Student Speakers

Rebecca Springer

Nicolas Schlegel  Lab

The Double Threat: Interplay between Gut Barrier Dysfunction and Microbial Composition in High-Fat Diet Induced Obesity

Obesity is associated with metabolic disorders such as glucose intolerance and impaired intestinal epithelial barrier (IEB) function. Disruption of IEB integrity, marked by elevated serum lipopolysaccharide (LPS) levels, loss of tight-junction proteins, and changes in microbial diversity, may be key in obesity pathophysiology. This study explores the link between obesity, IEB breakdown, and gut microbiome alterations, with a focus on how microbial metabolites affect IEB function using a rat obesity model and intestinal organoids.

Salma Abosabie

David Stegner, Michael Schuhmann, Anish Sharda (External, Yale University, USA)

Endothelial dysfunction in myeloproliferative neoplasms

Classical myeloproliferative neoplasms (MPNs) involve excessive clonal hematopoiesis, resulting in an overproduction of mature blood cells which increases the risk of thromboembolic events. The exact mechanisms behind MPN-associated thromboembolic events are not fully understood. We evaluated blood outgrowth endothelial cells (BOECs), which are circulating cells with an endothelial phenotype, from peripheral blood from individuals with JAK2V617F-mutated MPN to uncover phenotypic and transcriptomic abnormalities that may exist in MPN endothelium.

Bernardo Papini Gabiatti

Prof. Dr. Susanne Kramer - Biomedicine

A novel comprehensive map the trypanosome nuclear pore and a trypanosomatid-unique mechanism of nuclear export

Nuclear export of mRNAs requires loading the mRNP to the transporter Mex67 at the nucleoplasm, controlled access to the nuclear pore complex (NPC) by the basket-localized TREX2 complex, and Mex67 release at the cytoplasmic side of the pore by the DEAD-box RNA helicase Dbp5, cooperatively ensuring the directionality of the process. The current model of the Trypanosoma brucei NPC is symmetric, except for the nuclear basket. Thus, no TREX2 ortholog is known, and no cytoplasmic-exclusive nucleoporins (NUPs) have been implicated in the release of the mRNP. We have revisited the trypanosome NPC, combining the methods of expansion microscopy, streptavidin imaging, and BioID, all with sub-NPC resolution. Asymmetric localization for several NUPs was found and cross-validated by these different methods. We established reference proteins for sub-NPC sites and mapped the localization of all known 75 proteins with nuclear pore localization using BioID. We found that most proteins that are not bona fide nucleoporins localize at the NPC's central and basket regions, including the newfound trypanosomatid equivalent of TREX2. The cytoplasmic side is limited to NUP76, a structural homolog to the yeast cytoplasmic-exclusive Nup82, NUP140, NUP149, and two proteins known as RanGAP and RanBP1, likely involved in the maintenance of the Ran GTPase gradient. Using the novel method of auxin-inducible degron, we degraded NUP76 in 2 hours and rapidly blocked mRNA export, confirming it as a functional homolog to Nup82. NUP76 depletion affected NPC localization of NUP140, RanBP1, and GAP, indicating a function of NUP76 in their position at the cytoplasmic side. Indeed, AlphaFold models are confident in a direct NUP76-NUP140 interaction. No Dbp5 was found, suggesting this conserved mechanism of Mex67 release is absent in trypanosomes. Mex67 shuttles over the NPC, as we visualize the signal of Mex67 fused to BioID across the NPC, and this requires its zinc-finger containing amino-terminal, a possible RNA binding interface. As we discovered that the putative NLS and the zinc finger overlap in this region our hypothesis is that the mechanism determining directionality of export involve importins. As Dpb5 is conserved even in Euglena, we believe this is to be a trypanosomatid-unique mechanism.

Tim de Martines

Eilers Lab, Biomedicine

Investigating the role of transcription termination in MYC-driven immune evasion in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with a 5-year survival rate of 13%. PDAC is invariably driven by mutations to the KRAS oncogene, which in turn stabilise MYC, a transcription factor binding the promoters of a vast range of coding genes. A key oncogenic function of MYC in PDAC is the establishment of an immune-suppressive tumour microenvironment. Indeed, depletion of MYC in mouse models of PDAC leads to an immune-dependent tumour regression. However, the mechanism by which MYC prevents PDAC immune recognition remains largely obscure. Our group has recently demonstrated that MYC is not exclusively a transcription factor, but also directly binds nascent RNA suggesting a broader role in transcription regulation. Accordingly, analysis of the MYC interactome in PDAC cells reveals interactions with multiple factors involved in the recognition of polyadenylation signals and transcription termination. Furthermore, MYC loss in the same cells leads to an aberrant accumulation of transcripts on cytoplasmic sensor-proteins of immunogenic RNAs. These transcripts are primarily small nucleolar (sno)RNAs, which stem from the introns of coding genes and undergo multiple processing steps in order to become fully functional. Our future research will investigate how MYC harnesses transcription termination machineries to prevent the leakage of immunogenic transcripts to the cytosol, thus ensuring immune evasion in PDAC.

