht, zeigt die deutsche Rezeption seiner Theorie, insbesondere Gottlob Benedikt von Schirachs Übertragung, wie sich der Kompromiss aufzulösen beginnt und wie sich neben der Durchsetzung der Individualstilpoetik auch eine Trennung zwischen Wissenschaft und Kunst anbahnt.
Für die Mitte des 18. Jahrhunderts wurde ein umfassender Wandel im Bereich des Stilverständnisses konstatiert, das ab 1750 von zwei gegensätzlichen Stilbegriffen geprägt ist: einem traditionell rhetorischen einerseits und einem sich neu etablierenden Individualstil andererseits. Der Beitrag versucht, mit einem Schlaglicht auf das Frühwerk Johann Georg Hamanns ("Sokratische Denkwürdigkeiten" und "Wolken") diesen für das Verständnis der stilgeschichtlichen Umbrüche zentralen Autor im skizzierten Diskursfeld zu verorten. Ein näherer Blick auf Hamanns sokratische Schreibart erlaubt es, die geläufige Rollenzuschreibung, die in Hamann vor allem einen Wegbereiter des Individualstils erkennt, zu problematisieren und ein Paradox herauszuarbeiten: Die Entwicklung zum Individualstil beginnt im Falle von Hamanns ironisch verstellter Maskenrede mit einer radikalen Depotenzierung der Autorinstanz.
Im vorliegenden Beitrag geht es um die Frage, wie sich Natürlichkeit als ein zentrales Stilkonzept im 18. Jahrhundert auf die syntaktische Gestaltung von Texten ausgewirkt hat. Grundlage der empirischen Untersuchung sind neunzig Musterbriefe, die aus drei Ausgaben des Schröter'schen Briefstellers (1,1743, 7,1767, 8,1785) stammen und die im Sinne der 'neuen' Stilauffassungen überarbeitet wurden. Die Briefe zeigen unter anderem einen Rückgang in der Satzkomplexität, eine Aufwertung der Selbstreferenz und eine verstärkte Einbindung mündlichkeitsnaher Strukturen.
Um 1750 zeichnet sich eine grundlegende Verschiebung in der Funktion des Stilbegriffes ab, die sowohl die Theorie als auch die Praxis literarischen Schreibens veränderte. Während sich das an der frühaufklärerischen Erkenntnistheorie orientierte Ideal der ersten Jahrhunderthälfte als analytischer Stil beschreiben lässt, zielt die Dichtungstheorie und -praxis in der zweiten Jahrhunderthälfte auf einen synthetischen Stil, der sich im poetischen Text als "übersummatives Ganzes" (Ulf Abraham) manifestiert; die poetische Absicht wird durch diesen Stil in einem korrelativen Verhältnis von Text und Einbildungskraft verwirklicht. In einer vergleichenden, den historischen Kontext einbeziehenden Analyse zweier Gedichte von Barthold Heinrich Brockes und Friedrich Gottlieb Klopstock wird nachgewiesen, dass sich das Verständnis von Stil von einer Art Verdoppelung des Erkenntnisprozesses (Brockes) zu einer kognitiven Funktion (Klopstock) hin verschiebt.
Hugh Blairs umfangreiche "Lectures on Rhetoric and Belles Lettres" sind eines der erfolgreichsten Werke der englischsprachigen Rhetoriktradition. Der Stilbegriff bildet das Zentrum von Blairs Ästhetikkonzept. Blair greift einerseits auf die rhetorische Tradition zurück, bezieht sich andererseits aber auch auf wahrnehmungstheoretische Überlegungen aus der zeitgenössischen empiristischen Psychologie. Neben den ästhetischen Qualitäten des Stils rücken dabei Fragen der Verständnissicherung durch stilistische Klarheit in den Fokus. Blairs "Lectures" greifen damit über das Feld der Ästhetik entscheidend hinaus.
