Biology subjects

Koch, W.

Publications and source records attributed to Koch, W..

9 recordsLinked to original sources

bioRxiv2026

scRNA-seq and genomics analyses reveal key mechanisms of inverted papilloma-associated sinonasal squamous cell carcinoma malignant transformation

Sinonasal inverted papilloma (IP) carries a 10% risk of malignant transformation to IP-associated sinonasal squamous cell carcinoma (IP-SNSCC), yet the molecular and immune drivers of this progression remain poorly defined. This study integrates single-cell RNA sequencing, multiplexed spatial proteomics, whole-exome sequencing, and functional assays across IP and IP-SNSCC cohorts to define mechanisms of malignant transformation. Respiratory epithelial basal cells are identified as the putative cell of origin, with progression marked by recurrent CDKN2A loss and TP53 mutations. Spatial profiling reveals immune reorganization at the lesional interface in IP-SNSCC, characterized by enrichment of alternatively activated M2 macrophages. CXCL14 is shown to directly induce an immunosuppressive myeloid phenotype that suppresses T-cell IFN{gamma} production through an IDO-pathway-dependent mechanism. Integration of these multimodal datasets defines a previously unrecognized CXCL14-IDO mechanism that constrains anti-tumor immunity at the tumor-stroma interface. These findings establish IDO-targeted immunomodulation as a rational adjuvant strategy and provide a comprehensive molecular framework for understanding IP-SNSCC pathogenesis.

genomics↗

bioRxiv2024

Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction

BackgroundAmyloidosis is a major long-term complication of chronic disease; however, whether it represents one of the complications of post-myocardial infarction (MI) is yet to be fully understood. MethodsUsing wild-type and knocked-out MI mouse models and characterizing in vitro the exosomal communication between bone marrow-derived macrophages and activated mesenchymal stromal cells (MSC) isolated after MI, we investigated the mechanism behind Serum Amyloid A 3 (SAA3) protein overproduction in injured hearts. ResultsHere, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived SAA3 monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from a subset of activated MSC, which, in response to MI, acquire the expression of a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin (PDPN). Cardiac MSCPDPN+ communicate with and activate macrophages through their extracellular vesicles or exosomes. Specifically, MSCPDPN+ derived exosomes (MSCPDPN+ Exosomes) are enriched in SAA3 and exosomal SAA3 protein engages with Toll-like receptor 2 (TRL2) on macrophages, triggering an overproduction and impaired clearance of SAA3 proteins, resulting in aggregation of SAA3 monomers as rigid amyloid deposits in the extracellular space. The onset of amyloid fibers deposition alongside extra-cellular-matrix (ECM) proteins in the ischemic heart exacerbates the rigidity and stiffness of the scar, hindering the contractility of viable myocardium and overall impairing organ function. Using SAA3 and TLR2 deficient mouse models, we show that SAA3 delivered by MSCPDPN+ exosomes promotes post-MI amyloidosis. Inhibition of SAA3 aggregation via administration of a retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils, positively modulates the scar formation, and improves heart function post-MI. ConclusionOverall, our findings provide mechanistic insights into post-MI amyloidosis and suggest that SAA3 may be an attractive target for effective scar reversal after ischemic injury and a potential target in multiple diseases characterized by a similar pattern of inflammation and amyloid deposition. NOVELTY AND SIGNIFICANCEWhat is known? O_LIAccumulation of rigid amyloid structures in the left ventricular wall impairs ventricle contractility. C_LIO_LIAfter myocardial infarction cardiac Mesenchymal Stromal Cells (MSC) acquire Podoplanin (PDPN) to better interact with immune cells. C_LIO_LIAmyloid structures can accumulate in the heart after chronic inflammatory conditions. C_LI What information does this article contribute? O_LIWhether accumulation of cumbersome amyloid structures in the ischemic scar impairs left ventricle contractility, and scar reversal after myocardial infarction (MI) has never been investigated. C_LIO_LIThe pathophysiological relevance of PDPN acquirement by MSC and the functional role of their secreted exosomes in the context of post-MI cardiac remodeling has not been investigated. C_LIO_LIAmyloid structures are present in the scar after ischemia and are composed of macrophage-derived Serum Amyloid A (SAA) 3 monomers, although mechanisms of SAA3 overproduction is not established. C_LI SUMMARY OF NOVELTY AND SIGNIFICANCEHere, we report that amyloidosis, a secondary phenomenon of an already preexisting and prolonged chronic inflammatory condition, occurs after MI and that amyloid structures are composed of macrophage-derived SAA3 monomers. Frequently studied cardiac amyloidosis are caused by aggregation of immunoglobulin light chains, transthyretin, fibrinogen, and apolipoprotein in a healthy heart as a consequence of systemic chronic inflammation leading to congestive heart failure with various types of arrhythmias and tissue stiffness. Although chronic MI is considered a systemic inflammatory condition, studies regarding the possible accumulation of amyloidogenic proteins after MI and the mechanisms involved in that process are yet to be reported. Here, we show that SAA3 overproduction in macrophages is triggered in a Toll-like Receptor 2 (TLR2)-p38MAP Kinase-dependent manner by exosomal communication from a subset of activated MSC, which, in response to MI, express a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin. We provide the full mechanism of this phenomenon in murine models and confirm SAA3 amyloidosis in failing human heart samples. Moreover, we developed a retro-inverso D-peptide therapeutic approach, "DRI-R5S," specifically designed to bind SAA3 monomers and prevent post-MI aggregation and deposition of SAA3 amyloid fibrils without interfering with the innate immune response.

