Biology subjects

Schmidt, M.

Publications and source records attributed to Schmidt, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Selective silencing of antibiotic-tethered ribosomes as a resistance mechanism against aminoglycosides

Antibiotic resistance is a growing threat, underscoring the need to understand the underlying mechanisms. Aminoglycosides kill bacteria by disrupting translation fidelity, leading to the synthesis of aberrant proteins. Surprisingly, mutations in fusA, a gene encoding translation elongation factor G (EF-G), frequently confer resistance, even though EF-G neither participates in mRNA decoding nor blocks aminoglycoside binding. Here, we show that EF-G resistance variants selectively slow ribosome movement along mRNA when aminoglycosides are bound. This delay increases the chance that the drug dissociates before misreading occurs. Over several elongation cycles, this selective silencing of drug-bound ribosomes prevents error cluster formation, preserving proteome and membrane integrity. As a result, fusA mutations confer resistance early in treatment by preventing self-promoted aminoglycoside uptake. Translation on drug-free ribosomes remains sufficiently rapid to sustain near-normal bacterial growth. This previously unrecognized resistance mechanism-- selective silencing of corrupted targets--reveals a novel antibiotic resistance strategy with potential therapeutic implications.

molecular biology↗

bioRxiv2025

Rapid proteasomal degradation of mutant feline McDonough sarcoma-like tyrosine kinase-3 overcomes tyrosine kinase inhibitor resistance of acute myeloid leukemia cells

BackgroundFeline McDonough sarcoma (FMS)-related receptor tyrosine kinase 3 with activating internal tandem duplications (FLT3-ITD) causes acute myeloid leukemia (AML). Targeted protein degraders for FLT3 have evolved as drugs against leukemia. MethodsWe synthesized and characterized MA191 as novel von Hippel-Lindau (VHL)-based proteolysis targeting chimera (PROTAC) for FLT3. We analyzed protein expression, protein degradation mechanisms, and posttranslational modifications by immunoblot. Selective proteasome modulation, an inactive stereoisomer of MA191, and siRNA confirmed the event-driven degradation of FLT3-ITD. Hematopoietic cell survival and differentiation were determined by flow cytometry using apoptosis and cell surface markers. As models, we used cultured and primary human AML cells, FLT3 inhibitor-resistant AML cells, mature blood cells, and hematopoietic stem cells. We scrutinized the databases DepMap, GEPIA2, Hemap, and HPA to assess FLT3 expression and patient survival. Experiments with Danio rerio larvae verified in vivo anti-leukemic activity of MA191. ANOVA and Bonferroni correction were used for statistics. ResultsMA191 is a rapid nanomolar apoptosis inducer in AML cells harboring FLT3-ITD (IC50=10.16-11.6 nM; EC50=0.015-0.883 {micro}M). A stereoisomer of MA191 that cannot recruit VHL demonstrates that elimination of FLT3-ITD is superior to its inhibition. MA191 abrogates FLT3 inhibitor resistance from rebound activation of mitogen-activated kinases. Rapid depletion of FLT3-ITD by MA191 (DC50=10 nM) requires VHL, neddylation, and the pro-apoptotic BH3-only protein BIM. Reduction of FLT3-ITD by MA191 precedes apoptosis. This reveals an apoptosis-independent function of BIM on protein stability. Leukemia cells express more FLT3 than healthy cells (n=3675/n=1249) and FLT3 expression is associated with worse AML patient survival (p=0.0099). MA191 does not harm blood cells and bone marrow progenitor cells and does not disturb myeloid blood cell differentiation. In Danio rerio, MA191 halts AML cell proliferation without significant toxicity. Anti-leukemic effects of MA191 are not susceptible to anti-apoptotic effects of human stromal cells and mutations in the tyrosine kinase of FLT3-ITD that confer resistance to selective FLT3 inhibitors. Conclusionsthese insights and the disclosure of the structure of MA191 provide a framework for an improved design of PROTACs that target mutant FLT3 and are not vulnerable to extrinsic and intrinsic resistance mechanisms. Degradation kinetics appear as determinant of such resistance breakers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/660791v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@17e5988org.highwire.dtl.DTLVardef@27fbc4org.highwire.dtl.DTLVardef@1023648org.highwire.dtl.DTLVardef@39bdcb_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Proximity labelling reveals the compartmental proteome of murine sensory neurons

