Biology subjects

Karner, A.

Publications and source records attributed to Karner, A..

7 recordsLinked to original sources

bioRxiv2025

A kinetic model of antigen-dependent IgG oligomerization and complement binding

The classical complement pathway (CCP), an important branch of the mammalian immune system, is initiated through multivalent binding of complement protein C1 to Immunoglobulin G (IgG) antibody oligomers assembled on the surface of pathogens, infected or malignant cells, culminating in the formation of the membrane attack complex (MAC) and subsequent cell lysis. IgG oligomers can further engage immune effector cells through Fc{gamma} receptors or complement receptors, facilitating antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Detailed knowledge of the factors that drive IgG oligomerization is thus vitally important to establish and improve IgG based therapies. We here focus on the kinetics of antigen-dependent IgG oligomerization and develop a comprehensive model capable of predicting oligomer formation as a function of IgG concentration, antigen density, IgG subclass and Fc point mutants, as well as the presence of Fc-binding and thus oligomerization-inhibiting factors such as staphylococcal protein A (SpA). We characterize the underlying molecular interactions in single molecule force spectroscopy (SMFS) and grating coupled interferometry (GCI) experiments. By fitting experimental data from high-speed atomic force microscopy (HS-AFM) experiments, we further quantify key rate constants and thermodynamic parameters, including free energy changes associated with oligomerization and apply the model to predict complement-mediated lysis in liposomal vesicle-based assays. The presented mechanistic framework may serve as a basis for optimizing antibody engineering and pharmacokinetic/pharmacodynamic modeling in the context of immunotherapies exploiting the CCP.

biophysics↗

bioRxiv2024

SpiDa-MRI, behavioral and (f)MRI data of adults with fear of spiders

Neuroimaging has greatly improved our understanding of phobic mechanisms. To expand on these advancements, we present data on the heterogeneity of neural patterns in spider phobia combined with various psychological dimensions of spider phobia, using spider-relevant stimuli of various intensities. Specifically, we have created a database in which 49 spider-fearful individuals viewed 225 spider-relevant images in the fMRI scanner and performed behavioral avoidance tasks before and after the fMRI scan. For each participant, the database consists of the neuroimaging part, which includes an anatomical scan, 5 passive-viewing and 2 resting-state functional runs in both raw and pre-processed form along with associated quality control reports. Additionally, a behavioral section includes self-report questionnaires and avoidance tasks collected in pre- and post-sessions. The dataset is well suited for investigating neural mechanisms of phobias, brain-behavior correlations, and also contributes to the existing phobic neuroimaging datasets with spider-fearful samples. O_TBL View this table: org.highwire.dtl.DTLVardef@f76a39org.highwire.dtl.DTLVardef@15eeaa2org.highwire.dtl.DTLVardef@7e4f1borg.highwire.dtl.DTLVardef@7b78f1org.highwire.dtl.DTLVardef@413e78_HPS_FORMAT_FIGEXP M_TBL C_TBL

neuroscience↗

bioRxiv2023

Amygdala habituation during exposure is associated with failure to reduce phobic symptoms

Exposure therapy is an established treatment for anxiety disorders but the mechanisms underpinning its effectiveness remain unclear. Two theories offer contrasting perspectives: the traditional habituation model posits that a form of stimulus desensitization is required during exposure, while the inhibitory learning model emphasizes the formation of new non-fearful associations. Crucially, while the former may manifest as amygdala habituation, the latter may not. To distinguish between the two models, this study uses functional magnetic resonance imaging to examine the amygdala responses of spider-fearful participants during fear exposure. We hypothesized that intervention success might align with stable or even increased amygdala activation - an indicator of active engagement and re-learning as proposed by the inhibitory learning model. Conversely, decreasing amygdala activity might not be a sign of reduced fear memory as proposed by the habituation model, but could signal mental detachment, leading to suboptimal treatment outcomes. Our results corroborated our hypotheses: individuals with escalating amygdala responses during exposure exhibited better clinical progress, while those showing amygdala habituation benefited less. Our results strengthen the case for the inhibitory learning model and highlight that therapy may not aim to diminish fear per se but rather to engage patients in active processing and association formation.