immunology↗

bioRxiv2022

intSDM: A reproducible framework for integrated species distribution models

1O_LIThere has been an exponential increase in quantity and type of biodiversity data in recent years, including presence-absence, counts, and presence-only citizen science data. Species Distribution Models (SDMs) have typically been used in ecology to estimate current and future ranges of species, and are a common tool used when making conservation prioritisation decisions. However integration of these data in a model-based framework is needed to address many of the current large-scale threats to biodiversity. C_LIO_LICurrent SDM practice typically underutilizes the large amount of publicly available biodi-versity data and does not follow a set of standard best practices. Integrating different data types with open-source tools and reproducible workflows saves time, increases collaboration opportunities, and increases the power of data inference in SDMs. C_LIO_LIWe aim to address this issue by (1) proposing methods and (2) generating a reproducible workflow to integrate different available data types to increase the power of SDMs. We provide the R package intSDM, as well as guidance on how to accommodate users diverse needs and ecological questions with different data types available on the Global Biodiversity Information Facility (GBIF), the largest biodiversity data aggregator in the world. C_LIO_LIFinally, we provide a case study of the application of our proposed reproducible workflow by creating SDMs for vascular plants in Norway, integrating presence-only and presence-absence species occurrence data and climate data. C_LI

ecology↗

bioRxiv2022

Recognizability bias in citizen science photographs

Citizen science initiatives and automated collection methods increasingly depend on image recognition in order to provide the amounts of observational data research and management needs. Training recognition models, meanwhile, also requires large amounts of data from these sources, creating a feedback loop between the methods and the tools. Species that are harder to recognize, both for humans and machine learning algorithms, are likely to be underreported, and thus be less prevalent in the training data. As a result, the feedback loop may hamper training mostly for species that already pose the greatest challenge. In this study, we trained recognition models for various taxa, and found evidence for a "recognizability bias", where species that models struggle with are also generally underreported. This has implications for the kind of performance one can expect from future models that are trained with more data, including such challenging species. We consider identification methods that rely on more than photographs alone to be important in improving future identification tools.

ecology↗

bioRxiv2022

Clavis: an open and versatile identification key format

The skills and knowledge needed to recognize and classify taxa are becoming increasingly scarce in the scientific community. At the same time, it is clear that these skills are strongly needed in biodiversity monitoring for management and conservation, especially when carried out by citizen scientists. Formalizing the required knowledge in the form of digital identification keys is one way of making such knowledge more available for professional and amateur observers of biodiversity. In this paper we describe Clavis, an open and versatile data format for capturing the knowledge required for taxon identification through digital keys, allowing for a level of detail beyond that of any current key format. We present the format independently from any particular implementation, as our aim is for Clavis to serve as a basis for interoperable tools and interfaces serving different needs and actors.

ecology↗

bioRxiv2022

Maximizing citizen scientists' contribution to automated species recognition

Technological advances and data availability have enabled artificial intelligence-driven tools that can increasingly successfully assist in identifying species from images. Especially within citizen science, an emerging source of information filling the knowledge gaps needed to solve the biodiversity crisis, such tools can allow participants to recognize and report more poorly known species. This can be an important tool in addressing the substantial taxonomic bias in biodiversity data, where broadly recognized, charismatic species are highly overrepresented. Meanwhile, the recognition models are trained using the same biased data, so it is important to consider what additional images are needed to improve recognition models. In this study, we investigated how the amount of training data influenced the performance of species recognition models for various taxa. We utilized a large Citizen Science dataset collected in Norway, where images are added independently from identification. We demonstrate that while adding images of currently under-represented taxa will generally improve recognition models more, there are important deviations from this general pattern. Thus, a more focused prioritization of data collection beyond the basic paradigm that "more is better" is likely to significantly improve species recognition models and advance the representativeness of biodiversity data.