IntroductionUnderstanding the molecular architecture of peripheral sensory neurons is critical as we pursue novel drug targets against pain and neuropathy. Sensory neurons in the dorsal root ganglion (DRG) show extensive compartmentalization, thus understanding each compartment - from the peripheral to central terminals - is key to this effort. MethodsTo systematically profile this spatial complexity, we generated a TurboIDfl/fl transgenic mouse line (ROSA26em1(TurboID)Bros), enabling targeted proximity labelling and deep proteomic profiling of DRG neuron compartments via Tg(Advillin-Cre)+. ResultsOur data reveal distinct proteomic signatures across neuronal compartments that reflect specialized neuronal functions. We provide proteomic insights into previously inaccessible nerve terminals both in the periphery (innervating the skin) and in the spinal cord. Further, using a DRG explant model of chemotherapy-induced peripheral neuropathy, we uncover novel and discrete proteome changes, highlighting neuronal vulnerability. ConclusionTogether, our findings provide a unique proteome atlas of the sensory neuron proteome across anatomical domains and demonstrate the utility of proximity labelling proteomics for detecting compartment-specific molecular alterations in a disease model.

neuroscience↗

bioRxiv2025

A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin

Alpha-ketoglutarate (KG) is required for chromatin demethylation but mechanisms controlling KG abundance in the nucleus are poorly defined. Therefore, we designed a biosensor system to monitor this metabolite pool in human cells using an KG-responsive cyanobacterial transcription factor, NtcA. We then coupled this system with a genetic screen to identify genes that regulate KG in the nucleus, defining an inter-organelle pathway in which sequential mitochondrial activities of the GPT2 transaminase and SLC25A11 transporter supply nuclear KG. Using a mouse model of GPT2 deficiency, a human inborn error of metabolism, we found that this pathway controls chromatin methylation in the developing brain. Our work provides a tool to assess KG signaling to chromatin and a framework for leveraging forward genetics to study nuclear metabolite pools.

synthetic biology↗

bioRxiv2025

From smartphones to satellites: Uniting crowdsourced biodiversity monitoring and Earth observation to fill the gaps in global plant trait mapping

Plant functional traits are fundamental to ecosystem dynamics and Earth system processes, but their global characterization is limited by the availability of field surveys and trait measurements. Recent expansions in biodiversity data aggregation, including large collections of vegetation surveys, citizen science observations, and trait measurements, offer new opportunities to overcome these constraints. Here we demonstrate that combining these diverse data sources with high-resolution Earth observation data enables accurate modeling of key plant traits at up to 1 km resolution. Our approach achieves high predictive power, reaching correlations up to 0.63 (15 of 31 traits exceeding 0.50) and improved spatial transferability, effectively bridging gaps in under-sampled regions. By capturing a broad range of traits with high spatial coverage, these maps can enhance our understanding of plant community properties and ecosystem functioning globally, and can serve as useful tools in modeling global biogeochemical processes and informing worldwide conservation efforts. Ultimately, our framework highlights the power and necessity of crowdsourced biodiversity data in high-resolution plant trait modeling. We anticipate that advancements in biodiversity data collection and remote sensing capabilities will further refine global trait mapping, fostering a dynamic trait-based understanding of the biosphere.

ecology↗

bioRxiv2025

New insights into the 17β-hydroxysteroid dehydrogenase type 10 and amyloid-β 42 derived cytotoxicity relevant to Alzheimer's disease

