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Microbial rhodopsins are omnipresent on Earth, however the vast majority of them remain uncharacterized. Here we describe a new rhodopsin group from cold-adapted organisms and cold environments, such as glaciers, denoted as CryoRhodopsins (CryoRs). Our data suggest that CryoRs have dual functionality switching between inward transmembrane proton translocation and photosensory activity, both of which can be modulated with UV light. CryoR1 exhibits two subpopulations in the ground state, which upon light activation lead to transient photocurrents of opposing polarities. A distinguishing feature of the group is the presence of a buried arginine residue close to the cytoplasmic face of its members. Combining single-particle cryo-electron microscopy and X-ray crystallography with the rhodopsin activation by lit, we demonstrate that the arginine stabilizes a UV-absorbing intermediate of an extremely slow CryoRhodopsin photocycle. Together with extensive spectroscopic characterization, our investigations on CryoR1 and CryoR2 proteins reveal mechanisms of photoswitching in the newly identified group and demonstrate principles of the adaptation of these rhodopsins to low temperatures.Microbial rhodopsins are omnipresent on Earth, however the vast majority of them remain uncharacterized. Here we describe a new rhodopsin group from cold-adapted organisms and cold environments, such as glaciers, denoted as CryoRhodopsins (CryoRs). Our data suggest that CryoRs have dual functionality switching between inward transmembrane proton translocation and photosensory activity, both of which can be modulated with UV light. CryoR1 exhibits two subpopulations in the ground state, which upon light activation lead to transient photocurrents of opposing polarities. A distinguishing feature of the group is the presence of a buried arginine residue close to the cytoplasmic face of its members. Combining single-particle cryo-electron microscopy and X-ray crystallography with the rhodopsin activation by light, we demonstrate that the arginine stabilizes a UV-absorbing intermediate of an extremely slow CryoRhodopsin photocycle. Together with extensive spectroscopic characterization, our investigations on CryoR1 and CryoR2 proteins reveal mechanisms of photoswitching in the newly identified group and demonstrate principles of the adaptation of these rhodopsins to low temperatures.
EF-P and its paralog EfpL (YeiP) differentially control translation of proline containing sequences
(2024)
Polyproline sequences (XPPX) stall ribosomes, thus being deleterious for all living organisms. In bacteria, translation elongation factor P (EF-P) plays a crucial role in overcoming such arrests. 12% of eubacteria possess an EF-P paralog – YeiP (EfpL) of unknown function. Here, we functionally and structurally characterize EfpL from Escherichia coli and demonstrate its yet unrecognized role in the translational stress response. Through ribosome profiling, we analyzed the EfpL arrest motif spectrum and discovered additional stalls beyond the canonical XPPX motifs at single-proline sequences (XPX), that both EF-P and EfpL can resolve. Notably, the two factors can also induce pauses. We further report that, contrary to the housekeeping EF-P, EfpL can sense the metabolic state of the cell, via lysine acylation. Together, our work uncovers a new player in ribosome rescue at proline-containing sequences, and provides evidence that co-occurrence of EF-P and EfpL is an evolutionary driver for higher bacterial growth rates.
Coarse-grained modeling has become an important tool to supplement experimental measurements, allowing access to spatio-temporal scales beyond all-atom based approaches. The GōMartini model combines structure- and physics-based coarse-grained approaches, balancing computational efficiency and accurate representation of protein dynamics with the capabilities of studying proteins in different biological environments. This paper introduces an enhanced GōMartini model, which combines a virtual-site implementation of Gō models with Martini 3. The implementation has been extensively tested by the community since the release of the new version of Martini. This work demonstrates the capabilities of the model in diverse case studies, ranging from protein-membrane binding to protein-ligand interactions and AFM force profile calculations. The model is also versatile, as it can address recent inaccuracies reported in the Martini protein model. Lastly, the paper discusses the advantages, limitations, and future perspectives of the Martini 3 protein model and its combination with Gō models.
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.
Evidence-based and comprehensible health information is a key element of evidence-based medicine and public health. The goal is informed decision-making based on realistic estimations of health risks and accurate expectations about benefits and harms of interventions. In Germany, standards of evidence-based risk information were poorly followed during the COVID-19 pandemic. Frequently, public information was biased, fragmentary and misleading. Pandemic-related threat scenarios induced emotional distress and unnecessary anxiety. A systematic and comprehensive evaluation of the pandemic measures is crucial, but still pending in Germany. A critical analysis of risk communication by experts, politicians and the media during the pandemic should be a key element of the evaluation process. Evaluation of decision making and media reporting during the pandemic should improve preparedness for future crises.
