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Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection
No full textNeutralising antibodies against the SARS-CoV-2 spike (S) protein are major determinants of protective immunity, though insufficient antibody responses may cause the emergence of escape mutants. We studied the humoral immune response causing intra-host evolution in a B-cell depleted, haemato-oncologic patient experiencing clinically severe, prolonged SARS-CoV-2 infection with a virus of lineage B.1.177.81. Following bamlanivimab treatment at an early stage of infection, the patient developed a bamlanivimab-resistant mutation, S:S494P. After five weeks of apparent genetic stability, the emergence of additional substitutions and deletions within the N-terminal domain (NTD) and the receptor binding domain (RBD) of S was observed. Notably, the composition and frequency of escape mutations changed in a short period with an unprecedented dynamic. The triple mutant S:Delta141-4 E484K S494P became dominant until virus elimination. Routine serology revealed no evidence of an antibody response in the patient. A detailed analysis of the variant-specific immune response by pseudotyped virus neutralisation test, surrogate virus neutralisation test, and immunoglobulin-capture enzyme immunoassay showed that the onset of an IgM-dominated antibody response coincided with the appearance of escape mutations. The formation of neutralising antibodies against S:Delta141-4 E484K S494P correlated with virus elimination. One year later, the patient experienced clinically mild re-infection with Omicron BA.1.18, which was treated with sotrovimab and resulted in an increase in Omicron-reactive antibodies. In conclusion, the onset of an IgM-dominated endogenous immune response in an immunocompromised patient coincided with the appearance of additional mutations in the NTD and RBD of S in a bamlanivimab-resistant virus. Although virus elimination was ultimately achieved, this humoral immune response escaped detection by routine diagnosis and created a situation temporarily favouring the rapid emergence of various antibody escape mutants with known epidemiological relevance
Characterizing Foveal Hypoplasia Using Optical Coherence Tomography Angiography: Evaluation of Microvascular Abnormalities and Clinical Significance
No full textThis study aimed to evaluate foveal avascular zone (FAZ) features and macular flow density (FD) in various retinal layers in a cohort of patients with foveal hypoplasia (FH) using optical coherence tomography angiography (OCTA), in order to characterize microvascular abnormalities and explore their potential clinical significance. FAZ parameters and FD, as well as retinal thickness and volume values were analyzed and compared between patients with FH and an age- and gender-matched control cohort. Correlations between disease severity and visual acuity (VA), as well as between disease severity and FAZ features were evaluated. A total of 19 eyes with FH and 19 control eyes were included. The study group showed significantly higher FD values in the foveal sectors of the superficial and deep capillary plexus compared to controls. FAZ area, perimeter, and acircularity index (ACI) were noticeably altered in eyes with FH; however, they did not correlate with disease severity. Visual acuity was negatively correlated with disease severity. The results of this study provide evidence of altered microvasculature architecture specifically in the foveal sectors of patients with FH. The higher FD values in the foveal sectors of FH patients suggest a potential compensatory response of the retinal microvasculature. FAZ parameters and FD values of the foveal sectors could be used as part of an OCTA-based grading system in FH patients
Cloxyquin activates hTRESK by allosteric modulation of the selectivity filter
No full textThe TWIK-related spinal cord K+ channel (TRESK, K2P18.1) is a K2P channel contributing to the maintenance of membrane potentials in various cells. Recently, physiological TRESK function was identified as a key player in T-cell differentiation rendering the channel a new pharmacological target for treatment of autoimmune diseases. The channel activator cloxyquin represents a promising lead compound for the development of a new class of immunomodulators. Identification of cloxyquin binding site and characterization of the molecular activation mechanism can foster the future drug development. Here, we identify the cloxyquin binding site at the M2/M4 interface by mutational scan and analyze the molecular mechanism of action by protein modeling as well as in silico and in vitro electrophysiology using different permeating ion species (K+ / Rb+). In combination with kinetic analyses of channel inactivation, our results suggest that cloxyquin allosterically stabilizes the inner selectivity filter facilitating the conduction process subsequently activating hTRESK
