Biology subjects

Simon, M.

Publications and source records attributed to Simon, M..

At least 19 recordsLinked to original sources

bioRxiv2026

A brain immune phenotype independent of Alzheimer's Disease associates with amyloid susceptibility and systemic inflammation

Transcriptomic and proteomic studies have consistently demonstrated substantial molecular heterogeneity across patients with Alzheimer's disease (AD) and other neurodegenerative disorders, leading to the proposal of multiple disease subtypes. However, almost all previous studies have focused on heterogeneity within diseased cohorts, whereas comparatively little attention has been paid to the molecular diversity of neurologically healthy individuals. In the present study, we demonstrate that one of the most prominent transcriptomic programs characterized by a strong immune component previously interpreted as an AD-specific immune subtype is in fact a brain phenotype that exists independently of AD yet interacts with AD susceptibility and is selectively associated with amyloid pathology. The transcriptional effect of the immune phenotype exceeds that of AD pathology-induced changes and is accompanied by alterations of brain cellular compositions and a distinct systemic inflammation. Our findings suggest that part of the molecular heterogeneity observed in neurological diseases might arise from pre-existing brain phenotypes rather than representing disease-specific subtypes. These insights support a precision medicine approach for Alzheimer's disease, whereby individuals with an immune phenotype of the brain could be prospectively identified and monitored, enabling the application of targeted preventive strategies before substantial neuropathology and cognitive decline emerge.

neuroscience↗

bioRxiv2026

Multimodal evidence for impaired glymphatic brain clearance as a mediator of "inflammaging" in schizophrenia - integrating insights from in vivo neuroimaging, omics, and post-mortem single nucleus-RNA-Seq data

Persistent cognitive impairment and reduced life expectancy in schizophrenia may arise from inflammation-driven accelerated aging ("inflammaging"), yet the underlying mechanisms remain unclear. Impaired glymphatic clearance, dependent on polarized aquaporin-4 (AQP4) localization at astrocytic endfeet, offers a plausible mechanistic link between inflammation and brain aging. Here, we integrate in vivo neuroimaging with post-mortem single-nucleus transcriptomics from distinct patient cohorts to demonstrate glymphatic dysfunction in schizophrenia and define its molecular basis. We identify reduced astrocytic expression of components of the dystrophin-associated protein complex (SNTA1, DAG1) required for AQP4 polarization. Both in vivo neuroimaging and post-mortem gene expression signatures of glymphatic dysfunction are restricted to an inflammatory subgroup characterized by peripheral immune activation and pro-inflammatory glial transcriptional profiles. Moreover, imaging signatures of glymphatic impairment are associated with schizophrenia polygenic risk scores enriched for immune - and oxidative stress - related aging pathways as well as cognitive dysfunction. At the cellular level, glymphatic dysfunction coincides with loss of homeostatic programs in microglia and astrocytes, increased inflammatory signaling, and endothelial signatures of blood-brain barrier disruption. Across modalities, glymphatic impairment is linked to accelerated aging, including increased brain and epigenetic age, and aging-related gene expression signatures.

neuroscience↗

bioRxiv2026

An automated machine vision-based index for Rett Syndrome provides a generalizable framework for modeling rare disease therapeutics

Rare diseases collectively affect millions of people, yet therapeutic development remains limited by preclinical phenotyping which is often dependent on subjective, low-resolution manual behavioral assessment. Rett syndrome (RTT), a rare disease affecting 1 in 10,000 female births, is caused by a MeCP2 deficiency. In mouse models for this disease, symptom severity is measured primarily with the observational Bird score. This subjective six-item ordinal scale was used to demonstrate that MeCP2 deficiency is reversible, but offers limited resolution for ranking candidate therapies or detecting partial rescue. We applied an automated machine learning (ML) pipeline to a humanized Mecp2 R270X mouse model. We conducted weekly Bird scoring and recorded one-hour open-field trials from 3 to 10 weeks of age in 24 hemizygous (Mecp2-/Y) males and 24 wild-type littermates, then extracted over 400 behavioral features spanning gait kinematics, open-field activity, body morphometrics, and trained behavior classifiers. Manual Bird scoring tracked overall disease trajectory, but most of its dynamic range derived from two of six items. In contrast, ML features separated genotypes as early as three weeks and identified disease-relevant behaviors not captured by the Bird protocol, including increased tail-tip amplitude, repetitive wall-directed jumping, and prolonged behavioral arrest. Sparse PLS-DA separated genotypes at every age tested. A composite score modeled from the ML features reproduced the temporal pattern of the total Bird score with substantially less variability. Subsampling analyses showed that the ML feature set reached 5% cross-validated genotype misclassification error with only 12 to 16 animals, whereas the Bird score did not reach the 5% threshold even with 44 animals before week 6, a reduction in animal use consistent with the 3Rs. Applied to a Mecp2 minigene rescue study, the composite score reproduced genotype separation in an independent cohort and detected both a partial shift of treated hemizygous survivors toward wild-type values and adverse effects of the construct in wild-type mice. These results establish an objective, high-resolution severity index for RTT and a generalizable framework for preclinical phenotyping in a rare disease.