ecology↗

bioRxiv2021

Sugar beet cold-induced PMT5a and STP13 carriers are poised for taproot proton-driven plasma membrane sucrose and glucose import

Sugar beet (Beta vulgaris) is the major sugar-producing crop in Europe and Northern America, as the taproot stores sucrose at a concentration of around 20%. Genome sequence analysis together with biochemical and electrophysiological approaches led to the identification and characterization of the TST sucrose transporter driving vacuolar sugar accumulation in the taproot. However, the sugar transporters mediating sucrose uptake across the plasma membrane of taproot parenchyma cells remained unknown. As with glucose, sucrose stimulation of taproot parenchyma cells caused inward proton fluxes and plasma membrane depolarization, indicating a sugar/proton symport mechanism. To decipher the nature of the corresponding proton-driven sugar transporters, we performed transcriptomic taproot profiling and identified the cold-induced PMT5a and STP13 transporters. When expressed in Xenopus laevis oocytes, BvPMT5a was characterized as a voltage- and H+-driven low-affinity glucose transporter, which does not transport sucrose. In contrast, BvSTP13 operated as a high-affinity H+/sugar symporter, transporting glucose better than sucrose, and being more cold-tolerant than BvPMT5a. Modeling of the BvSTP13 structure with bound mono- and disaccharides suggests plasticity of the binding cleft to accommodate the different saccharides. The identification of BvPMT5a and BvSTP13 as taproot sugar transporters could improve breeding of sugar beet to provide a sustainable energy crop. Significance StatementIn vivo electrophysiological studies with sugar beet taproots provide clear evidence for proton-coupled glucose and sucrose uptake into taproot parenchyma cells. In search for the molecular entities, the taproot-expressed BvPMT5a and BvSTP13 carriers were studied in detail, because they mediate proton-driven import of glucose and sucrose and thus provide proper candidates for sugar beet plasma membrane sugar-proton cotransporters.

plant biology↗

bioRxiv2021

Cold-triggered induction of ROS- and raffinose metabolism in freezing-sensitive taproot tissue of sugar beet

Sugar beet (Beta vulgaris subsp. vulgaris) is the exclusive source of sugar in the form of sucrose in temperate climate zones. There, sugar beet is grown as an annual crop from spring to autumn because of the damaging effect of freezing temperatures to taproot tissue. Natural and breeded varieties display variance in the degree of tolerance to freezing temperatures and genotypes with elevated tolerance to freezing have been isolated. Here we compare initial responses to frost between genotypes with either low and high winter survival rates. The selected genotypes differed in the severity of frost injury. We combined transcriptomic and metabolite analyses of leaf- and taproot tissues from such genotypes to elucidate mechanisms of the early freezing response and to dissect genotype- and tissue-dependent responses. Freezing temperatures induced drastic downregulation of photosynthesis-related genes in leaves but upregulation of genes related to minor carbohydrate metabolism, particularly of genes involved in raffinose metabolism in both, leaf and taproot tissue. In agreement with this, it has been revealed that raffinose and the corresponding intermediates, inositol and galactinol, increased markedly in these tissues. We found that genotypes with improved tolerance to freezing, showed higher accumulation of raffinose in a defined interior region within the upper part of the taproot, the pith, representing the tissue most susceptible to freeze damages. This accumulation was accompanied by specific upregulation of raffinose synthesizing enzymes in taproots, suggesting a protective role for raffinose and its precursors for freezing damage in sugar beet.

plant biology↗

bioRxiv2020

Vernalization alters sugar beet (Beta vulgaris) sink and source identities and reverses phloem translocation from taproots to shoots

During vegetative growth, biennial sugar beets maintain a steep gradient between the shoot (source) and the sucrose-storing taproot (sink). To shift from vegetative to generative growth, they require a chilling phase, called vernalization. Here, we studied sugar beet sink-source dynamics upon cold temperature-induced vernalization and revealed a pre-flowering taproot sink to source reversal. This transition is induced by transcriptomic and functional reprogramming of sugar beet tissue, resulting in a reversal of flux direction in long distance transport system, the phloem. As a key process for this transition, vacuolar sucrose importers and exporters, BvTST2;1 and BvSUT4, are oppositely regulated, leading to re-mobilization of sugars from taproot storage vacuoles. Concomitant changes in the expression of floral regulator genes suggest that the now deciphered processes are a prerequisite for bolting. Our data may thus serve dissecting metabolic and developmental triggers for bolting, which are potential targets for genome editing or breeding approaches.

plant biology↗