Continuous beam scanning by transverse mode-locking in a Pound-Drever-Hall stabilized resonator
No full textMode-locking, i.e., the phase-locked superposition of resonator modes, enables ultrafast laser beam dynamics. Here, high-speed beam scanning at 79.6 MHz is achieved by generating sets of phase-locked transverse resonator modes. Such transverse mode-locked (TML) beams are obtained via conversion in an empty, optical resonator from incident longitudinal mode-locked beams. In this conversion scheme the modal power and phase distributions can be controlled to alter the dynamics of the emerging scanning beams. It is shown, that the Pound-Drever-Hall stabilization scheme is applicable to compound TML resonances and it is used to maintain resonance between the incident beam’s spectral components and the transverse mode resonances. This way, TML states are reliably generated and continuously emitted
Co-Usage of Media in Germany:Report of the years 2017 to 2021
No full textDie Studie untersucht, wie Massenmedien in Deutschland gemeinsam mit anderen Menschen genutzt werden. Der Bericht beschreibt die Co-Nutzung auf der Grundlage einer laufenden Befragungsstudie an der Universität Münster. Mehr als 50% der Fernsehnutzung, mehr als 30% der Radio- und Spielenutzung und zwischen 10% und 20% der Zeitungs-, Buch- und Internetnutzung sind gemeinsame Nutzungen. Wenn die Befragten in der Woche vor der Befragung Massenmedien gemeinsam nutzten, dann geschah dies mit unterschiedlichen Personengruppen: Das Fernsehen wurde zu 50% mit dem Partner, zu 40% mit der Familie und zu 30% mit Freunden gemeinsam genutzt. Beim Radio waren es 40% mit dem Partner, 25% mit der Familie und 25% mit Freunden, beim Internet 40% mit dem Partner, 35% mit der Familie und 35% mit Freunden, bei Spielen 10% mit dem Partner, 10% mit der Familie und 20% mit Freunden, bei Zeitungen 30% mit dem Partner und 25% mit Freunden und bei Büchern 20% mit dem Partner, der Familie und mit Freunden.The study analyses how mass media in Germany are used together with other people. The report describes co-use on the basis of an ongoing survey study at the University of Münster. More than 50% of television use, more than 30% of radio and games use and between 10% and 20% of newspaper, book and internet use are shared use. If the respondents used mass media together in the week before the survey, this was with different groups of people: Television was shared 50% with a partner, 40% with family and 30% with friends. In the case of radio, 40% were shared with their partner, 25% with family and 25% with friends; for the Internet, 40% with their partner, 35% with family and 35% with friends; for games, 10% with their partner, 10% with family and 20% with friends; for newspapers, 30% with their partner and 25% with friends; and for books, 20% with their partner, family and friends
Literarische Darstellungen grausamer oder ungebräuchlicher Strafen
No full textIn weltgeschichtlicher Perspektive widerspricht das moderne Verbot grausamer und ungebräuchlicher Strafen einer uralten, kosmologisch, theologisch, kulturell, moralisch, ästhetisch und nicht zuletzt auch literarisch gestützten Tradition, die derartige Strafen gut geheißen, wenn nicht gar gefordert hatte. Fast durchgängig wurden grausame und auch ungebräuchliche Strafen in der gesamten Rechts- und Kulturgeschichte zumindest für bestimmte Fälle als gerechtfertigt und notwendig angesehen. Grausame oder ungewöhnliche Strafen stellen seit je her einen faszinierenden, häufig und vielfältig angesprochenen Gegenstand der Literatur dar, wobei die affektiven Reaktionen von Befriedigung bis Abscheu reichen. Literatur und Kultur im Allgemeinen erweisen sich in ihrem Umgang mit grausamen und ungebräuchlichen Strafen oft als urtümlicher und weniger liberal oder rational als die einschlägigen Normen des modernen Rechts.In world-historical terms, the modern liberal prohibition against cruel and unusual punishment runs counter to an age-old, cosmological, theological, cultural, moral, aesthetic, and literary approval of and investment in such punishment. For most of the history of law and culture, cruel and unusual punishment has been seen as, at least in part, right.
