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Abstract Background Imaging-based assessment of sarcopenia is a well-validated prognostic tool for patients with chronic liver disease. However, little is known about its value in patients with primary sclerosing cholangitis (PSC). This cross-sectional study aimed to investigate the predictive value of the cross-sectional imaging-based skeletal muscle index (SMI) for transplant-free survival (TFS) in patients with PSC. Methods A total of 95 patients with PSC who underwent abdominal cross-sectional imaging between 2008 and 2022 were included in this retrospective study. SMI was measured at the third lumbar vertebra level (L3-SMI). The cut-off values to define sarcopenia were 10% at 12 months, which is used as MELD standard exception (SE) criterion in Eurotransplant (in Germany only until September 2023), was not significantly associated with TFS in the multivariate Cox regression analysis (HR = 1.417; p = 0.330). Substitution of BMI reduction with L3-SMI in the German SE criteria improved the predictive accuracy of TFS compared to the established SE criteria (multivariable Cox regression analysis: HR = 4.007, p

Abstract Background Peritoneal dialysis (PD) remains underutilised in Germany, prompting the initiation of the Sustainable Intensification of Peritoneal Dialysis in Schleswig–Holstein (SKIP-SH) project. The SKIP-SH cohort study aims to demonstrate the presumed benefits of PD, including enhanced quality of life and reduced healthcare personnel requirements, and to generate data to strengthen the use of PD. Methods The prospective SKIP-SH cohort study recruits patients with advanced chronic kidney disease (CKD) and their caregivers. Comprehensive data, including demographic information, medical history, clinical course, laboratory data, and quality-of-life assessments, are collected. Additionally, biomaterials will be obtained. Primary study objectives are documenting the clinical course and complications, time on therapy for new dialysis patients, reasons influencing treatment modality choices, circumstances at the initiation of dialysis, and quality of life for patients with CKD and their caregivers. The collected biomaterials will serve as a basis for further translational research. Secondary objectives include identifying factors impacting disease-related quality of life, clinical complications, and therapy dropout, estimating ecological footprints, and evaluating healthcare costs and labour time for initiating and sustaining PD treatment. Discussion PD is notably underutilised in Germany. The current therapy approach for advanced CKD often lacks emphasis on patient-focused care and quality-of-life considerations. Furthermore, adequate explorative research programs to improve our knowledge of mechanisms leading to disease progression and therapy failure in PD patients are scarce. The overarching goal of the SKIP-SH cohort study is to address the notably low PD prevalence in Germany whilst advocating for a shift towards patient-focused care, quality-of-life considerations, and robust translational research. Trial registration This study was registered with the German trial registry (Deutsches Register klinischer Studien) on November 7, 2023, under trial number DRKS00032983.

Abstract Research on the impact of auditory information on visual anticipation in tennis suggests that the intensity of racket-ball-contact sounds systematically biases estimates of the ball’s speed, thereby influencing anticipatory judgments. Here we examined whether the effect of auditory information on visual anticipation is dependent on the sport-specific context in two separate experiments. In Exp. 1, participants watched short videos of tennis rallies that were occluded at racket-ball-contact. Racket-ball-contact sounds of the final shot were either present or absent. Participants faced different tasks in two counterbalanced blocks: In one block they estimated the ball’s speed; in the other block they indicated the ball’s landing location. Results showed that participants estimated longer ball flight trajectories and higher ball speeds in the sound present condition than in the sound absent condition. To probe whether this effect is dependent on the sport-specific context, Exp. 2 introduced an abstract (i.e., context-free) version of the previous stimuli. Based on the ball locations in the original videos used in Exp. 1, we rendered new videos that displayed only a moving circle against a blank background. Sine tones replaced the original racket-ball contact sounds. Results showed no impact of sound presence on location anticipation judgments. However, similar to Exp. 1, object speeds were judged to be faster when the final sound was present. Together, these findings suggest that the impact of auditory information on anticipation does not seem to be driven by sound alone, but to be moderated by contextual information.