The multifunctional mitochondrial enzyme 17{beta}-hydroxysteroid dehydrogenase type 10 (HSD10) plays an important role in the pathology of several diseases, of which Alzheimers disease (AD) is the most debated. HSD10 overexpression and its interplay with amyloid-{beta} peptide (A{beta}) are considered a factor contributing to mitochondrial damage and neuronal stress observed in AD patients. This study confirms that individual overexpression of HSD10 or APP (amyloid precursor protein that gives rise to A{beta}) leads to cytotoxicity, and both pathological conditions are linked to mitochondrial damage. However, the metabolic changes caused by these two overexpressions significantly differ, particularly in their effect on the tricarboxylic acid cycle and {beta}-oxidation. Furthermore, the enzymatic activity of HSD10 is identified as the primary factor of HSD10 cytotoxicity, which is significantly exacerbated in an A{beta}-rich environment and can be partially reversed by HSD10 inhibitors. Notably, a previously published and competitive benzothiazole inhibitor was effective in restoring the viability of HSD10 overexpressing cells alone and in an A{beta}-rich environment, implying the potential benefit of HSD10 inhibitors in mitochondrial diseases and/or AD treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/639531v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@319d63org.highwire.dtl.DTLVardef@153e439org.highwire.dtl.DTLVardef@ac6a40org.highwire.dtl.DTLVardef@173aede_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

RB-TnSeq elucidates dicarboxylic acid specific catabolism in β-proteobacteria for improved plastic monomer upcycling

Dicarboxylic acids are key components of many polymers and plastics, making them a target for both engineered microbial degradation and sustainable bioproduction. In this study, we generated a comprehensive dataset of functional evidence for the genetic basis of dicarboxylic and fatty acid metabolism using randomly-barcoded transposon sequencing (RB-TnSeq). We identified four {beta}-proteobacteria that displayed robust growth with dicarboxylic acid sole carbon sources and cultured their mutant libraries with dicarboxylic and fatty acids with carbon chain lengths from C3 to C12. The resulting fitness data suggested that dicarboxylic and fatty acid metabolisms are largely distinct, and different sets of {beta}-oxidation genes are required for catabolizing dicarboxylic versus fatty acids of the same carbon chain lengths. Additionally, we identified transcriptional regulators and transporters with strong fitness phenotypes related to dicarboxylic acid utilization. In Ralstonia sp. UNC404CL21Col (R. CL21), we deleted two transcriptional repressors to improve its utilization of short chain dicarboxylic acids. We exploited the diacid-utilizing catabolism of R. CL21 to upcycle a mock mixture of the dicarboxylic acids produced when polyethylene is oxidized. After introducing a heterologous indigoidine production pathway, this engineered Rastonia produced 0.56 {+/-} 0.02 g/L indigoidine from a mixture of dicarboxylic acids as a carbon source, demonstrating the potential of R. CL21 to upcycle plastics waste to products derived from tricarboxylic acid (TCA) cycle intermediates. ImportanceUpcycling the carbon in plastic wastes to value-added products is a promising approach to address the plastics waste and climate crises, and dicarboxylic acid metabolism is an important facet of several approaches. Improving our understanding of the genetic basis of this metabolism has the potential to uncover new enzymes and genetic parts for engineered pathways involving dicarboxylic acids. Our dataset is the most comprehensive interrogation of dicarboxylic acid catabolism to date, and this work will be of utility to researchers interested in both plastics bioproduction and upcycling applications.

microbiology↗

bioRxiv2024

Endosome maturation is orchestrated by inside-out proton signaling through a Na+/H+ exchanger and pH-dependent Rab GTPase cycling

Endosome maturation requires progressive lumen acidification. To what extent is lumen acidification sensed by cytosolic-side molecules that drive endosome maturation? We show here that "inside-out" proton signaling through the endosomal Na+/H+ Exchanger 6 (NHE6) activates the late endosome master regulator Rab7. The mechanism involves potent inactivation of the Rab7 GTPase-activating protein (GAP) TBC1D5 with decreasing pH. NHE6 interacts with TBC1D5 in a complex with Rab7. Neurons from NHE6-null mice or mice engineered with a selective defect in NHE6 proton efflux exhibit blocked endosome maturation and decreased active Rab7, consistent with an overactive Rab7 GAP. Finally, epistatic knock-down of TBC1D5, thereby reducing Rab7 GAP activity, in NHE6-null neurons rescues Rab7 GTPase cycling and endosome maturation. Importantly, NHE6 is mutated in Christianson Syndrome underscoring the significance of these mechanisms to neurodegeneration. We conclude that lumen acidification regulates pH-dependent Rab GTPase cycling to coordinate late endosome maturation by a process involving proton signaling.