Um 1750 gelangt die ethopoetische Funktion des Stils in den Fokus verschiedener Autoren, welche die Kategorie in Rhetorik, Poetik und Ästhetik neu vermessen. Johann Christoph Gottscheds Rhetorik weiß den Stil als Übung zu nutzen, um Empfinden und Denken der Schüler zu trainieren. Der Charakter der Schüler resultiert somit aus einem Ausbildungsprogramm, das vom Spracherwerb bis zum Verfassen von Reden reicht. Johann Jacob Breitinger erläutert in seiner Poetik, wie die Sprache auf einer semiotischen Ebene auf verschiedene Arten Kraft ausübt, um das Gemüt zu bewegen und damit sinnliche Erkenntnisse zu generieren. Stil als Übung und Stil als Darstellungsverfahren vereint Alexander Gottlieb Baumgarten in seiner Wissenschaft der sinnlichen Erkenntnis, die sowohl eine Vervollkommnung des sinnlichen Erkennens anstrebt als auch die Verfahren beleuchtet, die für die Darstellung der sinnlichen Erkenntnis verantwortlich sind.
Der interdisziplinäre Sammelband eröffnet neue Perspektiven auf den Stil als bislang unterkonturierte literaturwissenschaftliche Leitkategorie unter transnationalen, wissens-, gattungs- und sprachgeschichtlichen Gesichtspunkten. Im 18. Jahrhundert zeichnet sich im Nachdenken über Schreibarten eine Neujustierung der Stilkategorie ab, die den Stil zur Reflexionsgröße für ästhetische Diskurse macht. Der Band sondiert die Pluralisierung, Historisierung und Individualisierung der Stilkategorie, die ihr neue literatur- und kulturtheoretische Anwendungsbereiche eröffnet. Die Bewegungen zwischen den Sprachen, Literaturen, Medien und semantischen Feldern erschließt die Publikation, indem sie europäische Vergleichshorizonte eröffnet und literatur- ebenso wie sprachwissenschaftliche Ansätze präsentiert. Damit leistet sie einen Beitrag zum Feld der komparatistisch ausgerichteten Germanistik, insbesondere der Literatur- und Kulturgeschichte des 18. Jahrhunderts und des europäischen Kulturtransfers.
Der interdisziplinäre Sammelband eröffnet neue Perspektiven auf den Stil als bislang unterkonturierte literaturwissenschaftliche Leitkategorie unter transnationalen, wissens-, gattungs- und sprachgeschichtlichen Gesichtspunkten. Im 18. Jahrhundert zeichnet sich im Nachdenken über Schreibarten eine Neujustierung der Stilkategorie ab, die den Stil zur Reflexionsgröße für ästhetische Diskurse macht. Der Band sondiert die Pluralisierung, Historisierung und Individualisierung der Stilkategorie, die ihr neue literatur- und kulturtheoretische Anwendungsbereiche eröffnet. Die Bewegungen zwischen den Sprachen, Literaturen, Medien und semantischen Feldern erschließt die Publikation, indem sie europäische Vergleichshorizonte eröffnet und literatur- ebenso wie sprachwissenschaftliche Ansätze präsentiert. Damit leistet sie einen Beitrag zum Feld der komparatistisch ausgerichteten Germanistik, insbesondere der Literatur- und Kulturgeschichte des 18. Jahrhunderts und des europäischen Kulturtransfers.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals with convolutional neural networks to achieve high single-molecule accuracy and outperforms other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals with convolutional neural networks to achieve high single-molecule accuracy and outperforms other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions, using signals from nanopore direct RNA sequencing. CHEUI processes observed and expected signals with convolutional neural networks to achieve high single-molecule accuracy and outperform other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A significant roadblock hindering progress in epitranscriptomics is the identification of more than one modification in individual transcript molecules. We address this with CHEUI (CH3 (methylation) Estimation Using Ionic current). CHEUI predicts N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual molecules from the same sample, the stoichiometry at transcript reference sites, and differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals to achieve high single-molecule, transcript-site, and stoichiometry accuracies in multiple tests using synthetic RNA standards and cell line data. CHEUI’s capability to identify two modification types in the same sample reveals a co-occurrence of m6A and m5C in individual mRNAs in cell line and tissue transcriptomes. CHEUI provides new avenues to discover and study the function of the epitranscriptome.
