Biology subjects

Mohr, A.

Publications and source records attributed to Mohr, A..

6 recordsLinked to original sources

bioRxiv2025

MSC-delivered High-Affinity Variants of soluble PD1 lead to tumour regression

Immune checkpoint therapies aim to restore anti-tumour immunity by blocking inhibitory signals that suppress T-cell activation. The most effective current strategies use humanised antibodies targeting PD1 or its ligand PDL1. However, due to their large size, antibodies often exhibit limited tissue diffusion, resulting in poor penetration into solid tumours. To address this challenge, we developed a novel checkpoint inhibitor approach that uses mesenchymal stromal cells (MSCs) to deliver a high-affinity, soluble PD1 receptor (sPD1HAC). We found that sPD1HAC produced as an IgG1-Fc fusion protein provided functional expression in MSCs. The sPD1HAC-IgG1-Fc fusion protein showed strong and specific binding to PDL1 and could outcompete recombinant PD1 and anti-PDL1 antibodies, including the clinically approved durvalumab. Although the sPD1HAC variant was designed to block human PD1-PDL1 signalling, it also bound murine PDL1 and blocked the binding of mouse-specific PD1 antibodies as well as recombinant murine PD1 protein. Accordingly, we found significant anti-tumour activity of intravenously administered MSCs.PD1HAC in an aggressive B16-F10 cancer model. This cell-based immune checkpoint approach offers a potential therapeutic option for targeting stroma-rich, treatment-resistant tumours.

cancer biology↗

bioRxiv2025

Age- and Sex- Driven Transcriptional and Metabolic Diversity in Myeloid-Derived Suppressor Cells After Mouse Sepsis

Sepsis induces profound immune dysregulation, often resulting in chronic critical illness characterized by persistent immunosuppression and poor outcomes. Myeloid-derived suppressor cells (MDSCs) are central mediators of this immunosuppressive phenotype, yet the influence of age and sex on their transcriptional and metabolic states remain poorly understood. Here, we employed single-cell RNA sequencing of splenic leukocytes from young (3-4 months) and older (18-24 months) adult male and female mice subjected to a clinically relevant murine sepsis model to define age- and sex-specific MDSC phenotypes. We identified significant differences regarding age and sex in MDSC expansion, transcriptome, canonical pathway activation, RNA velocity, mitochondrial metabolism, and predicted cell-cell communication after sepsis. Using drug2cell analysis of total leukocytes we also identified cohort-specific drug target profiles. These findings underscore the importance of age and sex in shaping sepsis-induced MDSC biology and suggest that personalized immunomodulatory strategies targeting MDSCs could improve sepsis outcomes.

immunology↗

bioRxiv2025

RHODOPSIN 7: An ancient non-retinal photoreceptor for contrast vision, darkness detection, and circadian regulation

1Animals rely on light not only for vision but also to adapt behavior to their environment through non-image-forming pathways. In Drosophila, most rhodopsins mediate retinal image formation, but RHODOPSIN 7 (RH7) is widely expressed in the brain and optic lobe, acting as a non-canonical light sensor reminiscent of mammalian melanopsin. We combined expression mapping, behavioral assays, and phylogenetic comparisons to investigate its function. RH7 detects temporal changes in luminance, guiding rapid behavioral responses, and regulating daily activity patterns. Flies lacking RH7 are less active during the dark phase, while strains with constitutively active RH7 show increased activity. Phylogenetic analyses suggest that RH7 is an ancient rhodopsin present across panarthropods, representing an intermediate between G protein-coupled receptors and specialized rhodopsins, highlighting a key step in the evolution of non-visual light perception. These findings show that RH7 functions as a melanopsin-like sensor, shaping behavior, and illuminating the origins of light detection.

neuroscience↗

bioRxiv2024

Autorepression of Yeast Hsp70 co-chaperones by intramolecular interactions involving their J-domains.

