Biology subjects

Schlosser, G.

Publications and source records attributed to Schlosser, G..

6 recordsLinked to original sources

bioRxiv2025

Hedonic experiences emerge from an orchestrated balance of synergistic and redundant information processing

Ketamine exerts rapid-acting, pro-hedonic effects, yet its precise mechanism remains elusive. Here, we present behavioral and fMRI data from a randomized, placebo-controlled crossover study in 38 healthy participants investigating ketamines sub-acute effects on multivariate information-processing during music-evoked peak hedonic experiences. Leveraging information-theoretical measures, our findings indicate that hedonic experiences depend on a distinct global (as measured by O-Information) and local (as measured by integrated information) balance between redundant - information shared across nodes - and synergistic - information emerging from joint interactions - processes. As hedonic intensity rises, neural dynamics shift toward greater synergy; with the one exception of a deliberate increase in redundancy particularly for key sensory information to ensure reliable transmission of and access to critical external information for subsequent hedonic processing. In contrast, ketamines sub-acute pro-hedonic effects arise potentially from enhancing redundant dynamics at rest, boosting the brains capability to robustly represent and access critical internal information, and thus, fostering an environment optimized to amplify the phenomenological hedonic experience, while simultaneously allowing for more efficient information integration.

neuroscience↗

bioRxiv2025

Covalent activation of the C-type lectin DC-SIGN

Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) is a C-type lectin receptor expressed on antigen-presenting cells, crucial for pathogen recognition and immune modulation. The shallow and polar carbohydrate binding site of DC-SIGN presents challenges for ligand design. Here, we explored covalent modification targeting specific lysine residues as a novel strategy to modulate DC-SIGN function. Screening a lysine-targeted electrophilic fragment library using orthogonal functional assays identified two potent activators. Structural analyses via NMR spectroscopy, mass spectrometry and computational modeling confirmed structural perturbations of the carbohydrate recognition domain and revealed distinct mechanisms of activation. While both activators significantly enhanced DC-SIGNs affinity for monosaccharide ligands, one compound induced oligomerization via covalent coupling and non-covalent secondary site interactions, whereas the other selectively modified lysine K373 directly within the primary carbohydrate-binding site. These findings demonstrate the potential of lysine-targeted covalent compounds as a novel therapeutic strategy for modulating DC-SIGN function and potentially C-type lectins in general. Table of contents O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=50 SRC="FIGDIR/small/674704v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1b44543org.highwire.dtl.DTLVardef@2f3feaorg.highwire.dtl.DTLVardef@d48e1org.highwire.dtl.DTLVardef@2baee1_HPS_FORMAT_FIGEXP M_FIG C_FIG We introduce the first covalent activators of a C-type lectin. Using GCI, NMR, MS/MS and computational modeling, we delineate mechanisms from a functional electrophile-first screen on DC-SIGN that yields two modes: NHS-ester 11 modifies K379 to induce CRD oligomerization via a secondary site, and squarate 33 modifies K373 in the carbohydrate site to strengthen glycan binding.

pharmacology and toxicology↗

bioRxiv2025

Subacute effects of ketamine on neural correlates of reward processing

ObjectivesKetamines prohedonic properties have been linked to enhanced reward-related brain activation during the early post-infusion phase. Its effects during the subacute period ([~]2-24 h post-infusion), when psychotomimetic symptoms fade and neuroplastic adaptations emerge, are less well characterised. This study assessed ketamines subacute effects on reward processing using the Monetary Incentive Delay (MID) task. MethodsIn a randomised, placebo-controlled, crossover study, 28 healthy participants received 0.5 mg/kg racemic ketamine or placebo via 40-minute intravenous infusion. Functional magnetic resonance imaging (fMRI) was acquired [~]5 h post-infusion. Plasma concentrations of ketamine and norketamine were obtained for individual area under the curve (AUC) estimation. Analyses focused on the contrast between expected and actual trial outcomes. ResultsAt five hours post-infusion, ketamine did not significantly modulate MID task-related brain activation, despite pronounced subjective drug effects. Pharmacokinetic modelling confirmed expected ketamine and norketamine profiles, but neither drug exposure (AUC) nor subjective measures correlated with neural activation. ConclusionsProhedonic effects of ketamine may not sufficiently manifest in MID task-related activation in healthy individuals [~]5 hours after infusion. The lack of significant effects provides valuable extension of the existing literature, as ketamines effects might be confined to a more acute time window or differ in clinical populations.

neuroscience↗

bioRxiv2025

High-temporal resolution metabolic connectivity resolved by component-based noise correction