The expanding field of epitranscriptomics might rival the epigenome in the diversity of the biological processes impacted. However, the identification of modifications in individual RNA molecules remains challenging. We present CHEUI, a new method that detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) at single-nucleotide and single-molecule resolution from Nanopore signals. CHEUI predicts methylation in Nanopore reads and transcriptomic sites in a single condition, and differential m6A and m5C methylation between any two conditions. Using extensive benchmarking with Nanopore data derived from synthetic and natural RNA, CHEUI showed higher accuracy than other existing methods in detecting m6A and m5C sites and quantifying the site stoichiometry levels, while maintaining a lower proportion of false positives. CHEUI provides a new capability to detect RNA modifications with high accuracy and resolution that can be cost-effectively expanded to other modifications to unveil the full span of the epitranscriptome in normal and disease conditions.
The translation eukaryotic elongation factor 1alpha (eEF1A) is a monomeric GTPase involved in protein synthesis. In addition, this protein is thought to participate in other cellular functions such as actin bundling, cell cycle regulation, and apoptosis. Here we show that eEF1A is associated with the alpha2 subunit of the inhibitory glycine receptor in pulldown experiments with rat brain extracts. Moreover, additional proteins involved in translation like ribosomal S6 protein and p70 ribosomal S6 protein kinase as well as ERK1/2 and calcineurin were identified in the same pulldown approaches. Glycine receptor activation in spinal cord neurons cultured for 1 week resulted in an increased phosphorylation of ribosomal S6 protein. Immunocytochemistry showed that eEF1A and ribosomal S6 protein are localized in the soma, dendrites, and at synapses of cultured hippocampal and spinal cord neurons. Consistent with our biochemical data, immunoreactivities of both proteins were partially overlapping with glycine receptor immunoreactivity in cultured spinal cord and hippocampal neurons. After 5 weeks in culture, eEF1A immunoreactivity was redistributed to the cytoskeleton in about 45% of neurons. Interestingly, the degree of redistribution could be increased at earlier stages of in vitro differentiation by inhibition of either the ERK1/2 pathway or glycine receptors and simultaneous N-methyl-D-aspartate receptor activation. Our findings suggest a functional coupling of eEF1A with both inhibitory and excitatory receptors, possibly involving the ERK-signaling pathway.
Mutations in the clk-1 gene result in slower development and increased life span in Caenorhabditis elegans. The Saccharomyces cerevisiae homologue COQ7/CAT5 is essential for several metabolic pathways including ubiquinone biosynthesis, respiration, and gluconeogenic gene activation. We show here that Coq7p/Cat5p is a mitochondrial inner membrane protein directly involved in ubiquinone biosynthesis, and that the defect in gluconeogenic gene activation in coq7/cat5 null mutants is a general consequence of a defect in respiration. These results obtained in the yeast model suggest that the effects on development and life span in C. elegans clk-1 mutants may relate to changes in the amount of ubiquinone, an essential electron transport component and a lipid soluble antioxidant.