neuroscience↗

bioRxiv2022

Pre- and post-task resting-state differs in clinical populations

Resting-state functional connectivity has generated great hopes as a potential brain biomarker for improving prevention, diagnosis, and treatment in psychiatry. This neuroimaging protocol can routinely be performed by patients and does not depend on the specificities of a task. Thus, it seems ideal for big data approaches that require aggregating data across multiple studies and sites. However, technical variability, diverging data analysis approaches, and differences in data acquisition protocols might introduce heterogeneity to the aggregated data. Besides these technical aspects, the psychological state of participants might also contribute to heterogeneity. In healthy participants, studies have shown that behavioral tasks can influence resting-state measures, but such effects have not yet been reported in clinical populations. Here, we fill this knowledge gap by comparing resting-state functional connectivity before and after clinically relevant tasks in two clinical conditions, namely substance use disorders and phobias. The tasks consisted of viewing craving-inducing and spider anxiety provoking pictures that are frequently used in cue-reactivity studies and exposure therapy. We found distinct pre- vs. post-task resting-state connectivity differences in each group, as well as decreased thalamo-cortical and increased intra-thalamic connectivity which might be associated with decreased vigilance in both groups. Notably, the pre- vs. post-task thalamus-amygdala connectivity change within a patient cohort seems more pronounced than the difference of that connection between the smoker vs. phobia clinical trait. Our results confirm that resting-state measures can be strongly influenced by changes in psychological states that need to be taken into account when pooling resting-state scans for clinical biomarker detection. This demands that resting-state datasets should include a complete description of the experimental design, especially when a task preceded data collection.

neuroscience↗

bioRxiv2020

DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens

T-cells detect with their T-cell antigen receptors (TCRs) the presence of rare peptide/MHC complexes (pMHCs) on the surface of antigen presenting cells (APCs). How they convert a biochemical interaction into a signaling response is poorly understood, yet indirect evidence pointed to the spatial antigen arrangement on the APC surface as a critical factor. To examine this, we engineered a biomimetic interface based on laterally mobile functionalized DNA origami platforms, which allow for nanoscale control over ligand distances without interfering with the cell-intrinsic dynamics of receptor clustering. We found that the minimum signaling unit required for efficient T-cell activation consisted of two ligated TCRs within a distance of 20 nanometers, if TCRs were stably engaged by monovalent antibody fragments. In contrast, antigenic pMHCs stimulated T-cells robustly as well-isolated entities. These results identify the minimal requirements for effective TCR-triggering and validate the exceptional stimulatory potency of transiently engaging pMHCs.

biophysics↗

bioRxiv2019

Binding of the motor protein SecA to the bacterial protein translocation channel SecYEG in the absence of ATP

Translocation of many secretory proteins through the bacterial plasma membrane is facilitated by a complex of the SecYEG channel with the motor protein SecA. The ATP-free complex is unstable in detergent, raising the question how SecA may perform several rounds of ATP hydrolysis without being released from the membrane embedded SecYEG. Here we show that dual recognition of (i) SecYEG and (ii) vicinal acidic lipids confers an apparent nanomolar affinity. High-speed atomic force microscopy visualizes the complexes between monomeric SecA and SecYEG as being stable for tens of seconds. These long-lasting events and complementary shorter ones both give rise to single ion channel openings of equal duration. Furthermore, luminescence resonance energy transfer reveals two conformations of the SecYEG-SecA complex that differ in the protrusion depth of SecAs two-helix finger into SecYEGs aqueous channel. Such movement of the finger is in line with the power stroke mechanism of protein translocation.

biophysics↗

bioRxiv2017

Relevance of host cell surface glycan structure for cell specificity of influenza A virus

Influenza A viruses (IAV) initiate infection via binding of the viral hemagglutinin (HA) to sialylated glycan receptors on host cells. HAs receptor specificity towards sialic acid (SA) is well studied and clearly critical for virus infection, but the contribution of the highly complex cellular plasma membrane to the cellular specificity remains elusive. In addition, some studies indicated that other host cell factors such as the epidermal growth factor receptor might contribute to the initial virus-cell contact and further downstream signaling1.\n\nHere we use two complementary methods, glycan arrays and single-virus force spectroscopy (SVFS) to compare influenza virus receptor specificity with actual host cell binding. Unexpectedly, our study reveals that HAs receptor binding preference does not necessarily reflect virus-cell specificity. We propose SVFS as a tool to elucidate the cell binding preference of IAV thereby including the complex environment of sialylated receptors within the plasma membrane of living cells.

microbiology↗