Recent advances in functional PET (fPET) allow for accurate modelling of metabolic processes with a temporal resolution in the range of seconds. This enables new applications such as imaging molecular connectivity at temporal resolutions comparable to fMRI. However, high-temporal resolution fPET data are more sensitive to noise and the extraction of a meaningful signal remains a challenge. We developed a component-based preprocessing approach adapted from fMRI, which models structured noise using tissue-specific regressors and removes low-frequency uptake trends from the fPET signal (CompCor). We applied this method to 20 high-temporal [18F]FDG fPET scans from a next-generation long-axial field of view PET/CT system (1s frames) and 16 scans from a conventional PET/MR scanner (3s frames). We compared filtering methods across frequency bands and examined their effects on metabolic connectivity (M-MC) estimates. Metabolic connectivity was markedly influenced by filtering strategy and scanner type. The CompCor filter produced more consistent and structured networks than standard bandpass filters. Intermediate frequency bands (0.01-0.1 Hz) yielded the most reliable connectivity patterns between PET/CT and PET/MR data (r=0.89). High sensitivity PET/CT data revealed structured connectivity patterns also at a higher frequency band (0.1-0.2 Hz). Compared to fMRI functional connectivity, fPET-derived networks were more spatially cohesive but less differentiated. High-temporal [18F]FDG fPET enables reliable estimation of individual resting-state M-MC when paired with appropriate denoising. Scanner choice and preprocessing significantly affect signal quality and interpretation, whereas the proposed physiologically informed pipeline improves comparability across systems and studies.

neuroscience↗

bioRxiv2025

A549 tumorigenic and BEAS-2B non-tumorigenic cell line derived small extracellular vesicles show distinct proteomic, N-glycoproteomic and chondroitin/dermatan sulfate profiles

Extracellular vesicles (EVs) are critical mediators of intercellular communication and hold promise as biomarkers and therapeutic targets in cancer, but their molecular alterations remain poorly understood. Protein glycosylation is a frequent post-translational modification; however, most EV studies focus only on proteomics, while mapping glycosylation changes of proteins are still underrepresented. To address this shortcoming, we analyzed the proteomic, N-glycoproteomic, and chondroitin/dermatan sulfate (CS/DS) glycosaminoglycan (GAG) profiles of small EVs (sEVs) derived from A549 lung adenocarcinoma and BEAS-2B non-tumorigenic epithelial cell lines. Principal component analysis and hierarchical clustering revealed that all three profiles are highly dependent on the origin of sEV, highlighting fundamental differences not only at the proteomic but also at the N-glycopeptide and CS/DS levels. Protein expression differences were primarily associated with the upregulation of cell cycle regulation, DNA repair, metabolism, and protein synthesis, while immune-related processes were predominantly downregulated. Proteomics revealed differential expressions of 5 CS proteoglycans, anticipating that their CS profile may also change. N-glycoproteomics highlighted a shift from complex to hybrid N-glycans in cancer sEVs, alongside a significant decrease in fucosylation. Prominent glycoproteins characterized with multiple glycosylation sites included versican, galectin-3-binding protein and laminins. The total amount of CS/DS increased 3.4-fold in cancer sEVs, while the ratio of the two monosulfated disaccharides changed 2-fold, suggesting altered sulfation mechanisms. These findings highlight the potential of N-glycoproteomics and GAG profiling to enhance biomarker discovery and EV-based cancer diagnostics. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/643059v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@c2dfdeorg.highwire.dtl.DTLVardef@1f79452org.highwire.dtl.DTLVardef@12a9dbborg.highwire.dtl.DTLVardef@d992da_HPS_FORMAT_FIGEXP M_FIG C_FIG Proteomic, N-glycoproteomic and chondroitin/dermatan sulfate disaccharide profiles differ between A549 lung adenocarcinoma and BEAS-2B non-tumorigenic epithelial cell derived small extracellular vesicles.

cancer biology↗

bioRxiv2024

Marcks and Marcks-like 1 proteins promote spinal cord development and regeneration in Xenopus

Marcks and Marcksl1 are abundant proteins that shuttle between the cytoplasm and membrane to modulate multiple cellular processes, including cytoskeletal dynamics, proliferation, and secretion. Here, we performed loss- and gain-of-function experiments in Xenopus laevis to reveal the novel roles of these proteins in spinal cord development and regeneration. We show that Marcks and Marcksl1 have partly redundant functions and are required for normal neurite outgrowth and proliferation of neuro-glial progenitors during embryonic spinal cord development and for its regeneration during tadpole stages. Rescue experiments in Marcks and Marcksl1 knockout animals further suggested that some of the functions of Marcks and Marcksl1 in the spinal cord are mediated by phospholipase D (PLD) signaling. Taken together, these findings identify Marcks and Marcksl1 as critical new players in spinal cord development and regeneration and suggest new pathways to be targeted for therapeutic stimulation of spinal cord regeneration in human patients.

developmental biology↗