cell biology↗

bioRxiv2024

Multi-omic integration with human DRG proteomics highlights TNFα signalling as a relevant sexually dimorphic pathway

The peripheral nervous system (PNS) plays a critical role in pathological conditions, including chronic pain disorders, that manifest differently in men and women. To investigate this sexual dimorphism at the molecular level, we integrated quantitative proteomic profiling of human dorsal root ganglia (hDRG) and peripheral nerve tissue into the expanding omics framework of the PNS. Using data-independent acquisition (DIA) mass spectrometry, we characterized a comprehensive proteomic profile, validating tissue-specific differences between the hDRG and peripheral nerve. Through multi-omic analyses and in vitro functional assays, we identified sex-specific molecular differences, with TNF signalling emerging as a key sexually dimorphic pathway with higher prominence in males. Genetic evidence from genome-wide association studies (GWAS) further supports the functional relevance of TNF signalling in the periphery, while clinical trial data and meta-analyses indicate a sex-dependent response to TNF inhibitors. Collectively, these findings underscore a functionally sexual dimorphism in the PNS, with direct implications for sensory and pain-related clinical translation.

neuroscience↗

bioRxiv2024

Volume conductor models for magnetospinography

The recent development of small, wearable, magnetic field sensors allow for the investigation of biomagnetic fields with a flexibility previously unavailable. We carry out forward computations to describe how current flow in the spinal cord and thorax gives rise to measurable magnetic fields outside the torso. We compare various open-access volume conductor models, in order to select the most parsimonious and accurate descriptor of the magnetic fields due to source current in the spinal cord. We find that fields produced due to current flow along the superior-inferior axis of the cord are relatively insensitive to the choice of volume conductor model. However, fields produced by current flow in predominantly left-right or anterior-posterior direction are significantly attenuated by the presence of bone in the forward model. Furthermore, volume conductors with bone demonstrate larger differences in field topographies for nearby sources compared to bone-free models. These findings suggest that precise modelling of spinal cord location and surrounding vertebrae will be important a-priori knowledge going forward.

neuroscience↗

bioRxiv2024

Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning

The macrodomain contained in the SARS-CoV-2 non-structural protein 3 (NSP3) is required for viral pathogenesis and lethality. Inhibitors that block the macrodomain could be a new therapeutic strategy for viral suppression. We previously performed a large-scale X-ray crystallography-based fragment screen and discovered a sub-micromolar inhibitor by fragment linking. However, this carboxylic acid-containing lead had poor membrane permeability and other liabilities that made optimization difficult. Here, we developed a shape- based virtual screening pipeline - FrankenROCS - to identify new macrodomain inhibitors using fragment X-ray crystal structures. We used FrankenROCS to exhaustively screen the Enamine high-throughput screening (HTS) collection of 2.1 million compounds and selected 39 compounds for testing, with the most potent compound having an IC50 value equal to 130 M. We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent having an IC50 equal to 220 M. Further optimization led to analogs with IC50 values better than 10 M, with X-ray crystal structures revealing diverse binding modes despite conserved chemical features. These analogs represent a new lead series with improved membrane permeability that is poised for optimization. In addition, the collection of 137 X-ray crystal structures with associated binding data will serve as a resource for the development of structure-based drug discovery methods. FrankenROCS may be a scalable method for fragment linking to exploit ever-growing synthesis-on- demand libraries.

biophysics↗

bioRxiv2024

Leveraging Chlorination-Based Mechanism for Resolving Subcellular Hypochlorous Acid

