The molecular machinery for maturation of primary mtDNA transcripts.

Human mitochondria harbour a circular, polyploid genome (mtDNA) encoding 11 messenger RNAs (mRNAs), two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs). Mitochondrial transcription produces long, polycistronic transcripts that span almost the entire length of the genome, and hence contain all three types of RNAs. The primary transcripts then undergo a number of processing and maturation steps, which constitute key regulatory points of mitochondrial gene expression. The first step of mitochondrial RNA processing consists of the separation of primary transcripts into individual, functional RNA molecules and can occur by two distinct pathways. Both are carried out by dedicated molecular machineries that substantially differ from RNA processing enzymes found elsewhere. As a result, the underlying molecular mechanisms remain poorly understood. Over the last years, genetic, biochemical and structural studies have identified key players involved in both RNA processing pathways and provided the first insights into the underlying mechanisms. Here, we review our current understanding of RNA processing in mammalian mitochondria and provide an outlook on open questions in the field.

Elevated Colon Cancer Rates Linked to Prior Appendicitis: A Retrospective Cohort Study Based on Data from German General Practices.

Background/Objective: The association between appendicitis and colon cancer is not yet fully understood. Previous studies have shown contradictory results. Currently, no population-based data from Germany are available with regard to the incidence of colon cancer following appendicitis. This study investigated the association between appendicitis and the incidence of colon cancer in Germany. Methods: In this retrospective cohort study, the incidence of colon cancer was compared for patients with appendicitis and patients without appendicitis, matched for age, sex, index year, average annual consultation frequency, and comorbidity. The aim of the study was to explore the relationship between appendicitis and the incidence of colon cancer. The evaluation was carried out using logistic regression analyses. Results: The study included 49,790 people with and without appendicitis, with a median age of 41 years. During a follow-up period of up to 15 years, 1.04% of cases with appendicitis and 0.60% of cases without appendicitis were newly diagnosed with colon cancer, with some 36.4% of colon cancer cases diagnosed within the first six months after appendicitis. Regression analyses revealed a significant association between appendicitis and colon cancer, particularly in men and in the age groups 41-50 (HR: 10.30; 95% CI: 1.03-43.82) and 18-30 years (HR: 8.17; 95% CI: 1.03-64.58). Conclusions: The present retrospective cohort study suggests an association between appendicitis and the incidence of colon cancer in Germany. Based on our results, we recommend offering a colonoscopy or at least a stool test within 12 months after appendicitis, especially for 18-50-year-olds and >60-year-olds in good general health.

Imaging-based diagnosis of sarcopenia for transplant-free survival in primary sclerosing cholangitis.

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 < 50 cm²/m² in male patients and < 39 cm²/m² in female patients. The primary outcome of this study was TFS, which was defined as survival without liver transplantation or death from any cause. RESULTS: Our study indicates that L3-SMI sarcopenia impairs TFS in patients with PSC (5-year TFS: 33.9% vs. 83.3%, p = 0.001, log-rank test). L3-SMI sarcopenia was independently associated with reduced TFS via multivariate Cox regression analysis (HR = 2.749; p = 0.028). Body mass index reduction > 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 < 0.001 vs. HR = 1.691, p = 0.141). CONCLUSION: Imaging-based diagnosis of sarcopenia via L3-SMI is associated with a low TFS in patients with PSC and may provide additional benefits as a prognostic factor in patient selection for liver transplantation.

Structure of the multi-subunit chloroplast RNA polymerase.

Chloroplasts contain a dedicated genome that encodes subunits of the photosynthesis machinery. Transcription of photosynthesis genes is predominantly carried out by a plastid-encoded RNA polymerase (PEP), a nearly 1 MDa complex composed of core subunits with homology to eubacterial RNA polymerases (RNAPs) and at least 12 additional chloroplast-specific PEP-associated proteins (PAPs). However, the architecture of this complex and the functions of the PAPs remain unknown. Here, we report the cryo-EM structure of a 19-subunit PEP complex from Sinapis alba (white mustard). The structure reveals that the PEP core resembles prokaryotic and nuclear RNAPs but contains chloroplast-specific features that mediate interactions with the PAPs. The PAPs are unrelated to known transcription factors and arrange around the core in a unique fashion. Their structures suggest potential functions during transcription in the chemical environment of chloroplasts. These results reveal structural insights into chloroplast transcription and provide a framework for understanding photosynthesis gene expression.