neuroscience↗

bioRxiv2026

Independent benchmark of H&E-based gene expression prediction in skin

Given the widespread availability of H&E slides, there is considerable interest in determining whether molecular information can be inferred directly from tissue morphology, potentially reducing the need for costly spatial transcriptomic profiling. We assessed three state-of-the-art methods for predicting single-cell gene expression from H&E images across three skin disease contexts and two Xenium panels. As controls, we included simple linear regression models trained on embeddings from multiple foundation models, totalling 16 models evaluated in this study. We show that all models performed poorly: for most genes, prediction accuracy was near zero, and reliable predictions were largely restricted to keratinocyte-associated genes. Predicted expression failed to preserve cell-type identity and spatial organisation, with only keratinocytes forming coherent clusters, while immune, fibroblast, and other dermal populations were extensively mixed. Notably, simple ridge regression on pretrained embeddings matched or outperformed the more complex published architectures, indicating that the predictive signal originates primarily from image representations rather than model design. Our results demonstrate that current H&E-based gene expression prediction methods are not yet suitable for single-cell-level interpretation of spatial transcriptomics in skin tissue.

bioinformatics↗

bioRxiv2026

Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states

Microglia are central mediators of Alzheimers disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk, neuropathology and cognitive decline. To model this state experimentally, we screened AD-relevant perturbations in human induced pluripotent stem cell (hiPSC)-derived microglia and found that ferric ammonium citrate (FAC) reproducibly induced a DLaM-like state characterized by lipid accumulation, lysosomal dysfunction and impaired A{beta} phagocytosis. Using a transcriptomics-based state-reversion screen, we identified LY2090314 as a potent modulator that restored microglial function and induced a distinct lysosomal-metabolic state. These findings establish a framework for transcriptomic disease-state-guided therapeutic discovery in AD.

neuroscience↗

bioRxiv2026

Progranulin deficiency perturbs lipid metabolism in white matter microglia

Progranulin (PGRN) deficiency is a common hallmark in frontotemporal dementia (FTD) patients with granulin (GRN) mutations (FTD-GRN). Previous studies by our group and others have observed that reduced PGRN perturbs lysosomal function and microglial activation, which is believed to accelerate neurodegeneration in FTD-GRN patients. Lysosomal function is intrinsically linked to lipid metabolism, and evidence suggests that GRN deficiency can alter lipid profiles in the brain. Unfortunately, studies to date have focused on whole brain or cortical extracts, limiting our ability to assess cell type-dependent changes in lipid metabolism under disease conditions. Here, we employed lipidomic analysis specifically within the pontine microglia of Grn knock-out (KO) mice, a cell population that was previously linked to disease phenotypes in this model. We observed a significant reduction in the endolysosomal lipid bis(monoacylglycero)phosphate (BMP) and the lipid metabolite phosphatidylethanolamine (PE); these microglial-specific lipid alterations mirror previous whole-brain findings, suggesting that similar changes may occur across multiple cell types in the brain. We also detected a significant increase in the myelin-composing factor galactosylceramide (GalCer), which may reflect an aberrant accumulation of myelin debris within microglia that arises due to defective lysosomal clearance. Notably, lipid perturbations were exacerbated with age within Grn KO microglia, suggesting that changes in lipid metabolism are both age- and genotype-dependent in this model. Together, our results support our hypothesis that PGRN acts as a master regulator of critical microglial processes - including lysosomal function, lipid metabolism, and the regulation of myelination - in an age-dependent manner.

neuroscience↗

bioRxiv2026

A scRNA-seq atlas of chronic inflammatory skin diseases

Inflammatory skin diseases (ISDs) affect up to 25% of the global population. Yet, large-scale comparative single-cell RNA-sequencing (scRNA-seq) analyses between ISDs are still missing. Here, we integrated scRNA-seq datasets spanning 27 skin diseases from 50 studies, comprising over 2 million cells from 441 samples. Using the healthy skin cell atlas as reference, we could build a robust ISD atlas that enabled us to differentiate universal inflammatory signatures and disease-specific ones. This highlighted, for example, a shared gene program between keratinocytes in atopic dermatitis and parapsoriasis, not present in cutaneous T-cell lymphoma, confirms the plasticity of Th17 cells throughout ISDs, defines specific macrophage signatures in acne, and reveals a yet undescribed role of mural cells in ISDs. This demonstrates the power of the ISD atlas as a resource to resolve disease-specific immune mechanisms. The complete atlas is available through an interactive online portal at https://isd-atlas.derma.meduniwien.ac.at.