Hypochlorous acid (HOCl) is crucial for pathogen defense, but an imbalance in HOCl levels can lead to tissue damage and inflammation. Existing HOCl indicators employ an oxidation approach, which may not truly reveal the chlorinative stress environment. We designed a suite of indicators with a new chlorination-based mechanism, termed HOClSense dyes, to resolve HOCl in sub-cellular compartments. HOClSense dyes allow the visualization of HOCl with both switch-on and switch-off detection modes with diverse emission colors, as well as a unique redshift in emission. HOClSense features a minimalistic design with impressive sensing performance in terms of HOCl selectivity, and our design also facilitates functionalization through click chemistry for resolving subcellular HOCl. As a proof of concept, we targeted plasma membrane and lysosomes with HOClSense for subcellular HOCl mapping. With utilizing HOClSense, we discovered the STING pathway-induced HOCl production and the abnormal HOCl production in Niemann-Pick diseases. To the best of our knowledge, this is the first chlorination-based HOCl indicator series for resolving subcellular HOCl.

cell biology↗

bioRxiv2024

Tunable Cytosolic Chloride Indicators for Real-Time Chloride Imaging in Live Cells

Chloride plays a crucial role in various cellular functions, and its level is regulated by a variety of chloride transporters and channels. However, to date, we still lack the capability to image instantaneous ion flux through chloride channels at single-cell level. Here, we developed a series of cell-permeable, pH-independent, chloride-sensitive fluorophores for real-time cytosolic chloride imaging, which we call CytoCl dyes. We demonstrated the ability of CytoCl dyes to monitor cytosolic chloride and used it to uncover the rapid changes and transient events of halide flux, which cannot be captured by steady-state imaging. Finally, we successfully imaged the proton-activated chloride channel-mediated ion flux at single-cell level, which is, to our knowledge, the first real-time imaging of ion flux through a chloride channel in unmodified cells. By enabling the imaging of single-cell level ion influx through chloride channels and transporters, CytoCl dyes can expand our understanding of ion flux dynamics, which is critical for characterization and modulator screening of these membrane proteins. A conjugable version of CytoCl dyes was also developed for its customization across different applications.

cell biology↗

bioRxiv2024

Red blood cell-tumour cell interactions promote tumour cell progression

One critical step in the metastatic cascade is the survival of circulating tumour cells (CTCs) within the bloodstream. While numerous interactions between CTCs and various hematopoietic cells have been described, the role of red blood cells (RBCs) in this process remains underexplored. This study investigates the interactions between tumour cells and RBCs from breast and lung cancer patients, revealing significant phenotypic and functional changes in the tumour cells, unlike when the contact is with RBCs from healthy donors. In vitro co-culture of cancer cell lines with RBCs from metastatic cancer patients resulted in increased tumour cell attachment accompanied by morphological changes. Additionally, RBCs-primed tumour cells showed increased adhesion and disruption of the endothelial barrier in vitro and increased invasiveness both in vitro and in vivo. Transcriptomic analysis showed that RBCs from metastatic breast cancer patients induce significant gene expression changes, notably upregulating PAK4, which enhances migration and epithelial-mesenchymal transition. PAK4 inhibition reduced these effects. Proteomic studies revealed substantial remodelling, including actin-related changes and the accumulation of VASP at cell edges, promoting directional migration. Clinically, higher RBC distribution width (RDW) in metastatic breast cancer patients is associated with increased CTC counts and worse outcome. This study highlights the previously unrecognized role of RBCs in promoting metastatic behaviours in cancer cells and suggests potential therapeutic targets, such as PAK4, to counteract these effects. Further exploration of RBCs-tumour cell interactions could provide new insights into metastatic mechanisms and improve cancer prognosis and treatment strategies. Key PointsO_LIThis study reveals the previously unknown role of RBCs in enhancing tumour cell invasiveness and metastatic potential. C_LIO_LITumour cells undergo significant phenotypic and functional changes after contact with RBCs from cancer patients. C_LI

cancer biology↗

bioRxiv2024

Ventral Morphology and Ecological Implications of Cindarella eucalla (Artiopoda, Xandarellida) from Chengjiang Biota, China