Cruel and unusual punishment is a longstanding, widespread, and extremely commonplace feature of literary works, and within those works carries various and complicated affective and visceral power ranging from glee to revulsion. Literature and culture are often less liberal and rational in their approach to cruel and unusual punishment and more primal than modern rights codes
Validation of the IWATE Criteria in Robotic-Assisted Liver Resections
No full textBackground/Objectives: The IWATE criteria are well-established as a helpful tool to preoperatively estimate the difficulty and perioperative outcome of laparoscopic liver resections. We evaluated the relationship between the IWATE criteria and the perioperative outcomes in robotic-assisted liver resections (RARLs). Methods: We retrospectively analyzed the data of 58 patients who underwent robotic-assisted liver surgery at our center between July 2019 and April 2023. The operative difficulty of every patient was graded according to the IWATE criteria and compared to the perioperative outcome. Results: The median operation time was 236.5 min (range 37–671 min), and the median length of stay was 6 days (range 3–37 min). The majority had no complications (65.5%; n = 38), 18 (31.0%) patients suffered from mild complications (CD ≤ 3A) and 2 patients (3.4%) suffered from relevant complications (CD ≥ 3B). We observed no deaths within 30 postoperative days. The surgery time, postoperative ICU stay and perioperative blood transfusions increased significantly with a higher difficulty level (p = < 0.001; p < 0.001; p = 0.016). The length of stay, conversion to open surgery (n = 2) and complication rate were not significantly linked to the resulting IWATE group. Conclusions: The IWATE criteria can be implemented in robotic-assisted liver surgery and can be helpful in preoperatively estimating the difficulty of robotic liver resections. Whether there is a “robotic effect” in minimally invasive liver resections has to be further clarified. The IWATE criteria can help to develop curricula for robotic training
Vor allem der Wille zählt – wie die Verkehrswende gelingen kann:Interview mit Prof. Dr. Gernot Sieg
No full textDas geplante 49-Euro-Ticket der Bundesregierung für den öffentlichen Nahverkehr kann nicht darüber hinwegtäuschen, dass die deutsche Verkehrswende eher schleppend vorangeht. Woran liegt das, und welche Lösungsansätze sollten verfolgt werden? Welche Schwachstellen hat der Bahnverkehr in Deutschland? War das 9-Euro-Ticket eine sinnvolle Maßnahme der Bundesregierung? All diese Fragen beantwortet der Verkehrwissenschaftler Prof. Dr. Gernot Sieg im Podcast
Was kann phänomenologische Ästhetik leisten? Eine metaästhetische Untersuchung zu Spezifik, Problemen und Potentialen einer Strömung philosophischer Ästhetik im deutschsprachigen Raum
No full textIn der vorliegenden metaästhetischen Arbeit wird exemplarisch anhand von ausgewählten deutschsprachigen phänomenologischen Positionen aufgezeigt, was phänomenologische Ästhetik leisten kann. D.h., dass der Frage nachgegangen wird, wie anschlussfähig Ansätze innerhalb der Strömung der phänomenologischen Ästhetik vor dem Hintergrund aktueller Debatten innerhalb der philosophischen Ästhetik bzw. Kunstphilosophie und der von ihr ausgehenden bzw. formulierbaren Kritik sind. Innerhalb der Arbeit zeigt sich, dass die Stärken der phänomenologischen Ästhetik am besten zur Geltung kommen, wenn das Bewusstsein für systematische Begriffsarbeit ausgefeilt und eine Offenheit gegenüber dem analytisch geprägten Diskurs in der philosophischen Ästhetik ausgebaut wird
Weaving CEFR Scales into Rubrics for EFL Writing Assessment in Indonesia
No full textDiese Studie untersuchte die Erstellung einer geeigneten Bewertungsskala, die aus den CEFR-Skalen gewebt wurde und zur EFL-Schreibbewertung in Indonesien passt. Zu diesem Zweck wurden die „Can-Do-Aussagen“ in den CEFR-Deskriptoren an die entwickelte Bewertungsskala angepasst. Diese Studie ergab drei Hauptergebnisse mit einem gemischten qualitativen und quantitativen Ansatz. Das erste war das Modell einer Bewertungsskala für die schriftliche Beurteilung, die von den CEFR-Skalen übernommen wurde und aus Inhalts-, Organisations-, Grammatik-, Wortschatz- und Mechanikkomponenten besteht. Die Standardisierung der Komponenten, das Niveau und die Gewichtung der entwickelten Bewertungsskala basierten auf dem EFL-Schreibbewertungskontext. Darüber hinaus kam es nach Verwendung der entwickelten Bewertungsskala zu einer signifikanten Verbesserung von einem moderaten auf ein starkes Niveau der Inter-Bewerter-Zuverlässigkeit, und die Übereinstimmung zwischen den Bewertern in Bezug auf die Intra-Bewerter-Zuverlässigkeit war stark. Schließlich waren die Reaktionen der Bewerter insgesamt positiv, als es um die Umsetzung der Bewerterschulung ging.This study investigated the production of a proper rating scale weaved from the CEFR scales that fit the EFL writing assessment in Indonesia. For this purpose, the “can-do statements” in the CEFR descriptors were adapted to the developed rating scale. This study had three main findings using a mixed qualitative and quantitative approach. The first was the model of a rating scale for writing assessment adopted from the CEFR scales, which consists of content, organization, grammar, vocabulary, and mechanics components. The standardization of the components, the level, and the weight of the developed rating scale were based on the EFL writing assessment context. Further, a significant improvement occurred from a moderate to a strong level in the inter-rater reliability after using the developed rating scale, and the agreement among raters in intra-rater reliability was strong. Finally, the raters’ responses were overall positive when discussing the implementation of the rater training