Biology subjects

Fritz, C.

Publications and source records attributed to Fritz, C..

7 recordsLinked to original sources

bioRxiv2025

B-cell activating factor plays a critical role in CAR-T cell-associated cytokine release syndrome

Cytokine release syndrome (CRS) is the most common and potentially life-threatening toxicity associated with CAR-T cell therapy and is related to a heightened immune effector state. In this work, we identified a novel role of the pro-tumorigenic cytokine B-cell activating factor (BAFF) in its pathophysiology. First, we observed that patients who experienced CAR-T cell-related CRS have elevated serum BAFF levels that coincide with elevated IL-6. Mechanistically, we show that IFN-{gamma}, produced by activated CAR-T cells, stimulates monocytes to release BAFF, which induces the expression of CRS-related cytokines from monocytes. Monocytes derived from CRS patients express BCMA, which is further induced by IFN-{gamma} stimulation. Neutralization of BAFF with belimumab significantly reduces production of various CRS and ICANS-related cytokines without impairing CAR-T cell activation or killing. Overall, we demonstrate that BAFF plays a critical role in CAR-T-cell-related CRS, and its neutralization may be a novel strategy for treating both CRS and ICANS. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/689920v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@187a0edorg.highwire.dtl.DTLVardef@1566904org.highwire.dtl.DTLVardef@896b5org.highwire.dtl.DTLVardef@1de5db6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Long-Term Ecological Baselines and Critical Thresholds in Ombrotrophic Peatlands of Europe: Implications for Restoration Strategies

Maintaining appropriate peatland hydration, particularly through the regulation of the depth to the water table (DWT), is crucial for peatland conservation, restoration, and the mitigation of greenhouse gas emissions. In this study, we assess the long-term ecological impact of hydrological changes, primarily induced by drainage, on ombrotrophic peatlands across Europe. Our analysis is based on novel palaeoecological data from seven peat cores collected from sites that have experienced varying degrees of anthropogenic disturbance. We reconstructed historical DWT fluctuations using plant macrofossil and testate amoeba analyses at high resolution. By applying Threshold Indicator Taxa Analysis (TITAN), we identified species-specific and community-level response thresholds to changes in water level. This approach revealed two distinct change points: the first, at approximately 7 cm DWT, corresponds to hydrological conditions favourable for moisture-dependent Sphagnum species, while the second, near 22 cm DWT, is associated with more drought-adapted taxa and signals ecosystem degradation. The interval between these points represents a transition zone between optimal and suboptimal conditions for peatland functioning. An additional TITAN analysis aimed at identifying the timing of the most significant ecological changes indicates that peatland degradation intensified over the past two centuries and has accelerated in recent decades. Our findings also show that even after hydrological restoration, microbial and plant communities often remain distinct from those in undisturbed peatlands. This underscores the importance of preserving sites that still retain near-natural conditions. Based on our results (and consistent with previous studies) we recommend maintaining a DWT of approximately 10 cm below the surface as an optimal target for both peatland conservation and restoration. Such conditions not only support ecological integrity but are also associated with reduced greenhouse gas emissions and higher peat accumulation rates, reinforcing the role of ombrotrophic peatlands as long-term carbon sinks.

ecology↗

bioRxiv2024

Plasma membrane and cytoplasmic compartmentalization: a dynamic structural framework required for pollen tube tip growth

Rapid, unidirectional pollen tube tip growth is essential for fertilization and is widely employed as a model of polar cell expansion, a process crucial for plant morphogenesis. Different proteins and lipids with key functions in the control of polar cell expansion are associated with distinct domains of the plasma membrane (PM) at the pollen tube tip. These domains need to be dynamically maintained during tip growth, which depends on massive secretory and endocytic membrane traffic. Very little is currently known about the regulatory and cellular mechanisms responsible for the compartmentalization of the pollen tube PM. To provide a reliable structural framework for the further characterization of these mechanisms, an integrated quantitative map was compiled of the relative positions in normally growing tobacco pollen tubes of PM domains 1) enriched in key signaling proteins or lipids, 2) displaying high membrane order, or 3) in contact with cytoplasmic structures playing important roles in apical membrane traffic. Previously identified secretory and endocytic PM domains were also included into this map. Internalization of regulatory proteins or lipids associated with PM regions overlapping with the endocytic domain was assessed based on brefeldin A (BFA) treatment. These analyses revealed remarkable aspects of the structural organization of tobacco pollen tube tips, which enhance our understanding of tip growth by providing important insights into 1) RAC/ROP signaling, 2) phosphatidylinositol 4,5-bisphosphate (PI4,5P2) metabolism and functions, 3) trafficking of signaling lipids, 4) functions of domains displaying high membrane order, and 5) Ca2+ regulation of secretion. SummaryQuantitative mapping of plasma membrane and cytoplasmic domains at the tip of elongating tobacco pollen provides important insights into regulatory and cellular mechanisms essential for tip growth.

