Biology subjects

Muth, S.

Publications and source records attributed to Muth, S..

5 recordsLinked to original sources

bioRxiv2026

Comparative analysis of neuronal proteolytic pathways reveals neuron-specific and sub-compartmental-specific capacities with aging

Proteostasis is essential for maintaining neuronal function, and its dysregulation is a hallmark of aging and neurodegeneration. The ubiquitin-proteasome system (UPS) and macroautophagy are the two major proteolytic pathways responsible for protein degradation. However, their capacity and regulation differ between cell types and across aging. To elucidate the activity of both proteolytic pathways with aging, we performed a comparative analysis of the activity of UPS and macroautophagy in distinct neuronal subcellular compartments, in the cytosol and at synaptic terminals, across aging in neurons of Mus musculus (mouse) and Caenorhabditis elegans (nematode). In mice, our results identified differences between brain areas. While the cortical proteasomal activity declined with aging in both the cytoplasmic as well as synaptic neuronal subcompartments, the cerebellar proteasomal activity decreased only in the cytoplasmic compartment with aging. In C. elegans, we detected a decrease of proteasomal activity in both cytoplasmic and synaptic compartments of neurons. Interestingly, we observed a dysregulation of macroautophagy in both neuronal subcompartments of the cortex and cerebellum in mice as well as in C. elegans neurons with aging. Thus, we uncovered neuron-specific and subcompartmental-specific proteolytic capacities with aging that could manifest in different neuronal vulnerabilities for proteotoxic challenges with aging.

biochemistry↗

bioRxiv2025

Transient YAP/TAZ inhibition exposes therapeutic vulnerabilities in advanced cancers

YAP and TAZ, key effectors of the Hippo pathway, are frequently hyperactivated in cancer, where they drive tumor progression and resistance to therapy. Their oncogenic activity relies on interaction with TEAD transcription factors, making the TEAD-YAP/TAZ complex an attractive therapeutic target. Using translational mouse models, we demonstrate that sustained systemic YAP/TAZ depletion leads to severe side effects. However, even transient YAP/TAZ inhibition alone is sufficient to suppress tumor growth in advanced stages. Mechanistically, YAP/TAZ activity promotes T cell exclusion from the tumors by inducing target genes involved in tissue remodeling. Consequentially, YAP/TAZ inhibition induces immune infiltration, but the infiltrating T cells rapidly become exhausted. Combining YAP/TAZ inhibition with immune checkpoint blockade (ICB) overcomes this exhaustion and sensitizes previously resistant tumors to immunotherapy.

cancer biology↗

bioRxiv2024

SynapseNet: Deep Learning for Automatic Synapse Reconstruction

Electron microscopy is an important technique for the study of synaptic morphology and its relation to synaptic function. The data analysis for this task requires the segmentation of the relevant synaptic structures, such as synaptic vesicles, active zones, mitochondria, presynaptic densities, synaptic ribbons, and synaptic compartments. Previous studies were predominantly based on manual segmentation, which is very time-consuming and prevented the systematic analysis of large datasets. Here, we introduce SynapseNet, a tool for the automatic segmentation and analysis of synapses in electron micrographs. It can reliably segment synaptic vesicles and other synaptic structures in a wide range of electron microscopy approaches, thanks to a large annotated dataset, which we assembled, and domain adaptation functionality we developed. We demonstrated its capability for (semi-)automatic biological analysis in two applications and made it available as an easy-to-use tool to enable novel data-driven insights into synapse organization and function.

bioinformatics↗

bioRxiv2023

Tumor- and Nerve-Derived Axon Guidance Molecule Promotes Pancreatic Ductal Adenocarcinoma Progression and Metastasis through Macrophage Reprogramming