Eva Herrmann

Prof. Heike Rittner - Clinical Science

Deep phenotyping and possible biomarkers in diagnosing chronic postsurgical inguinal pain (CPIP)

Chronic postsurgical inguinal pain (CPIP) affects approximately one in ten patients following inguinal hernia surgery, which accounts for 20 million procedures annually worldwide. CPIP is characterized by the emergence or significant increase of pain lasting more than three months after surgery, often accompanied by neuropathic symptoms. Known risk factors include severe pre- and postoperative pain, as well as psychological factors such as anxiety and depression. The sensory stimuli in the groin are detected by intraepidermal pain fibers whose cell bodies reside in the dorsal root ganglia (DRG) of the L1 spinal segment, with pain signals transmitted to the brain via the dorsal horn and thalamus. However, the relevance of inflammatory and neuropathic processes in CPIP remains unclear, and there is a lack of objective diagnostic markers and tailored treatment approaches. This study combined the analysis of anonymized billing data from a health insurance company and a cross-sectional study aimed at identifying potential biomarkers for CPIP through quantitative sensory testing (QST), blood and tissue sample analysis, patient-reported outcomes, and DRG imaging. To establish normative values for QST and intraepidermal nerve fiber density (IENFD), 141 control subjects were assessed and compared to 17 CPIP patients. Both completed validated questionnaires such as the Beck Depression Inventory II (BDI) and State-Trait Anxiety Inventory (STAI). The DRGs of these patients were examined using high-resolution 3D MRI. Detailed phenotyping of CPIP patients revealed moderate to severe pain with a neurological component, mild sensory changes in QST (e.g., allodynia, reduced temperature perception), and normal IENFD. Notably, unilateral DRG atrophy in the affected groin was observed on MRI, along with upregulation of CCL2, IL-4, and brain-derived neurotrophic factor (BDNF), and a reduction in Apolipoprotein A1 (ApoA1), both of which are associated with inflammation and central sensitization of pain stimuli. A correlation between anxiety (STAI) and pain intensity was also identified, with DRG atrophy most pronounced in patients without prior groin pain. These findings suggest that a combination of clinical, sensory, molecular, histological, and imaging assessments improves understanding of CPIP pathophysiology and aids in identifying biomarkers for personalized diagnostics and treatment. DRG imaging, ApoA1, BDNF, and STAI have emerged as key markers for CPIP.

Elias Neuser

Prof. Grit Hein - Neuroscience

 Social Buffering: Influence of agents on the perception of anxiety and stress in virtual reality

In psychology, the phenomenon of social buffering refers to the positive influence that a conspecific can have on the processing of aversive stimuli. Studies have shown that this effect leads to reduced autonomic responses such as blood pressure or skin conductance both in real life and virtual reality settings. Expanding on these findings, my study focuses on the extent to which social buffering occurs in the presence of a male or an abstract agent within a virtual environment.

Yuanjie Wei

Munschauer Lab - Infection and Immunity

How does host RNA binding protein orchestrate viral replication?

To characterize host RNA-binding proteins (RBPs) involved in this process, we biochemically identified proteins bound to genomic and subgenomic SARS-CoV-2 RNAs. We find that the host protein SND1 binds the 5' end of negative-sense viral RNA and is required for SARS-CoV-2 RNA synthesis. SND1-depleted cells form smaller replication organelles and display diminished virus growth kinetics. We discover that NSP9, a viral RBP and direct SND1 interaction partner, is covalently linked to the 5' ends of positive- and negative-sense RNAs produced during infection. These linkages occur at replication-transcription initiation sites, consistent with NSP9 priming viral RNA synthesis. Mechanistically, SND1 remodels NSP9 occupancy and alters the covalent linkage of NSP9 to initiating nucleotides in viral RNA. Our findings implicate NSP9 in the initiation of SARS-CoV-2 RNA synthesis and unravel an unsuspected role of a cellular protein in orchestrating viral RNA production.