Calreticulin is a Ca2+ -binding chaperone that resides in the lumen of the endoplasmic reticulum and is involved in the regulation of intracellular Ca2+ homeostasis and in the folding of newly synthesized glycoproteins. In this study, we have used site-specific mutagenesis to map amino acid residues that are critical in calreticulin function. We have focused on two cysteine residues (Cys(88) and Cys(120)), which form a disulfide bridge in the N-terminal domain of calreticulin, on a tryptophan residue located in the carbohydrate binding site (Trp(302)), and on certain residues located at the tip of the "hairpin-like" P-domain of the protein (Glu(238), Glu(239), Asp(241), Glu(243), and Trp(244)). Calreticulin mutants were expressed in crt(-/-) fibroblasts, and bradykinin-dependent Ca2+ release was measured as a marker of calreticulin function. Bradykinin-dependent Ca2+ release from the endoplasmic reticulum was rescued by wild-type calreticulin and by the Glu(238), Glu(239), Asp(241), and Glu(243) mutants. The Cys(88) and Cys(120) mutants rescued the calreticulin-deficient phenotype only partially ( approximately 40%), and the Trp(244) and Trp(302) mutants did not rescue it at all. We identified four amino acid residues (Glu(239), Asp(241), Glu(243), and Trp(244)) at the hairpin tip of the P-domain that are critical in the formation of a complex between ERp57 and calreticulin. Although the Glu(239), Asp(241), and Glu(243) mutants did not bind ERp57 efficiently, they fully restored bradykinin-dependent Ca2+ release in crt(-/-) cells. This indicates that binding of ERp57 to calreticulin may not be critical for the chaperone function of calreticulin with respect to the bradykinin receptor.
Antigen presentation to cytotoxic T lymphocytes via major histocompatibility complex class I (MHC I) molecules depends on the heterodimeric transporter associated with antigen processing (TAP). For efficient antigen supply to MHC I molecules in the ER, TAP assembles a macromolecular peptide-loading complex (PLC) by recruiting tapasin. In evolution, TAP appeared together with effector cells of adaptive immunity at the transition from jawless to jawed vertebrates and diversified further within the jawed vertebrates. Here, we compared TAP function and interaction with tapasin of a range of species within two classes of jawed vertebrates. We found that avian and mammalian TAP1 and TAP2 form heterodimeric complexes across taxa. Moreover, the extra N-terminal domain TMD0 of mammalian TAP1 and TAP2 as well as avian TAP2 recruits tapasin. Strikingly, however, only TAP1 and TAP2 from the same taxon can form a functional heterodimeric translocation complex. These data demonstrate that the dimerization interface between TAP1 and TAP2 and the tapasin docking sites for PLC assembly are conserved in evolution, whereas elements of antigen translocation diverged later in evolution and are thus taxon specific.
GTPase-activating proteins are required to terminate signaling by Rap1, a small guanine nucleotide-binding protein that controls integrin activity and cell adhesion. Recently, we identified Rap1GAP2, a GTPase-activating protein of Rap1 in platelets. Here we show that 14-3-3 proteins interact with phosphorylated serine 9 at the N terminus of Rap1GAP2. Platelet activation by ADP and thrombin enhances serine 9 phosphorylation and increases 14-3-3 binding to endogenous Rap1GAP2. Conversely, inhibition of platelets by endothelium-derived factors nitric oxide and prostacyclin disrupts 14-3-3 binding. These effects are mediated by cGMP- and cAMP-dependent protein kinases that phosphorylate Rap1GAP2 at serine 7, adjacent to the 14-3-3 binding site. 14-3-3 binding does not change the GTPase-activating function of Rap1GAP2 in vitro. However, 14-3-3 binding attenuates Rap1GAP2 mediated inhibition of cell adhesion. Our findings define a novel crossover point of activatory and inhibitory signaling pathways in platelets.