The Hsp70 chaperones control protein homeostasis in all ATP-containing cellular compartments. J-domain proteins (JDPs) co-evolved with Hsp70s to trigger ATP-hydrolysis and catalytically upload various substrate polypeptides in need to be structurally modified by the chaperone. Here, we measured the protein disaggregation and refolding activities of the main yeast cytosolic Hsp70, Ssa1, in the presence of its most abundant JDPs, Sis1 and Ydj1, and two swap mutants, in which the J-domains have been interchanged. The observed differences by which the four constructs differently cooperate with Ssa1 and cooperate with each other, as well as their observed intrinsic ability to bind misfolded substrates and trigger Ssa1s ATPase, indicates the presence of yet uncharacterized intra-molecular dynamic interactions between the J-domains and their remaining C-terminal domains. Taken together, the data suggest an auto-regulatory role to these intra-molecular interactions within both type A and B JDPs, which might have evolved to reduce energy-costly ATPase cycles by the Ssa1-4 chaperones that are the most abundant Hsp70s in the yeast cytosol. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/578849v1_figa1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@d895d3org.highwire.dtl.DTLVardef@1545221org.highwire.dtl.DTLVardef@dc08b3org.highwire.dtl.DTLVardef@1bf286a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract:C_FLOATNO Lower panel: autoinhibited DnaJA or DnaJB dimers, drawn here as Swiss army knives with sequestered J-domains as folded blades, can bind misfolded polypeptides (violet). Upper panel: DnaJA or DnaJB become active when their J-domains are exposed and can bind ATP-Hsp70s, and transfer the misfolded polypeptides, respectively, onto Hsp70s nucleotide binding (Cyan) and protein binding domains (Orange and Green). Hsp70s interdomain linker (DLLLLDV, Magenta). C_FIG

biochemistry↗

bioRxiv2023

IgG4 serum levels are not elevated in cases of Post-COVID syndrome

Recently, unexpectedly high virus-specific IgG4 levels were reported after more than two mRNA vaccinations. Class switch towards IgG4 occurs after long-term antigen exposure, downregulates immune responses and is associated with several autoimmune diseases. Here, we examined differences in antigen-specific IgG subtypes in serum samples from 64 Post-COVID patients and an equally sized cohort of convalescent controls. In both cohorts, the relative amounts of spike protein-specific IgG subtypes were comparable. IgG1 was the most frequent, followed by IgG3, IgG2, and IgG4. A difference between cohorts was observed only for IgG2, which was significantly lower in the Post-COVID cohort. Further analysis of the reactive IgG4 revealed a small but significant difference for the spike protein receptor-binding domain but not for the spike ectodomain. Since the total IgG4 levels are very low, we do not expect a biologically relevant role in Post-COVID syndrome. However, reduced virus-specific IgG2 levels could contribute to the persistence of SARS-CoV-2, causing chronic inflammation in the setting of Post-COVID syndrome.

immunology↗

bioRxiv2020

Fas-threshold signalling in MSCs causes tumour progression and metastasis

Mesenchymal stem cells (MSCs) are part of the tumour microenvironment and have been implicated in tumour progression. We found the number of MSCs significantly increased in tumour-burdened mice driven by Fas-threshold signalling. Consequently, MSCs lacking Fas lost their ability to induce metastasis development in a pancreatic cancer model. Mixing of MSCs with pancreatic cancer cells led to sustained production of the pro-metastatic cytokines CCL2 and IL6 by the stem cells. The levels of these cytokines depended on the number of MSCs, linking Fas-mediated MSC-proliferation to their capacity to promote tumour progression. Furthermore, we discovered that CCL2 and IL6 were induced by pancreatic cancer cell-derived IL1. Analysis of patient transcriptomic data revealed that high FasL expression correlates with high levels of MSC markers as well as increased IL6 and CCL2 in pancreatic tumours. Moreover, both FasL and CCL2 are linked to elevated levels of markers specific for monocytes known to possess further pro-metastatic activities. These results confirm our experimental findings of a FasL-MSC-IL1-CCL2/IL6 axis in pancreatic cancer and highlight the role MSCs play in tumour progression.

cancer biology↗