Axon guidance molecules were found to be the gene family most frequently altered in pancreatic ductal adenocarcinoma (PDA) through mutations and copy number changes. However, the exact molecular mechanism regarding PDA development remained unclear. Using genetically engineered mouse models to examine one of the axon guidance molecules, semaphorin 3D (SEMA3D), we found a dual role for tumor-derived SEMA3D in malignant transformation of pancreatic epithelial cells and a role for nerve-derived SEMA3D in PDA development. This was demonstrated by the pancreatic-specific knockout of the SEMA3D gene from the KRASG12D and TP53R172H mutation knock-in, PDX1-Cre (KPC) mouse model which demonstrated a delayed tumor initiation and growth comparing to the original KPC mouse model. Our results showed that SEMA3D knockout skews the macrophages in the pancreas away from M2 polarization, providing a potential mechanistic role of tumor-derived SEMA3D in PDA development. The KPC mice with the SEMA3D knockout remained metastasis-free, however, died from primary tumor growth. We then tested the hypothesis that a potential compensation mechanism could result from SEMA3D which is naturally expressed by the intratumoral nerves. Our study further revealed that nerve-derived SEMA3D does not reprogram macrophages directly, but reprograms macrophages indirectly through ARF6 signaling and lactate production in PDA tumor cells. SEMA3D increases tumor-secreted lactate which is sensed by GPCR132 on macrophages and subsequently stimulates pro-tumorigenic M2 polarization in vivo. Tumor intrinsic- and extrinsic-SEMA3D induced ARF6 signaling through its receptor Plexin D1 in a mutant KRAS-dependent manner. Consistently, RNA sequencing database analysis revealed an association of higher KRASMUT expression with an increase in SEMA3D and ARF6 expression in human PDAs. Moreover, multiplex immunohistochemistry analysis showed an increased number of M2-polarized macrophages proximal to nerves in human PDA tissue expressing SEMA3D. Thus, this study suggests altered expression of SEMA3D in tumor cells lead to acquisition of cancer-promoting functions and the axon guidance signaling originating from nerves is "hijacked" by tumor cells to support their growth. Other axon guidance and neuronal development molecules may play a similar dual role which is worth further investigation. One sentence summaryTumor- and nerve-derived SEMA3D promotes tumor progression and metastasis through macrophage reprogramming in the tumor microenvironment. STATEMENT OF SIGNIFICANCEThis study established the dual role of axon guidance molecule, SEMA3D, in the malignant transformation of pancreatic epithelial cells and of nerve-derived SEMA3D in PDA progression and metastasis. It revealed macrophage reprogramming as the mechanism underlying bothroles. Together, this research elucidated how inflammatory responses promote invasive PDA progression and metastasis through an oncogenic process.

cancer biology↗

bioRxiv2018

Strongyloides stercoralis: spatial distribution of a highly prevalent and ubiquitous soil-transmitted helminth in Cambodia

BackgroundStrongyloides stercoralis is a neglected soil-transmitted helminth that occurs worldwide and can cause long-lasting and potentially fatal infections due to its ability to replicate within its host. S. stercoralis causes gastrointestinal and dermatological morbidity. The objective of this study was to assess the S. stercoralis infection risk, and using geostatistical models, to predict its geographical distribution in Cambodia.\n\nMethodology / Principal FindingsA nation-wide community-based parasitological survey was conducted among the population aged 6 years and above. S. stercoralis was diagnosed using a serological diagnostic test detecting antigens in urine. Data on demography, hygiene and knowledge about helminth infection were collected. S. stercoralis prevalence among 7,246 participants with complete data record was 30.5% and ranged across provinces between 10.9% and 48.2%. The parasite was ubiquitous in Cambodia, with prevalence rates below 20% only in five south-eastern provinces. Infection risk increased with age both in men and women although girls aged less than 13 years and women aged 50 years and above had lower odds of infection than their male counterparts. Open defecation was associated with higher odds of infection while declaring having some knowledge about health problems caused by worms was protective. Infection risk was positively associated with night maximum temperature, minimum rainfall, and distance to water, and negatively associated with land occupied by rice fields.\n\nConclusions / SignificanceS. stercoralis infection is ubiquitous and rampant in Cambodia. The parasite needs to be addressed by control programs delivering ivermectin. However the high cost of this drug in Cambodia currently precludes control implementation. Donations, subsidization or the production of affordable generic production are needed so S. stercoralis, which infests almost a third of the Cambodian population, can be addressed by an adequate control program.\n\nAuthors SummaryThe threadworm, Strongyloides stercoralis, is a most neglected worm infection transmitted through infective larvae on the soil. Threadworms occur worldwide and particularly in tropical climates. It may cause long-lasting and potentially fatal infections due to its ability to replicate within its host. This study aimed to assess the risk of threadworm infection in at the national level in Cambodia.\n\nWe conducted a nation-wide community-based parasitological survey among the population aged 6 years and above. The threadworm was diagnosed using a serological diagnostic test detecting antigens in urine. Data on demography, hygiene and knowledge about helminth infection were collected. The threadworm infection risk was calculated by using geostatistical models to predict its geographical distribution in Cambodia. About one third (30.5%) of the enrolled study participants (n=7,246) were infected with threadworms. The lowest and hightest infection rates a province level was 10.9% and 48.2%, respectively. Prevalence rates below 20% were found only in five south-eastern provinces. The risk of an infection with threadworms increased with age in men and women. Open defecation was associated with higher risk of infection while declaring having some knowledge about health problems caused by worms was protective. Furthermore, the threadworm infection risk was positively associated with environmental factors such as night maximum temperature, minimum rainfall, and distance to water, and negatively associated with land occupied by rice fields.\n\nThreadworm infection is highly prevalent in Cambodia and adequate control measures are warranted, including access to treatment, in order to address the burden of this NTD in Cambodia.

epidemiology↗