Abstract Visual working memory (VWM) is typically measured using arrays of two-dimensional isolated stimuli with simple visual identities (e.g., color or shape), and these studies typically find strong capacity limits. Science, technology, engineering and mathematics (STEM) experts are tasked with reasoning with representations of three-dimensional (3D) connected objects, raising questions about whether those stimuli would be subject to the same limits. Here, we use a color change detection task to examine working memory capacity for 3D objects made up of differently colored cubes. Experiment 1a shows that increasing the number of parts of an object leads to less sensitivity to color changes, while change-irrelevant structural dimensionality (the number of dimensions into which parts of the structure extend) does not. Experiment 1b shows that sensitivity to color changes decreases similarly with increased complexity for multipart 3D connected objects and disconnected 2D squares, while sensitivity is slightly higher with 3D objects. Experiments 2a and 2b find that when other stimulus characteristics, such as size and visual angle, are controlled, change-irrelevant dimensionality and connectivity have no effect on performance. These results suggest that detecting color changes on 3D connected objects and on displays of isolated 2D stimuli are subject to similar set size effects and are not affected by dimensionality and connectivity when these properties are change-irrelevant, ruling out one possible explanation for scientists’ advantages in storing and manipulating representations of complex 3D objects.

Jochheim et al report an alternative, dimeric form of the coronavirus SARS-CoV-2 RNA dependent RNA polymerase (RdRp), which is used to replicate and transcribe its genome. They resolve its structure at 5.5 Å resolution and speculate that the dimer facilitates template switching during production of sub-genomic RNAs.

Maturation of the ribosomal peptidyl transferase center (PTC) is mediated by universally conserved GTPases. Here, cryo-EM structures of mitochondrial ribosomal large subunit assembly intermediates and of mature ribosomes offer insight into the roles of several assembly factors, including GTPBP6’s role in both ribosome biogenesis and recycling.

Abstract In co-located, multi-user settings such as multi-touch tables, user interfaces need to be accessible from multiple viewpoints. In this project, we investigated how this goal can be achieved for depictions of data in bar graphs. We designed a laboratory task in which participants answered simple questions based on information depicted in bar graphs presented from differently rotated points of view. As the dependent variable, we measured differences in response onsets relative to the standard viewpoint (i.e., upright graphs). In Experiment 1, we manipulated graph and label orientation independently of each other. We observed that rotations of the labels rather than rotations of the graph itself pose a challenge for accessing depicted information from rotated viewpoints. In Experiment 2, we studied whether replacing word labels with pictographs could overcome the detrimental effects of rotated labels. Rotated pictographs were less detrimental than rotated word labels, but performance was still worse than in the unrotated baseline condition. In Experiment 3, we studied whether color coding could overcome the detrimental effects of rotated labels. Indeed, for multicolored labels, the detrimental effect of label rotation was in the negligible range. We discuss the implications of our findings for the underlying psychological theory as well as for the design of depicted statistical information in multi-user settings.

Abstract The cognitive load of many everyday life tasks exceeds known limitations of short-term memory. One strategy to compensate for information overload is cognitive offloading which refers to the externalization of cognitive processes such as reminder setting instead of memorizing. There appears to be remarkable variance in offloading behavior between participants which poses the question whether there is a common factor influencing offloading behavior across different tasks tackling short-term memory processes. To pursue this question, we studied individual differences in offloading behavior between two well-established offloading paradigms: the intention offloading task which tackles memory for intentions and the pattern copy task which tackles continuous short-term memory load. Our study also included an unrelated task measuring short-term memory capacity. Each participant completed all tasks twice on two consecutive days in order to obtain reliability scores. Despite high reliability scores, individual differences in offloading behavior were uncorrelated between the two offloading tasks. In both tasks, however, individual differences in offloading behavior were correlated with the individual differences in an unrelated short-term memory task. Our results therefore show that offloading behavior cannot simply be explained in terms of a single common factor driving offloading behavior across tasks. We discuss the implications of this finding for future research investigating the interrelations of offloading behavior across different tasks.

Remdesivir is a nucleoside analog that inhibits the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and is used as a drug to treat COVID19 patients. Here, the authors provide insights into the mechanism of remdesivir-induced RdRp stalling by determining the cryo-EM structures of SARS-CoV-2 RdRp with bound RNA molecules that contain remdesivir at defined positions and observe that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation.

