Rolle von CFHR5 Proteins bei der Pathogenese der C3-Glomerulopathie

Die C3- Glomerulopathie ist eine schwerwiegende Nierenerkrankung mit definierten C3- Komplementablagerungen im Bereich der Glomerulären Basalmembran. Aktuell gibt es keine kausale Therapie. Es wird postuluiert, dass die C3- Glomerulopathie durch eine Deregulation des Komplementsystems hervorgerufen wird. Eine wichtige genetische Ursache ist die Expression von CFHR5- Hybridproteinen. Um die Rolle von CFHR5- Hybridproteinen bei der Pathogenese der C3- Glomerulopathie zu untersuchen, wurden das CFHR5 Protein, sowie CFHR5 Deletionsmutanten generiert und funktionell charakterisiert. Das Ziel war die Ligandeninteraktions- und Oberflächenbindungsdomänen von CFHR5 zu lokalisieren. Es wurde getestet, ob CFHR5 und die CFHR5 Deletionsmutanten mit Heparin, Properdin und C3- Aktivierungsfragmenten interagieren und ob CFHR5 und die CFHR5 Deletionsmutanten an intakte sowie modifizierte humane Zellen binden. CFHR5 interagiert mit Heparin, Properdin und C3- Aktivierungsfragmenten. Die Mittelregion von CFHR5 repräsentiert die Interaktionsdomäne für die Liganden. CFHR5 bindet an intakte und mit höchster Intensität an modifizierte humane Endothelzellen. Die Oberflächenbinderegion von CFHR5 ist in der Mittelregion lokalisiert. Im Weiteren wurde eine neue Interaktionsdomäne im C- Terminus von CFHR5 identifiziert. Die Untersuchungen deuten darauf hin, dass CFHR5 den Alternativen Weg des Komplement-systems über die Interaktion mit Properdin und C3b auf modifizierten körpereigenen Zellen aktiviert, und so die nicht- inflammatorische Beseitigung der veränderten Partikel durch Phagozytose gewährleistet. Die CFHR5- Hybridproteine deregulieren das Komplementsystem, indem sie die Komplementaktivierung verstärken und können so zur Schädigung der Nieren führen. Bis die zielgerichtete Hemmung der C3- Konvertase als Therapie zur Verfügung steht, sollte eine Komplementmodulation mit dem Antikörper Eculizumab versucht werden

Better together? Social distance affects joint probability discounting

Deciding together is common in our everyday life. However, the process of this joint decision-making plays out across different levels, for example language, intonation, or non-verbal behaviour. Here we focused on non-verbal interaction dynamics between two participants in probability discounting. We applied a gamified decision-making task in which participants performed a series of choices between a small but safe and a large but risky reward. In two experiments, we found that joint decision-making resulted in lower discounting and higher efficiency. In order to understand the underlying mechanisms in greater detail, we studied through which process this variation occurred and whether this process would be modulated by the social distance between both participants. Our findings suggested that socially close participants managed to reduce their discounting by interactive processes while socially distant participants were influenced by the social context itself. However, a higher level of efficiency was achieved through interactive processes for both groups. In summary, this study served as a fine-grained investigation of collaborative interaction processes and its significant impact on the outcome of choices with probabilistic consequences. [Abstract copyright: © 2022. The Author(s).

Neurophysiological correlates of holistic face processing in adolescents with and without autism spectrum disorder

Background: Face processing has been found to be impaired in autism spectrum disorders (ASD). One hypothesis is that individuals with ASD engage in piecemeal compared to holistic face processing strategies. To investigate the role of possible impairments in holistic face processing in individuals with autism, the current study investigated behavioral and electroencephalography (EEG) correlates of face processing (P1/N170 and gamma-band activity) in adolescents with ASD and sex-, age-, and IQ-matched neurotypical controls. Methods: Participants were presented with upright and inverted Mooney stimuli; black and white low information faces that are only perceived as faces when processed holistically. Participants indicated behaviorally the detection of a face. EEG was collected time-locked to the presentation of the stimuli. Results: Adolescents with ASD perceived Mooney stimuli as faces suggesting ability to use holistic processing but displayed a lower face detection rate and slower response times. ERP components suggest slowed temporal processing of Mooney stimuli in the ASD compared to control group for P1 latency but no differences between groups for P1 amplitude and at the N170. Increases in gamma-band activity was similar during the perception of the Mooney images by group, but the ASD group showed prolonged temporal elevation in activity. Conclusion: Overall, our results suggest that adolescents with ASD were able to utilize holistic processing to perceive a face within the Mooney stimuli. Delays in early processing, marked by the P1, and elongated elevation in gamma activity indicate that the neural systems supporting holistic processing are slightly altered suggesting a less automatic and less efficient facial processing system

Is value-based choice repetition susceptible to medial frontal transcranial direct current stimulation (tDCS)? A preregistered study.

Funder: Technische Universität Dresden (1019)In value-based decision making, people have to weigh different options based on their subjective value. This process, however, also is influenced by choice biases, such as choice repetition: in a series of choices, people are more likely to repeat their decision than to switch to a different choice. Previously, it was shown that transcranial direct current stimulation (tDCS) can affect such choice biases. We applied tDCS over the medial prefrontal cortex to investigate whether tDCS can alter choice repetition in value-based decision making. In a preregistered study, we applied anodal, cathodal, and sham tDCS stimulation to 52 participants. While we found robust choice repetition effects, we did not find support for an effect of tDCS stimulation. We discuss these findings within the larger scope of the tDCS literature and highlight the potential roles of interindividual variability and current density strength

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

Mid-frontal Theta during Conflict in a Value-based Decision Task

Mid-frontal theta is a sensitive marker for cognitive conflict. However, most research focuses on cognitive control paradigms (e.g., the Flanker task). Here, we ask if mid-frontal theta is also sensitive to response conflicts within value-based decision-making. We recorded electroencephalography activity during a value-based binary decision task. In this task, participants collect rewards in a virtual two-dimensional world. In each trial, we present two reward options that are either quick to collect but are smaller in value, or take longer to collect but are larger in value. The subjective value of each option is driven by the options' value and how quickly they can be reached. We used this task to investigate three types of potential conflicts: choice ambiguity, choice repetitions, and temporal delay. We investigated choice repetition by biasing participants toward one option for two trials and then testing how that affects the subsequent decision. We manipulated choice ambiguity by varying the subjective values of the decision options, and temporal delay by making one option quick to collect and one longer to collect. The behavioral results showed the expected effects: Decision times were shorter for unambiguous choices, participants showed a tendency to repeat the previous choice and decision times were shorter for repetitions, and decision times were shorter for earlier available choices. Response-locked mid-frontal theta power was increased for choice switches as compared to choice repetitions, and for the later available as compared to the earlier available option, but we found no effect of ambiguity

Scripts

contains data import scripts, data processing script "analyze_data.m", csv files (folder "CSV_Files") produced by the processing script, and JASP files (folder "JASP_Files") for all statistical analyses using the csv files produced by the analysis scrip

Data

contains data for experiment 1 and experiment 2, as well as .mat files with aggregated participant data for each experiment as produced by the "import_data_experiment1" and "import_data_experiment2" scripts (see Scripts