The Intersectoral Coordination Unit for the Sustainable Intensification of Peritoneal Dialysis in Schleswig-Holstein (SKIP-SH) cohort study.

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.

The Beep-Speed Illusion Cannot Be Explained With a Simple Selection Bias.

An object appears to move at higher speed than another equally fast object when brief nonspatial tones coincide with its changes in motion direction. We refer to this phenomenon as the beep-speed illusion (Meyerhoff et al., 2022, Cognition, 219, 104978). The origin of this illusion is unclear; however, attentional explanations and potential biases in the response behavior appear to be plausible candidates. In this report, we test a simple bias explanation that emerges from the way the dependent variable is assessed. As the participants have to indicate the faster of the two objects, participants possibly always indicate the audio-visually synchronized object in situations of perceptual uncertainty. Such a response behavior potentially could explain the observed shift in perceived speed. We therefore probed the magnitude of the beep-speed illusion when the participants indicated either the object that appeared to move faster or the object that appeared to move slower. If a simple selection bias would explain the beep-speed illusion, the response pattern should be inverted with the instruction to indicate the slower object. However, contrary to this bias hypothesis, illusion emerged indistinguishably under both instructions. Therefore, simple selection biases cannot explain the beep-speed illusion.

Gaze coherence reveals distinct tracking strategies in multiple object and multiple identity tracking.

In dynamic environments, a central task of the attentional system is to keep track of objects changing their spatial location over time. In some instances, it is sufficient to track only the spatial locations of moving objects (i.e., multiple object tracking; MOT). In other instances, however, it is also important to maintain distinct identities of moving objects (i.e., multiple identity tracking; MIT). Despite previous research, it is not clear whether MOT and MIT performance emerge from the same tracking mechanism. In the present report, we study gaze coherence (i.e., the extent to which participants repeat their gaze behaviour when tracking the same object locations twice) across repeated MOT and MIT trials. We observed more substantial gaze coherence in repeated MOT trials compared to the repeated MIT trials or mixed MOT-MIT trial pairs. A subsequent simulation study suggests that MOT is based more on a grouping mechanism than MIT, whereas MIT is based more on a target-jumping mechanism than MOT. It thus appears unlikely that MOT and MIT emerge from the same basic tracking mechanism.

The Impact of Audio-Visual, Visual and Auditory Cues on Multiple Object Tracking Performance in Children with Autism.

Previous studies have documented differences in processing multisensory information by children with autism compared to typically developing children. Furthermore, children with autism have been found to track fewer multiple objects on a screen than those without autism, suggesting reduced attentional control. In the present study, we investigated whether children with autism (n = 33) and children without autism (n = 33) were able to track four target objects moving amongst four indistinguishable distractor objects while sensory cues were presented. During tracking, we presented various types of cues - auditory, visual, or audio-visual or no cues while target objects bounced off the inner boundary of a centralized circle. We found that children with autism tracked fewer targets than children without autism. Furthermore, children without autism showed improved tracking performance in the presence of visual cues, whereas children with autism did not benefit from sensory cues. Whereas multiple object tracking performance improved with increasing age in children without autism, especially when using audio-visual cues, children with autism did not show age-related improvement in tracking. These results are in line with the hypothesis that attention and the ability to integrate sensory cues during tracking are reduced in children with autism. Our findings could contribute valuable insights for designing interventions that incorporate multisensory information.

Mutual interplay between cognitive offloading and secondary task performance.

Various modern tools, such as smartphones, allow for cognitive offloading (i.e., the externalization of cognitive processes). In this study, we examined the use and consequences of cognitive offloading in demanding situations in which people perform multiple tasks concurrently-mimicking the requirements of daily life. In a preregistered study, we adapted the dual-task paradigm so that one of the tasks allowed for cognitive offloading. As a primary task, our participants (N = 172) performed the pattern copy task-a highly demanding working memory task that allows for offloading at various degrees. In this task, we manipulated the temporal costs of offloading. Concurrently, half of the participants responded to a secondary N-back task. As our main research question, we investigated the impact of offloading behavior on secondary task performance. We observed that more pronounced offloading in the condition without temporal costs was accompanied by a more accurate performance in the N-back task. Furthermore, the necessity to respond to the N-back task increased offloading behavior. These results suggest an interplay between offloading and secondary task performance: in demanding situations, individuals increasingly use cognitive offloading, which releases internal resources that can then be devoted to improving performance in other, concurrent tasks.

