Biology subjects

Geissler, S.

Publications and source records attributed to Geissler, S..

7 recordsLinked to original sources

bioRxiv2026

A comparative investigation of the mannose binding interface in DC-SIGN and MRC1 carbohydrate recognition domains with all-atom molecular dynamics simulations

Protein-carbohydrate interactions play a key role in numerous biological processes, including immune response, and glycan-based ligands that can target specific protein receptors on a cell surface represent promising candidates for therapeutics applications. For example, in retinoblastoma, the DC-SIGN mannose receptor is overexpressed on the surface of pathogenic cells and represents an interesting target for mannose-based ligands. At the same time, these ligands should not bind to the MRC1 receptor, which is expressed by adjacent, healthy, retinal pigment epithelial cells and presents a carbohydrate recognition domain (CRD) similar to the one of DC-SIGN. Therefore, the challenge remains to obtain a detailed picture of the recognition process between carbohydrates and proteins, in order to design effective and selective therapeutic compounds. In this work we used classical, all-atom molecular dynamics (MD) simulations to investigate the interaction between several mannose based ligands and the CRDs from DC-SIGN and MRC1. The analysis of the protein-carbohydrate contacts from the resulting trajectories highlights the variability of the mannose binding modes on both CRDs, and shows how the increased affinity of mannose for the MRC1 CRD can be related to a specific mannose binding state that is not accessible in the DC-SIGN CRD. TOC image: For Table of Contents use only O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/699853v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1ea6c2forg.highwire.dtl.DTLVardef@164a064org.highwire.dtl.DTLVardef@15e1348org.highwire.dtl.DTLVardef@1441309_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

A complex osteoporotic milieu is associated with arterial stiffening and PDGF-BB-mediated calcification of human smooth muscle cells

Accumulating evidence links skeletal and vascular aging, yet the pathological cross-talk between osteoporotic bone and vascular calcification remains insufficiently understood. In this retrospective exploratory study, we show that osteoporotic individuals exhibit a distinct systemic milieu characterized by elevated eosinophil, neutrophil, and platelet counts, as well as altered levels of sCD40L, PDGF-BB, osteopontin, and SDF-1. These changes correlate with both bone metabolism and arterial stiffness, indicating a multifactorial bone-vascular interplay. Moreover, osteoporotic sera accelerated calcification of human vascular smooth muscle cells in vitro, with PDGF-BB emerging as a central mediator. Inhibition of PDGF-BB downstream signaling blocked this effect, suggesting a mechanistic role of PDGF-BB in linking the osteoporotic milieu to vascular calcification. Conceptualizing this cross-talk as a complex adaptive system advances our understanding of the disease dynamics between localized bone loss and vascular pathologies. Furthermore, it may guide therapeutic strategies, with PDGF-BB as a potential target, to support healthier aging.

cell biology↗

bioRxiv2025

Infection-Specific Reprogramming of Microglia Reveals Distinct Virulence Pathways Linking Periodontal Pathogens to Alzheimer's Disease

Microglial dysregulation is increasingly recognized as a driver of Alzheimers disease (AD), yet how pathogen-specific cues sculpt microglial diversity remains unclear. Here we integrate high-dimensional single-cell cytometry in vitro with spatial proteomics in vivo to dissect the impact of two major periodontal pathogens on microglia. Using a 36-marker CyTOF panel, we exposed SIM-A9 microglia to wild-type Porphyromonas gingivalis (Pg) or Tannerella forsythia (Tf) and to gingipain-deficient or S-layer-deficient mutants, resolving 38 clusters. Virulence-factor "switches" redirected cells from homeostatic states toward i) oxidative, antigen-presenting programmes driven by Pg gingipains and ii) an immunosuppressive, exhausted-like state driven by the Tf S-layer. Complementary 37-marker imaging mass cytometry of 5xFAD x hTau knock-in mice chronically infected with Pg identified 21 microglial subclusters. The cortex--but not hippocampus--lost two Arg1/IL-10 immunoregulatory subsets (>2-fold decrease) while NADPH-oxidase-high microglia accumulated around amyloid-{beta} and tau aggregates. These data demonstrate pathogen-specific reprogramming of microglia across model systems and brain regions, linking virulence-factor activity to AD-relevant neuroinflammation. By pinpointing gingipains and the bacterial S-layer as molecular "switches," our study highlights tractable therapeutic targets for limiting infection-driven microglial dysfunction in Alzheimers disease.

neuroscience↗

bioRxiv2025

Unraveling the Co-Morbidity between COVID-19 and Neurodegenerative Diseases Through Multi-scale Graph Analysis: A Systematic Investigation of Biological Databases and Text Mining