Artiopoda, an early arthropod group, displays post-antennal appendages resembling trilobite limbs, but relationships with other ealy arthropods remain enigmatic. Limited studies and morphological details hinder the understanding of internal relationships within Artiopoda. Recently, exceptionally well preserved arthropod fossils from the Chengjiang Biota were studied using X-ray computed tomography, revealing detailed morphologies. In this study, Cindarella eucalla, a xandarellid from the Chengjiang Biota, was re-investigated using X-ray computed tomography and fluorescent microscopy to reconstruct its morphology and understand its phylogeny and ecology. This study successfully reconstructed a three-dimensional model of Cindarella eucalla, revealing features, such as spindle-shaped trunk tergites with the anterior six covered by the head shield and axial spines extending from the last four, natant hypostome, four post-antennal cephalic appendage pairs, dorsoventral mismatch existed between trunk tergites and limb pairs. This research suggests that Cindarella eucalla could escape in a very short time when it encounters an enemy, and it probably lived in muddy environments with ample light. Phylogenetic analysis indicates that Xandarellids may have close relationship with concililiterga or a clade composed of Nektaspida + (Conciliterga + (Phytophilaspis pergamena + Trilobita)).

evolutionary biology↗

bioRxiv2024

Ultra-sensitive metaproteomics (uMetaP) redefines the dark field of metaproteome, enables single-bacterium resolution, and discovers hidden functions in the gut microbiome

The gut microbiome is a complex ecosystem with significant inter-individual variability determined by hundreds of low-abundant species as revealed by genomic methods. Functional redundancy demands direct quantification of microbial biological functions to understand their influence on host physiology. This functional landscape remains unexplored due to limited sensitivity in metaproteomics methods. We present uMetaP, an ultra-sensitive metaproteomic solution combining advanced LC-MS technologies with a novel FDR- controlled de novo strategy. uMetaP improves the taxonomic detection limit of the gut "dark metaproteome" by 5,000-fold with exceptional quantification precision and accuracy. In a mouse model of colonic injury, uMetaP extended metagenomics findings and identified host functions and microbial metabolic networks linked to disease. We obtained orthogonal validation using transcriptomic data from biopsies of 204 Crohns patients and presented the concept of a "druggable metaproteome". Among the drug-protein interactions discovered are treatments for intestinal inflammatory diseases, showcasing uMetaPs potential for disease diagnostics and data-driven drug repurposing strategies.

microbiology↗

bioRxiv2024

Connectomic reconstruction of a cortical column

The cerebral cortex of mammals has long been proposed to comprise unit-modules, so-called cortical columns. The detailed synaptic-level circuitry of such a neuronal network of about 104 neurons is still unknown. Here, using 3-dimensional electron microscopy, AI-based image processing and automated proofreading, we report the connectomic reconstruction of a defined cortical column in mouse barrel cortex. The cortical column appears as a structural feature in the connectome, without need for geometrical or morphological landmarks. We then used the connectome for definition of neuronal cell types in the column, to determine intracolumnar circuit modules, analyze the logic of inhibitory circuits, investigate the circuits for combination of bottom-up and top-down signals in the column and the specificity of bottom-up and top-down cortical input, search for higher-order circuit structure within homogeneous neuronal populations, and estimate the degree and symmetry of Hebbian learning in the various connection types. With this, we provide a first column-level connectomic description of the cerebral cortex, the likely substrate for a synaptic-level mechanistic understanding of sensory-conceptual integration and learning.

neuroscience↗

bioRxiv2024

Cancer-associated fibroblasts reveal aberrant DNA methylation across different types of cancer

Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment. Several studies demonstrated molecular differences between CAFs and normal tissue-associated fibroblasts (NAFs). In this study, we isolated CAFs and NAFs from liver tumors and analyzed their DNA methylation profiles. A subset of the CAFs exhibited aberrant DNA methylation, which was also reflected on gene expression level. The DNA methylation at liver-CAF-specific CG dinucleotides (CpGs) was associated with survival in liver cancer data. An integrative analysis with public datasets of CAF versus NAF in different cancer types, including lung, prostate, esophagus, and gastric cancer, revealed overlapping epigenetic aberrations. CpGs with common aberrations in DNA methylation included cg09809672 (EDARADD), cg07134930 (HDAC4), and cg05935904 (intergenic). Aberrant DNA methylation at these sites was associated with prognosis in several cancer types. Thus, activation of CAFs by the tumor environment is associated with characteristic epigenetic modifications that could be used as biomarkers for disease stratification.

cancer biology↗