In this study the clinical value of the method of 31P und 1 H MRI spectroscopy is analyzed in the evaluation of tumors of the liver and the cerebrum. At first 39 patients (HCC n=30, metastases of colorectal carcinomas n=9) undergoing transarterial chemoembolization (TACE) were evaluated MR tomographically with 1.5 Tesla using 31P CSI spectroscopy. Moreover, 53 patients with cerebral tumors (17 meningiomas, 11 gliomas WHO grades I-II, 6 gliomas WHO grade III, 13 gliomas WHO grade IV and 6 metastases) were evaluated 1 H spectroscopically with the ISIS technique in different echo times. The results of both groups were correlated with the histopathological findings and compared with a study group. For evaluation the area under the curve of the measurable signal intensities were calculated, the ratios were determined and statistically evaluated. In patients with livertumors undergoing TACE, the 31P spectroscopy was performed before and after each course of TACE. Pretherapeutic evaluation revealed the tumor tissue with increased PME peak, PME/ß-ATP ratio, and PME/PDE ratio. In all cases the tumor spectres were to be differentiated from the spectra of the study group. If chemoembolization was technically successful, we found an increase in the Pi peak (+90.1%) and a decrease in the ß-ATP peak (-19.1%). After each course of therapy a number of patient groups could be differentiated depending on the changes in the different peaks and ratios. A response was characterized by a decrease of the PME/ß-ATP and PME/PDE ratios and an increase of the PDE/ß-ATP ratio. In non-responders, there was no decrease of the PME/ß-ATP and PME/PDE ratios, and these ratios increased 6 weeks later. The PDE/ß-ATP ratio decreased. Constant ratios were found if a steady state of the disease was achieved. Regrowth of tumor was accompanied by elevated PME and decreased PDE peaks. With regard to the 1 H spectroscopical findings the following statements can be made: The tumor spectra can be distinctly differentiated from the study group spectres. In this respect highly significant differences for the NAA/Cho and PCr/Cho ratios can be seen. The spectra of the meningiomas can be often characterized by the missing NAA. A small peak at 2.0 ppm can probably be due to a part of healthy brain tissue in the VOI at the rim of the tumor in some of the spectra. Moreover, some of the meningiomas show Alanin at 1.47 ppm, which, however, can also be overlain by fat signal in this area. On average, the PCr peak is reduced by half with regard to the referene; Inositol can hardly be detected even with short echo times. The metastases show a decreased NAA/Cho and PCr/Cho ratio. In few cases Ins/Cho can be measured, and then below the level of the study group. Additionally, two distinct peaks could be seen at 0.9 and 1.25 ppm according to strongly increased free fatty acids. All gliomas show a reduced NAA signal. In this respect, the reduction of the NAA/Cho ratio shows a nonsignificant dependence on malignity, which can be reflected in an almost completely reduced NAA signal in glioblastomas. PCr and Ins are also decreased. With increasing malignity of the lesion the Inositol signal increases and reaches the normal values of the study group. Using 1 H spectroscopy it is possible to support the differential diagnosis of the imaging modalities. Due to its sensitivity it is possible to use the 31P spectroscopy in therapy control. In order to establish these methods in the daily routine further improvements are necessary, particularly in regard to measurement sequences, automatisms and standardized evaluation protocols.
Taphonomy and palaeoecology of Laetoli as well as Makuyuni, Arusha region in northern Tanzania
(2004)
This thesis is the result of the Hominid Corridor research Project in Tanzania since 1993 to 1995 that include Pliocene and Pleistocene localities. The localities under study include Laetoli and Manyara area in Arusha Region, northern Tanzania. The thesis has the following specific objectives: firstly, to identify taxa recovered from the studied assemblages; secondly, to underpin taphonomic history of the assemblages under study; thirdly, to elucidate further palaeoecological reconstruction of the assemblages; and finally, to examine surface fossil fauna modifications including agents of modifications either hominids or carnivores.
The Upper Laetolil Beds are dated at 3.5 million years ago (Ma) and the Ndolanya Beds are bracketed in age between 3.5 and 2.41 Ma. The Naibadad Beds, also from Laetoli area, are date to be between 2.2 to 2.1 Ma. The Naibadad Beds are correlated with the base of Bed I at Olduvai Gorge. There are so far no absolute dates for Manyara assemblages. Based on biostratigraphic correlation, the younger overlying unit, the Upper Manyara Beds are estimated to belong to Later Pleistocene and the Lower Manyara Beds are estimated to belong to Early Pleistocene. The Upper Manyara Beds are correlated to the age of Bed III at Olduvai Gorge, while the Lower Manyara Beds are interpreted to span the same contemporaneity with the upper part of Bed II at Olduvai Gorge.