Background: Urachal cancer (UrC) is a rare disease with limited availability of representative incidence and clinical data. Although, the prevalence is accounting for less than 1% of bladder tumors, the 5-year survival rate is around only 50% for patients with resectable tumors, and even worse for patients with metastatic disease. Due to the lack of comprehensive prospective studies, our current knowledge of UrC is still limited.
Objective: The present study aimed to summarize the available registry-based studies with unselected UrC patients to evaluate its incidence and clinicopathological characteristics.
Material and methods: We conducted a systematic literature search of registry-based UrC publications on the 15th of May 2023 in 5 databases, which identified 4,748 publications. After duplicate removal and selection by 2 independent investigators, 6 publications proved to be appropriate for the final meta-analysis. Estimated incidence and clinicopathological parameters were extracted.
Results: Estimated incidence ranged between 0.022 and 0.060/ 100.000 person-years, with the highest occurrence in Japan and the lowest in Canada, while the random effect model calculated an overall incidence rate of 0.04 (95%CI: 0.03–0.05) 100.000 person-years. The median age at first diagnosis was 60 years (range: 58–64). The female to male ratio was 2:3. Lymph node or distant metastases were present in 9% and 14% of patients. The predominant tumour type was adenocarcinoma (86%) followed by urothelial carcinoma (12%) and squamous cell carcinoma (2%). The 5-year survival rate was 51.0% with 95%CI: 45.2–57.4.
Conclusions: Our study provides an up-to-date comparison of estimated incidence rates between 6 countries of 3 continents based on rigorously selected registry-based studies. The results suggest low incidence rates for UrC with considerable geographic differences. The present meta-analysis provides unbiased registry-based data on the incidence, clinicopathological parameters and survival of UrC.
Highlights
• Students have limited concerns about privacy in learning analytics (LA).
• Students' privacy concerns in LA vary across countries.
• Culture shapes students' privacy concerns in LA.
• Power distance, uncertainty avoidance and masculinity affect privacy concerns in LA.
• Cultural values should be considered in LA privacy management.
Abstract
Applications of learning analytics (LA) can raise concerns from students about their privacy in higher education contexts. Developing effective privacy-enhancing practices requires a systematic understanding of students’ privacy concerns and how they vary across national and cultural dimensions. We conducted a survey study with established instruments to measure privacy concerns and cultural values for university students in five countries (Germany, South Korea, Spain, Sweden, and the United States; N = 762). The results show that students generally trusted institutions with their data and disclosed information as they perceived the risks to be manageable even though they felt somewhat limited in their ability to control their privacy. Across the five countries, German and Swedish students stood out as the most trusting and least concerned, especially compared to US students who reported greater perceived risk and less control. Students in South Korea and Spain responded similarly on all five privacy dimensions (perceived privacy risk, perceived privacy control, privacy concerns, trusting beliefs, and non-self-disclosure behavior), despite their significant cultural differences. Culture measured at the individual level affected the antecedents and outcomes of privacy concerns. Perceived privacy risk and privacy control increase with power distance. Trusting beliefs increase with a desire for uncertainty avoidance and lower masculinity. Non-self-disclosure behaviors rise with power distance and masculinity and decrease with more uncertainty avoidance. Thus, cultural values related to trust in institutions, social equality and risk-taking should be considered when developing privacy-enhancing practices and policies in higher education.
Interferon-stimulated gene-15 (ISG15) is an interferon-induced protein with two ubiquitin-like (Ubl) domains linked by a short peptide chain, and the conjugated protein of the ISGylation system. Similar to ubiquitin and other Ubls, ISG15 is ligated to its target proteins with a series of E1, E2, and E3 enzymes known as Uba7, Ube2L6/UbcH8, and HERC5, respectively. Ube2L6/UbcH8 plays a literal central role in ISGylation, underscoring it as an important drug target for boosting innate antiviral immunity. Depending on the type of conjugated protein and the ultimate target protein, E2 enzymes have been shown to function as monomers, dimers, or both. UbcH8 has been crystalized in both monomeric and dimeric forms, but the functional state is unclear. Here, we used a combined approach of small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy to characterize UbcH8′s oligomeric state in solution. SAXS revealed a dimeric UbcH8 structure that could be dissociated when fused with an N-terminal glutathione S-transferase molecule. NMR spectroscopy validated the presence of a concentration-dependent monomer-dimer equilibrium and suggested a backside dimerization interface. Chemical shift perturbation and peak intensity analysis further suggest dimer-induced conformational dynamics at ISG15 and E3 interfaces - providing hypotheses for the protein′s functional mechanisms. Our study highlights the power of combining NMR and SAXS techniques in providing structural information about proteins in solution.