The COVID-19 pandemic has generated a vast volume of research, yet much of it focuses on individual diseases, overlooking complex comorbidity relationships. While extensive literature exists on both neurodegenerative diseases (NDDs), such as Alzheimers and Parkinsons, and COVID-19, their intersection remains underexplored. Co-morbidity modeling is crucial, particularly for hospitalized patients often presenting with multiple conditions. This study investigates the interplay between COVID-19 and NDDs by integrating knowledge graphs (KGs) built from curated biomedical datasets and text mining tools. We performed comprehensive analyses--including path analysis, phenotype coverage, and mapping of cellular and genetic factors--across multiple KGs, such as PrimeKG, DrugBank, OpenTargets, and those generated via natural language processing (NLP) methods. Our findings reveal notable variability in graph density and connectivity, with each KG offering unique insights into molecular and phenotypic links between COVID-19 and NDDs. Key genetic and inflammatory markers, especially immune response genes, consistently appeared across graphs, suggesting a shared pathogenic basis. By unifying structured biological data with unstructured textual evidence, we enhance co-morbidity modeling and improve recall in identifying mechanisms underlying COVID-19- NDD interactions. This integrative framework supports the development of a co-morbidity hypothesis database aimed at facilitating therapeutic target discovery. All data, methods, and instructions for accessing the co-morbidity hypothesis database are publicly available at: https://github.com/SCAI-BIO/covid-NDD-comorbidity-NLP.

bioinformatics↗

bioRxiv2022

Odd skipped-related 1 controls the pro-regenerative response of Fibro-Adipogenic Progenitors

Skeletal muscle regeneration requires the coordinated interplay of diverse tissue-resident- and infiltrating cells. Fibro-adipogenic progenitors (FAPs) are an interstitial cell population that provides a beneficial microenvironment for muscle stem cells (MuSCs) during muscle regeneration. Here we show that the transcription factor Osr1 is essential for FAPs to communicate with MuSCs and infiltrating macrophages, thus coordinating muscle regeneration. Conditional inactivation of Osr1 impaired muscle regeneration with reduced myofiber growth and formation of excessive fibrotic tissue with reduced stiffness. Osr1-deficient FAPs acquired a fibrogenic identity with altered matrix secretion and cytokine expression resulting in impaired MuSC viability, expansion and differentiation. Immune cell profiling suggested a novel role for Osr1-FAPs in macrophage polarization. In vitro analysis suggested that increased TGF{beta} signaling and altered matrix deposition by Osr1-deficient FAPs actively suppressed regenerative myogenesis. In conclusion, we show that Osr1 is central to FAP function orchestrating key regenerative events such as inflammation, matrix secretion and myogenesis.

developmental biology↗

bioRxiv2022

Integrative analysis to identify shared mechanisms between schizophrenia and bipolar disorder and their comorbidities

Schizophrenia and bipolar disorder are characterized by highly similar neuropsychological signatures, implying shared neurobiological mechanisms between these two disorders. These disorders also have comorbidities with other indications, such as type 2 diabetes mellitus (T2DM). To date, an understanding of the mechanisms that mediate the link between these two disorders remains incomplete. In this work, we identify and investigate shared patterns across multiple schizophrenia, bipolar disorder and T2DM gene expression datasets through multiple strategies. Firstly, we investigate dysregulation patterns at the gene-level and compare our findings against disease-specific knowledge graphs (KGs). Secondly, we analyze the concordance of co-expression patterns across datasets to identify disease-specific as well as common pathways. Thirdly, we examine enriched pathways across datasets and disorders to identify common biological mechanisms between them. Lastly, we investigate the correspondence of shared genetic variants between these two disorders and T2DM as well as the disease-specific KGs. In conclusion, our work reveals several shared candidate genes and pathways, particularly those related to the immune and nervous systems, which we propose mediate the link between schizophrenia and bipolar disorder and its shared comorbidity, T2DM.

bioinformatics↗

bioRxiv2018

Placental-expanded, mesenchymal cells improve muscle function following hip arthroplasty

BackgroundNo regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite high frequency and associated functional deficits. We sought to address surgical trauma related muscle injuries using local intraoperative application of allogeneic placenta-derived, mesenchymal-like adherent cells (PLX-PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type.\n\nMethodsOur pilot phase I/IIa study was prospective, randomized, double blind and placebo-controlled. Twenty patients undergoing hip arthroplasty via a direct lateral approach were injected with 3.0x108 or 1.5x108 PLX-PAD or a placebo into the gluteus medius muscle.\n\nResultsWe did not observe any relevant PLX-PAD-related adverse events at the 2-year follow-up. Improved gluteus medius strength was noted as early as week 6 in the treatment-groups. Surprisingly, until week 26 the low-dose outperformed the high-dose group and reached significantly improved strength compared to placebo, mirrored by an increase in muscle volume. Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that low-dose treatment reduced the surgery-related immunological stress reaction more than high-dose. Signs of late-onset immune reactivity after high-dose treatment corresponded to reduced functional improvement.\n\nConclusionAllogeneic PLX-PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress-related immunological reactions.\n\nTrial RegistrationClinicalTrials.gov (number NCT01525667) and EudraCT (number 2011-003934-16)\n\nFundingThe study was funded by the Sponsor, Pluristem Therapeutics, the Israeli innovation authority and the German Federal Ministry of Education and Research.\n\nConflict of interestT. Winkler, C. Perka and G.N. Duda are members of a clinical advisory board of Pluristem Ltd for future indications. T. Winkler, C. Perka, G.N. Duda, P. von Roth filed a patent together with Pluristem Ltd. E. Lukasiewicz Hagai, R. Ofir, L. Pinzur and E. Eyal are current or former employees of Pluristem Ltd. T. Winkler, P. Reinke and H.-D. Volk received in the past consulting fees from Pluristem Ltd. but not for this project.

clinical trials↗