At Laetoli localities, terrestrial mammals while localities from Manyara besides terrestrial mammals dominate fauna; they include aquatic species such as fish, crocodiles and hippopotamus. The main families recovered from Upper Laetolil Beds complement those already recovered from former research works by other workers. This is also true for the younger overlying stratigraphic horizon, the Upper Ndolanya Beds. Thus, mammalian families recovered from Upper Laetolil Beds include Bovidae, Carnivora, Elephantidae, Equidae, Lagomorpha, Suidae, Rodentia, Hominoidea and Rhenocerotidae. Remains of an invertebrate, Gastropoda were also recovered. For Upper Ndolanya Beds include almost the same families recovered from Upper Laetolil Beds, but based on former recovery of fossil fauna, these Beds outnumber greatly the Upper Laetolil Beds in bovid composition by 20 per cent. Such a change in species composition is noticed also from South African localities and East African localities such as the East Turkana. This is interpreted to be due to climatic change drier environments that included species adapted to such palaeoclimates.
For the first time, our team has been able to retrieve specimens identifiable to taxa, a pattern that not possible from previous workers who claimed to have recovered too sparse specimens to be identifiable to any taxon.
The Upper Manyara Beds as well as Lower Manyara taxonomic composition include aquatic species besides the large terrestrial mammalian fauna retrieved from there. In due regard, the former horizon is attributed to have affinity with Olduvai Bed III components and the latter, older horizon, is attributed to have affinity with upper parts of Bed II times at Olduvai Gorge. The Lower Manyara Beds can be said to have, in relative terms, affinity to species recovered from site RC 11 of the Chiwondo Beds, Malema region in northern Malawi, although the former site may be equable to the terminal age of the latter locality.
Fossil hominid remains; attributable to genus Homo and possibly species Homo erectus have been recovered from two localities, Mk 2 and Mk, along Lower Manyara Beds. On the other hand, stone tools, identified to belong to the Acheulian industrial technocomplex, were recovered from site Mk 4.
All of fossil fauna from Laetoli sites were mostly exfoliated and there shows to be little effect in terms of hydrodynamic sorting of the fossil bones. However, intense carnivore activity is witnessed due to the almost one to one ratio of proximal to distal ends. This is also true for the Lower Manyara Beds locality. Through examination of surface modifications of the fossil fauna, it has been established that there was carnivore consumption of ungulates. There is no evidence of hominid involvement that has to be testified by stone tools.
In online video games toxic interactions are very prevalent and often
even considered an imperative part of gaming.
Most studies analyse the toxicity in video games by analysing the messages that are sent during a match, while only a few focus on other interactions. We focus specifically on the in-game events to try to identify toxic matches, by constructing a framework that takes a list of time-based events and projects them into a graph structure which we can then analyse with current methods in the field of graph representation learning.
Specifically we use a Graph Neural Network and Principal Neighbour-
hood Aggregation to analyse the graph structure to predict the toxicity of a match.
We also discuss the subjectivity behind the term toxicity and why the
process of only analysing in-game messages with current state-of-the-art NLP methods isn’t capable to infer if a match is perceived as toxic or not.
Über einen Schriftsteller und seinen Körper : Aris Fioretos wird neuer Frankfurter Poetikdozent
(2024)
Der unter der Ägide der Freunde und Förderer der Goethe-Universität von der Paul Ehrlich-Stiftung ausgelobte Paul Ehrlich-und-Ludwig Darmstaedter-Preis ist die renommierteste Auszeichnung, die in Deutschland für medizinische Forschung verliehen wird. Den mit 120.000 Euro dotierten Preis nahm in der Frankfurter Paulskirche in diesem Jahr der Arzt und Immunologe Prof. Dennis L. Kasper (81) von der Harvard Medical School entgegen. Er hat die ersten Wörter der biochemischen Sprache entdeckt, mit der Darmbakterien unserem Immunsystem zu einer gesunden Entwicklung verhelfen. Den mit 60.000 Euro dotierten Nachwuchspreis erhielt der Chemiker Dr. Johannes Karges (31) von der Ruhr-Universität Bochum für die Entwicklung eines Verfahrens zur ferngesteuerten Tumortherapie.