Nasal polyposis often is characterized by a persistent inflammation of the sinonasal mucosa, disease recurrence after medical or surgical intervention, and asthma comorbidity. Dysregulated complement activation may contribute to immunologic alterations and disease. To date, there is only scattered knowledge on the source and regulation of the central complement factors in the pathogenesis of nasal polyps. Here, we aim to study complement signatures, especially the C3-C3aR axis, and focus on cellular sources and targets in nasal polyps. Expression of complement factors, including C3, C5, and the anaphylatoxin receptors, was analyzed in nasal polyp tissue samples, the corresponding inferior turbinates, and healthy controls using transcriptomic methods and protein measurements. Distinct patterns of complement expression were found in nasal polyps compared to controls, characterized by an increased C3 activation and an increase in C3aR-bearing cells. In contrast, no difference was shown for epithelial-dependent C3 production. Besides low intracellular C3-expression levels for lymphocytes in general, we could identify an enlarged B lymphocyte population in nasal polyps displaying high amounts of intracellular C3. Our data suggest a prominent role for the C3-C3aR-axis in nasal polyps and, for the first time, describe a B cell population containing high levels of intracellular C3, suggesting a new role of B cells in the maintenance of the inflammation by complement.

The secretome is an important mediator in the permanent process of reciprocity between cells and their environment. Components of secretome are involved in a large number of physiological mechanisms including differentiation, migration, and extracellular matrix modulation. Alteration in secretome composition may therefore trigger cell transformation, inflammation, and diseases. In the kidney, aberrant protein secretion plays a central role in cell activation and transition and in promoting renal fibrosis onset and progression. Using comparative proteomic analyses, we investigated in the present study the impact of cell transition on renal fibroblast cells secretome. Human renal cell lines were stimulated with profibrotic hormones and cytokines, and alterations in secretome were investigated using proteomic approaches. We identified protein signatures specific for the fibrotic phenotype and investigated the impact of modeling secretome proteins on extra cellular matrix accumulation. The secretion of peptidyl-prolyl cis-trans isomerase A (PPIA) was demonstrated to be associated with fibrosis phenotype. We showed that the in-vitro inhibition of PPIA with ciclosporin A (CsA) resulted in downregulation of PPIA and fibronectin (FN1) expression and significantly reduced their secretion. Knockdown studies of PPIA in a three-dimensional (3D) cell culture model significantly impaired the secretion and accumulation of the extracellular matrix (ECM), suggesting a positive therapeutic effect on renal fibrosis progression.

In complex graphical representations, the relevant information for a specific task is often distributed across multiple spatial locations. In such situations, understanding the representation requires internal transformation processes in order to extract the relevant information. However, digital technology enables observers to alter the spatial arrangement of depicted information and therefore to offload the transformation processes. The objective of this study was to investigate the use of such a representation control (i.e. the users' option to decide how information should be displayed) in order to accomplish an information extraction task in terms of solution time and accuracy. In the representation control condition, the participants were allowed to reorganize the graphical representation and reduce information density. In the control condition, no interactive features were offered. We observed that participants in the representation control condition solved tasks that required reorganization of the maps faster and more accurate than participants without representation control. The present findings demonstrate how processes of cognitive offloading, spatial contiguity, and information coherence interact in knowledge media intended for broad and diverse groups of recipients.

In order to obtain a coherent representation of the outside world, auditory and visual information are integrated during human information processing. There is remarkable variance among observers in the capability to integrate auditory and visual information. Here, we propose that visuo-perceptual capabilities predict detection performance for audiovisually coinciding transients in multi-element displays due to severe capacity limitations in audiovisual integration. In the reported experiment, we employed an individual differences approach in order to investigate this hypothesis. Therefore, we measured performance in a useful-field-of-view task that captures detection performance for briefly presented stimuli across a large perceptual field. Furthermore, we measured sensitivity for visual direction changes that coincide with tones within the same participants. Our results show that individual differences in visuo-perceptual capabilities predicted sensitivity for the presence of audiovisually synchronous events among competing visual stimuli. To ensure that this correlation does not stem from superordinate factors, we also tested performance in an unrelated working memory task. Performance in this task was independent of sensitivity for the presence of audiovisually synchronous events. Our findings strengthen the proposed link between visuo-perceptual capabilities and audiovisual integration. The results also suggest that basic visuo-perceptual capabilities provide the basis for the subsequent integration of auditory and visual information.

Recent research addresses the question whether motion information of multiple objects contributes to maintaining a selection of objects across a period of motion. Here, we investigate whether target and/or distractor motion information is used during attentive tracking. We asked participants to track four objects and changed either the motion direction of targets, the motion direction of distractors, neither, or both during a brief flash in the middle of a tracking interval. We observed that a single direction change of targets is sufficient to impair tracking performance. In contrast, changing the motion direction of distractors had no effect on performance. This indicates that target- but not distractor motion information is evaluated during tracking.