Cryo-EM for Structure Determination of Mitochondrial Ribosome Samples.

Single-particle cryoelectron microscopy (cryo-EM) allows structure determination of large macromolecular complexes from conformationally and compositionally heterogeneous mixtures of particles. This technique has been used to reveal the architecture of the mitochondrial ribosome and to visualize transient states that occur during the translation cycle or during mitoribosome biogenesis. Here, we outline an exemplary workflow for the analysis of single-particle cryo-EM data of human mitoribosome samples. In addition, we provide an example dataset which can be used for training purposes alongside the protocol.

When linguistic uncertainty spreads across pieces of information: Remembering facts on the news as speculation.

Modern media enable rapid reporting that does not refer to facts alone but is often interspersed with unconfirmed speculations. Whereas previous research has concentrated primarily on how unconfirmed contents might propagate, potential memory effects of reporting confirmed facts among speculations have so far been widely disregarded. Across four experiments, we show that the presence of speculative news (indexed by uncertainty cues such as "might") can reduce the remembered certainty of unrelated facts. The participants read headlines with exclusively speculative news, exclusively factual news, or a mixture of both. Our results indicate that uncertainty cues spread onto one's recollection of unrelated facts after having read a mixture of facts and speculations. This tendency persisted when both types of news were presented sequentially (e.g., factual news first), suggesting that the presence of speculative news does not specifically affect encoding-but can overshadow memories of facts in retrospect. Further, the tendency to misremember facts as speculations emerged even when the proportion of speculations among factual news was low (6/24 headlines) but increased linearly with the number of speculations intermingled. Given the widespread dissemination of speculative news, this bias poses a challenge in effectively getting confirmed information across to readers. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Long-term memory representations for audio-visual scenes.

In this study, we investigated the nature of long-term memory representations for naturalistic audio-visual scenes. Whereas previous research has shown that audio-visual scenes are recognized more accurately than their unimodal counterparts, it remains unclear whether this benefit stems from audio-visually integrated long-term memory representations or a summation of independent retrieval cues. We tested two predictions for audio-visually integrated memory representations. First, we used a modeling approach to test whether recognition performance for audio-visual scenes is more accurate than would be expected from independent retrieval cues. This analysis shows that audio-visual integration is not necessary to explain the benefit of audio-visual scenes relative to purely auditory or purely visual scenes. Second, we report a series of experiments investigating the occurrence of study-test congruency effects for unimodal and audio-visual scenes. Most importantly, visually encoded information was immune to additional auditory information presented during testing, whereas auditory encoded information was susceptible to additional visual information presented during testing. This renders a true integration of visual and auditory information in long-term memory representations unlikely. In sum, our results instead provide evidence for visual dominance in long-term memory. Whereas associative auditory information is capable of enhancing memory performance, the long-term memory representations appear to be primarily visual.

The influence of tDCS on perceived bouncing/streaming.

Processing ambiguous situations is a constant challenge in everyday life and sensory input from different modalities needs to be integrated to form a coherent mental representation on the environment. The bouncing/streaming illusion can be studied to provide insights into the ambiguous perception and processing of multi-modal environments. In short, the likelihood of reporting bouncing rather than streaming impressions increases when a sound coincides with the moment of overlap between two moving disks. Neuroimaging studies revealed that the right posterior parietal cortex is crucial in cross-modal integration and is active during the bouncing/streaming illusion. Consequently, in the present study, we used transcranial direct current stimulation to stimulate this brain area. In the active stimulation conditions, a 9 cm2 electrode was positioned over the P4-EEG position and the 35 cm2 reference positioned over the left upper arm. The stimulation lasted 15 min. Each participant did the bouncing/streaming task three times: before, during and after anodal or sham stimulation. In a sample of N = 60 healthy, young adults, we found no influence of anodal tDCS. Bayesian analysis showed strong evidence against tDCS effects. There are two possible explanations for the finding that anodal tDCS over perceptual areas did not modulate multimodal integration. First, upregulation of multimodal integration is not possible using tDCS over the PPC as the integration process already functions at maximum capacity. Second, prefrontal decision-making areas may have overruled any modulated input from the PPC as it may not have matched their decision-making criterion and compensated for the modulation.

ost in promiscuity? An evolutionary and biochemical evaluation of HSD10 function in cardiolipin metabolism.