cell biology↗

bioRxiv2022

Helical ultrastructure of the oncogenic metalloprotease meprin α in complex with a small molecule hydroxamate inhibitor

The zinc-dependent metalloprotease meprin is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal tissue homeostasis meprin performs key roles in inflammation, immunity, and extracellular matrix remodelling. The latter activity is furthermore important for driving aggressive metastasis in the context of certain cancers such as colorectal carcinoma. Accordingly, meprin is the target of drug discovery programs. In contrast to meprin {beta}, meprin is secreted into the extracellular space, whereupon it oligomerises to form giant assemblies and is the largest extracellular protease identified to date (~6 MDa). Here, using cryo-electron microscopy, we determine the high-resolution structure of the zymogen and mature form of meprin , as well as the structure of the active form in complex with a prototype small molecule inhibitor and human fetuin-B. Our data reveal that meprin forms a giant, flexible, left-handed helical assembly of roughly 22 nm in diameter. We find that oligomerisation improves proteolytic and thermal stability but does not impact substrate specificity or enzymatic activity. Furthermore, structural comparison with meprin {beta} reveal unique features of the active site of meprin , and helical assembly more broadly.

biochemistry↗

bioRxiv2021

Sensory attenuation for external events is produced by a competition for attentional resources

Sensory events appear reduced in intensity when we actively produce them. Here, we investigated sensory attenuation in a virtual reality setup that allowed us to manipulate the time of tactile feedback when pressing a virtual button. We asked whether tactile motor attention might shift to the tactile location that makes contact with the button. In experiment one, we found that a tactile impulse was perceived as more intense when button pressing. In a second experiment, participants pushed a button and estimated the intensity of sounds. We found sensory attenuation for sounds only when tactile feedback was provided at the time the movement goal was reached. These data indicate that attentional prioritization for the tactile modality during a goal-directed hand movement might lead to a transient reduction in sensitivity in other modalities, resulting in sensory attenuation for sounds.

neuroscience↗

bioRxiv2020

Proteogenomic heterogeneity of localized human prostate cancer progression

BackgroundTumor-specific genomic aberrations are routinely determined by high throughput genomic measurements. It remains unclear though, how complex genome alterations affect molecular networks through changing protein levels, and consequently biochemical states of tumor tissues. ResultsHere, we investigated the propagation of genomic effects along the axis of gene expression during prostate cancer progression. For that, we quantified genomic, transcriptomic and proteomic alterations based on 105 prostate samples, consisting of benign prostatic hyperplasia regions and malignant tumors, from 39 prostate cancer patients. Our analysis revealed convergent effects of distinct copy number alterations impacting on common downstream proteins, which are important for establishing the tumor phenotype. We devised a network-based approach that integrates perturbations across different molecular layers, which identified a sub-network consisting of nine genes whose joint activity positively correlated with increasingly aggressive tumor phenotypes and was predictive of recurrence-free survival. Further, our data revealed a wide spectrum of intra-patient network effects, ranging from similar to very distinct alterations on different molecular layers. ConclusionsThis study uncovered molecular networks with remarkably convergent alterations across tumor sites and patients, but it also exposed a diversity of network effects: we could not identify a single sub-network that was perturbed in all high-grade tumor regions.

systems biology↗

bioRxiv2019

High-throughput proteomic analysis of FFPE tissue samples facilitates tumor stratification

Formalin-fixed, paraffin-embedded (FFPE), biobanked tissue samples offer an invaluable resource for clinical and biomarker research. Here we developed a pressure cycling technology (PCT)-SWATH mass spectrometry workflow to analyze FFPE tissue proteomes and applied it to the stratification of prostate cancer (PCa) and diffuse large B-cell lymphoma (DLBCL) samples. We show that the proteome patterns of FFPE PCa tissue samples and their analogous fresh frozen (FF) counterparts have a high degree of similarity and we confirmed multiple proteins consistently regulated in PCa tissues in an independent sample cohort. We further demonstrate temporal stability of proteome patterns from FFPE samples that were stored between one to 15 years in a biobank and show a high degree of the proteome pattern similarity between two types histological region of small FFPE samples, i.e. punched tissue biopsies and thin tissue sections of micrometer thickness, despite the existence of certain degree of biological variations. Applying the method to two independent DLBCL cohorts we identified myeloperoxidase (MPO), a peroxidase enzyme, as a novel prognostic marker. In summary, this study presents a robust proteomic method to analyze bulk and biopsy FFPE tissues and reports the first systematic comparison of proteome maps generated from FFPE and FF samples. Our data demonstrate the practicality and superiority of FFPE over FF samples for proteome in biomarker discovery. Promising biomarker candidates for PCa and DLBCL have been discovered.

biochemistry↗