This study reports a field experiment investigating how instructional videos with and without background music contribute to the learning of examination techniques within a formal curriculum of medical teaching. Following a classroom teaching unit on the techniques for examining the knee and the shoulder joint, our participants (N = 175) rehearsed the studied techniques for either the knee or the shoulder joint with an instructional video with or without background music. As dependent measures, we collected a general questionnaire, a prediction of test performance, as well as performance on an exam-like knowledge test covering both joints. For both videos, the participants who had watched the particular video during rehearsal were more accurate in answering the corresponding questions than the participants who had seen the other video, signaling that instructional videos provide a useful tool for rehearsal (i.e., both groups reciprocally served as control groups). For the knee video (less difficult), we observed a detrimental effect of the background music, whereas we observed no such effect for the shoulder video (more difficult). Further explorations revealed that background music might be detrimental for learning, as it reduces the perceived demand characteristics. Because the impact of the demand characteristics might be more pronounced in less difficult instructional videos, we discuss video difficulty as a potential moderating factor. Overall, our study provides evidence that instructional videos could be usefully implemented in formal teaching curricula and that such instructional videos probably should be designed without background music.

Visual working memory (VWM) is typically measured using arrays of two-dimensional isolated stimuli with simple visual identities (e.g., color or shape), and these studies typically find strong capacity limits. Science, technology, engineering and mathematics (STEM) experts are tasked with reasoning with representations of three-dimensional (3D) connected objects, raising questions about whether those stimuli would be subject to the same limits. Here, we use a color change detection task to examine working memory capacity for 3D objects made up of differently colored cubes. Experiment 1a shows that increasing the number of parts of an object leads to less sensitivity to color changes, while change-irrelevant structural dimensionality (the number of dimensions into which parts of the structure extend) does not. Experiment 1b shows that sensitivity to color changes decreases similarly with increased complexity for multipart 3D connected objects and disconnected 2D squares, while sensitivity is slightly higher with 3D objects. Experiments 2a and 2b find that when other stimulus characteristics, such as size and visual angle, are controlled, change-irrelevant dimensionality and connectivity have no effect on performance. These results suggest that detecting color changes on 3D connected objects and on displays of isolated 2D stimuli are subject to similar set size effects and are not affected by dimensionality and connectivity when these properties are change-irrelevant, ruling out one possible explanation for scientists' advantages in storing and manipulating representations of complex 3D objects.

Research on the impact of auditory information on visual anticipation in tennis suggests that the intensity of racket-ball-contact sounds systematically biases estimates of the ball's speed, thereby influencing anticipatory judgments. Here we examined whether the effect of auditory information on visual anticipation is dependent on the sport-specific context in two separate experiments. In Exp. 1, participants watched short videos of tennis rallies that were occluded at racket-ball-contact. Racket-ball-contact sounds of the final shot were either present or absent. Participants faced different tasks in two counterbalanced blocks: In one block they estimated the ball's speed; in the other block they indicated the ball's landing location. Results showed that participants estimated longer ball flight trajectories and higher ball speeds in the sound present condition than in the sound absent condition. To probe whether this effect is dependent on the sport-specific context, Exp. 2 introduced an abstract (i.e., context-free) version of the previous stimuli. Based on the ball locations in the original videos used in Exp. 1, we rendered new videos that displayed only a moving circle against a blank background. Sine tones replaced the original racket-ball contact sounds. Results showed no impact of sound presence on location anticipation judgments. However, similar to Exp. 1, object speeds were judged to be faster when the final sound was present. Together, these findings suggest that the impact of auditory information on anticipation does not seem to be driven by sound alone, but to be moderated by contextual information.