A powerful technique to distinguish the enantiomers of a chiral molecule is the Coulomb Explosion Imaging (CEI). This technique allows us to determine the handedness of a single molecule. In CEI, the molecule becomes charged by losing many electrons in a very short period of time by interacting with the light. The repulsion forces between the positive charged particles of the molecule leads the molecule to break into parts-fragments. By measuring the three vector momentum of (at least) four fragments, the handedness observable can be determined. In this thesis, CEI is induced by absorption of a single high energy photon, which creates an inner-shell hole (K shell) of the molecule. The subsequent cascade of Auger decays lead to fragmentation. We decided to work with the formic acid molecule in this thesis. Two different experiments were conducted. The first experiment focused on exciting electrons to different energy states, while the second experiment focused on extracting directly a photoelectron to the continuum and measure the angular distribution of the photoelectron in the molecular frame. The primary goal was to search for chiral signal in a pure achiral planar molecule under the previous electron processes. The results of these findings were further implemented to two more molecules.
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.
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.
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 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.
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.
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 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.
In this brief discussion, I reflect on the significance of using the category of the global south for reconfiguring the scope of the history of knowledge. While I see this as a productive paradigm shift that has already given rise to mould-breaking works, I focus here on the cross-hemispheric histories of extractive capitalism and how both colonial violence and anticolonial resistance have shaped knowledge-making. I argue that thinking through 'entangled ecologies' can be a tool for countering the existing conceptual order, which has led to the north-south division in the first place. Attending to epistemic and ontological entanglements would enable us to ask better and deeper questions about the increasingly complex interconnections across human and nonhuman worlds, especially given the planetary crises we face today.
This chapter is a journey of thought exploring decolonial critique as a situated practice while thinking through exilic consciousness and its constitutive conditions. I begin by reflecting on decolonialities to gesture toward varied forms of decolonial projects that need to be situated, given that each location generates different sets of questions/problems that demand different answers. In this way, I reconfigure the exilic condition, and the space of displacement in general, as a plurilingual space that unsettles various colonial forms of epistemic monolingualism predicated on the selfsufficiency of thought. To this end, I reflect on the potentiality of exilic consciousness to generate decolonial critique when thinking from/about the Global South. Finally, this chapter demonstrates the significance of acknowledging the diverse locations and trajectories of decolonial critique and the plurality of thought embedded within the exilic intellectual formation that can potentially undo colonial forms of knowledge-making and being in the world.
In this reflection piece, I look at the feminist artistic landscape emerging in Berlin with its growing, diverse migrant community. I examine the ways in which women* artists challenge the imposed notions of their migrant status in the city and their states of belonging within it. I demonstrate this through two feminist initiatives I have been involved in that aim to amplify the voices of women* artists whose creative practices disrupt carefully constructed frameworks relating to borders of inclusion and exclusion. I argue that the artistic practices of women* in these networks are killjoy because they unapologetically get in the way, dismantling carefully constructed frameworks that delineate borders of inclusion and exclusion. By reflecting on homemaking practices in exile, I exemplify how feminisms from the global south decentralize claims to truth by taking the means of production into their own hands. By framing the chapter around the recent protests in Berlin unfolding in solidarity with the feminist revolution in Iran, I reveal the possible limits of such actions when they do not embrace intersectionality. Ultimately, I propose to invest in feminist artistic practices that destabilize exclusionary politics by creating visibility and bridging theory and practice.
The ICH M13A draft bioequivalence guideline allows the exclusion of very low plasma profiles from the statistical evaluation in exceptional cases, i.e., if such phenomenon occurs due to non-compliance of subjects (not swallowing the product). Moreover, the draft ICH guideline requests additional bioequivalence studies for medicinal products with pH-dependent solubility after concomitant administration of gastric pH modifying preparations, e.g., proton pump inhibitors. Both regulations are scientifically sound, however, would need further specification. Main problem in this context is that compounds with very low solubility and slow intrinsic dissolution in the intestinal environment will cause significant bioavailability problems if their solid oral dosage forms are emptied from the stomach undisintegrated. Also very low plasma profiles may result under these circumstances. Such cases can occur accidentally and are not resultant of non-compliance. Thus, limitation for one case per study only as suggested in the guideline is not justified.