Multifunctional proteins are challenging as it can be difficult to confirm pathomechanisms associated with disease-causing genetic variants. The human 17ß-hydroxysteroid dehydrogenase 10 (HSD10) is a moonlighting enzyme with at least two structurally and catalytically unrelated functions. HSD10 disease was originally described as a disorder of isoleucine metabolism, but the clinical manifestations were subsequently shown to be linked to impaired mtDNA transcript processing due to deficient function of HSD10 in the mtRNase P complex. A surprisingly large number of other, mostly enzymatic and potentially clinically relevant functions have been attributed to HSD10. Recently, HSD10 was reported to exhibit phospholipase C-like activity towards cardiolipins (CL), important mitochondrial phospholipids. To assess the physiological role of the proposed CL-cleaving function, we studied CL architectures in living cells and patient fibroblasts in different genetic backgrounds and lipid environments using our well-established LC-MS/MS cardiolipidomic pipeline. These experiments revealed no measurable effect on CLs, indicating that HSD10 does not have a physiologically relevant function towards CL metabolism. Evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro. The combination of an essential structural with a non-essential enzymatic function in the same protein could direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket, which is consistent with the results presented here.

Medical education videos as a tool for rehearsal: efficiency and the cases of background music and difficulty.

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.

Taste-immune associative learning amplifies immunopharmacological effects and attenuates disease progression in a rat glioblastoma model.

Mechanistic target of rapamycin (mTOR)-signaling is one key driver of glioblastoma (GBM), facilitating tumor growth by promoting the shift to an anti-inflammatory, pro-cancerogenic microenvironment. Even though mTOR inhibitors such as rapamycin (RAPA) have been shown to interfere with GBM disease progression, frequently chaperoned toxic drug side effects urge the need for developing alternative or supportive treatment strategies. Importantly, previous work document that taste-immune associative learning with RAPA may be utilized to induce learned pharmacological placebo responses in the immune system. Against this background, the current study aimed at investigating the potential efficacy of a taste-immune associative learning protocol with RAPA in a syngeneic GBM rat model. Following repeated pairings of a novel gustatory stimulus with injections of RAPA, learned immune-pharmacological effects could be retrieved in GBM-bearing animals when re-exposed to the gustatory stimulus together with administering 10 % amount of the initial drug dose (0.5 mg/kg). These inhibitory effects on tumor growth were accompanied by an up-regulation of central and peripheral pro-inflammatory markers, suggesting that taste-immune associative learning with RAPA promoted the development of a pro-inflammatory anti-tumor microenvironment that attenuated GBM tumor growth to an almost identical outcome as obtained after 100 % (5 mg/kg) RAPA treatment. Together, our results confirm the applicability of taste-immune associative learning with RAPA in animal disease models where mTOR overactivation is one key driver. This proof-of-concept study may also be taken as a role model for implementing learning protocols as alternative or supportive treatment strategy in clinical settings, allowing the reduction of required drug doses and side effects without losing treatment efficacy.

Context modulates the impact of auditory information on visual anticipation.

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.

WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly.

Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme's active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly.

Structural and mechanistic basis of RNA processing by protein-only ribonuclease P enzymes.

Ribonuclease P (RNase P) enzymes are responsible for the 5' processing of tRNA precursors. In addition to the well-characterised ribozyme-based RNase P enzymes, an evolutionarily distinct group of protein-only RNase Ps exists. These proteinaceous RNase Ps (PRORPs) can be found in all three domains of life and can be divided into two structurally different types: eukaryotic and prokaryotic. Recent structural studies on members of both families reveal a surprising diversity of molecular architectures, but also highlight conceptual and mechanistic similarities. Here, we provide a comparison between the different types of PRORP enzymes and review how the combination of structural, biochemical, and biophysical studies has led to a molecular picture of protein-mediated tRNA processing.