In co-located, multi-user settings such as multi-touch tables, user interfaces need to be accessible from multiple viewpoints. In this project, we investigated how this goal can be achieved for depictions of data in bar graphs. We designed a laboratory task in which participants answered simple questions based on information depicted in bar graphs presented from differently rotated points of view. As the dependent variable, we measured differences in response onsets relative to the standard viewpoint (i.e., upright graphs). In Experiment 1, we manipulated graph and label orientation independently of each other. We observed that rotations of the labels rather than rotations of the graph itself pose a challenge for accessing depicted information from rotated viewpoints. In Experiment 2, we studied whether replacing word labels with pictographs could overcome the detrimental effects of rotated labels. Rotated pictographs were less detrimental than rotated word labels, but performance was still worse than in the unrotated baseline condition. In Experiment 3, we studied whether color coding could overcome the detrimental effects of rotated labels. Indeed, for multicolored labels, the detrimental effect of label rotation was in the negligible range. We discuss the implications of our findings for the underlying psychological theory as well as for the design of depicted statistical information in multi-user settings.

The cognitive load of many everyday life tasks exceeds known limitations of short-term memory. One strategy to compensate for information overload is cognitive offloading which refers to the externalization of cognitive processes such as reminder setting instead of memorizing. There appears to be remarkable variance in offloading behavior between participants which poses the question whether there is a common factor influencing offloading behavior across different tasks tackling short-term memory processes. To pursue this question, we studied individual differences in offloading behavior between two well-established offloading paradigms: the intention offloading task which tackles memory for intentions and the pattern copy task which tackles continuous short-term memory load. Our study also included an unrelated task measuring short-term memory capacity. Each participant completed all tasks twice on two consecutive days in order to obtain reliability scores. Despite high reliability scores, individual differences in offloading behavior were uncorrelated between the two offloading tasks. In both tasks, however, individual differences in offloading behavior were correlated with the individual differences in an unrelated short-term memory task. Our results therefore show that offloading behavior cannot simply be explained in terms of a single common factor driving offloading behavior across tasks. We discuss the implications of this finding for future research investigating the interrelations of offloading behavior across different tasks.

Previous research has demonstrated that cognitive offloading (i.e., externalizing mental processes) is useful for immediate problem solving. However, long-term effects of cognitive offloading on subsequent problem solving without offloading are remarkably understudied. Our main goal was to investigate the effects of representation control (i.e., adjusting the format of the representation to task requirements) on incidental procedural learning in an information extraction task with interactive visualizations. More specifically, we tested how the availability of representation control for solving tasks in a practice phase affects procedural learning measured in a testing phase in which representation control is no longer available. In both phases, we explored time on task as well as proportion correct as proxies of task performance and analyzed how often participants used representation control. We conducted three experiments in which participants could modify and reorganize information displays in the practice phase, whereas in the testing phase, they had to solve equivalent and near transfer problems without this offloading opportunity. We show that representation control is beneficial for immediate task solution, particularly for problems that require a spatial transformation. This benefit was more pronounced for automated (i.e., system-controlled) types of control (Experiment 3). In contrast, in subsequent problem solving without representation control (up to 24 hr later), participants who had been using representation control previously fell back to the level of an untrained baseline condition (Experiments 1 and 2). However, the detrimental effect of representation control was confined to equivalent tasks and did not generalize to a near transfer task.

Filmmakers have established editing rules that aim to create cinematic continuity across filmic cuts, thereby avoiding viewers' confusion despite the abrupt changes in perception. In our present project, we investigated the impact of 3D films, as opposed to 2D films, on the salience of filmic cuts. We employed a cut detection task and focused on within-scene cuts with mere changes in camera perspective. We presented short video clips to our participants and asked them to press a key whenever they noticed a filmic cut, and we measured their cut detection performance. In addition to viewing mode (2D vs. 3D presentation), we considered cross-modal auditory influences (visual vs. audiovisual presentation) on the salience of filmic cuts. Participants detected cuts more accurately and faster when the video clips were presented in 3D rather than in 2D and when the video clips were presented only visually (without soundtrack) rather than audiovisually (with soundtrack). Both factors influenced cut detection performance independently. We conclude that while the regular audiovisual presentation of films supports the filmmakers' mission to achieve cinematic continuity, filmmakers should also be aware of the additional salience of cuts that comes with 3D film presentation and consider its effects on cinematic continuity. [ABSTRACT FROM AUTHOR]

Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system.sup.1-6. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS.sup.7-17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease. Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies., Author(s): Nina A. Bonekamp [sup.1] , Bradley Peter [sup.2] , Hauke S. Hillen [sup.3] , Andrea Felser [sup.4] , Tim Bergbrede [sup.5] , Axel Choidas [sup.5] , Moritz Horn [sup.6] [...]