immunology↗

bioRxiv2026

Global quantification of mammalian gene expression noise

Even cells of the same type growing in the same environment show cell-to-cell differences in protein abundance, a phenomenon known as gene expression noise. This variability can be decomposed into intrinsic components, reflecting molecular randomness, and extrinsic components, arising from differences in cellular state. While gene expression noise has been studied genome-wide in microbes, its global organization remains largely unknown in mammalian cells. Here, we develop a spike-in-based stable isotope single-cell proteomics approach that enables robust quantification of protein-level gene expression noise across thousands of human proteins. We find that protein noise scales inversely with abundance until reaching a plateau, consistent with an extrinsic noise floor and conserved scaling principles observed in bacteria and yeast. Cell cycle stage and cell size contribute substantially to protein variability but do not fully account for the observed heterogeneity. Gene-specific features such as mRNA and protein half-lives and translation efficiency show only weak associations with protein noise, and variability at the mRNA level is a weak predictor of protein variability. Instead, protein noise is largely extrinsic, with coordinated variation across proteins encoding biologically organized cellular states. Consistently, coordinated proteome programs predict intercellular differences in proteome dynamics, linking protein variability to cellular function. Together, these results provide a proteome-wide view of gene expression noise in mammalian cells, establishing that protein-level variability encodes structured and functionally relevant differences in cellular state.

systems biology↗

bioRxiv2026

Controlled intramural fluid injection to quantify propensity to thoracic aortic dissection

Dissection of the thoracic aorta includes delamination of medial lamellae and permeation of blood within the media. Quantifying how biaxial loading of a vulnerable wall and fluid mechanics interact to drive dissection remains a central challenge. Here we combine controlled distension-extension testing of intact porcine descending thoracic aortas with forced intramural fluid injection to investigate how axial stretch, injection rate, and needle gauge modulate the initiation and propagation of intramural delamination. Across experiments, injection pressure-volume curves exhibited nonlinear responses characterized by pressure peaks followed by stepwise pressure drops, suggesting progressive micro-delamination events within the medial lamellar networks. Increasing axial stretch significantly elevated peak injection pressure and promoted preferential axial propagation of the permeation / delamination front. Higher injection rates induced abrupt lamellar separation and larger dissected areas, whereas smaller needle gauges generated higher upstream pressures due to increased hydraulic resistance. Synchrotron imaging revealed the microstructural transition from intralamellar fluid permeation and wall swelling to the formation of a large fluid-filled delamination cavity. These results support a mechanistic framework in which the introduction of pressurized fluid within the aortic media behaves as a hydraulic fracture process in a layered poroelastic tissue, governed by balance across fluid pressurization, wall loading, and interlamellar strength. The findings provide quantitative insight into the biomechanical conditions that contribute to the initiation and propagation of aortic dissection.

bioengineering↗

bioRxiv2026

Histone H4 acetyl-methyllysine marks accessible chromatin that resists compaction

Certain regulatory DNA regions remain accessible even under conditions of widespread chromatin compaction. These regions are often marked by specific protein factors and histone modifications that help maintain their accessibility. Here, we examine the genomic landscape of acetyl-methyllysine (Kacme), a recently discovered histone post-translational modification. Across multiple systems, Kacme is highly enriched at sites of accessible chromatin, including active promoters, enhancers, silencers, and CTCF-binding sites. We find that Kacme is selectively retained at loci that resist condensation during mitosis, marks XIST and escapee regions on the inactive X chromosome in female cells and demarcates the boundaries of broad heterochromatin domains. Kacme-marked insulator elements block heterochromatin spreading and protect adjacent genes from transcriptional repression, even when H3K27me3 levels are pharmacologically elevated through KDM6A/6B inhibition. Taken together, our findings establish the chromatin features associated with Kacme and support a model in which Kacme helps safeguard chromatin accessibility at loci that resist compaction.

molecular biology↗

bioRxiv2026

Mitochondrial protein import stress causes progressive neurodegeneration opposed by PERK - eIF2α signalling

Mitochondrial dysfunction and impairments of the mitochondrial protein import system are often linked to neurodegenerative disease, but whether import stress per se causes neurodegeneration has not been tested. Here, we adapted the yeast clogger system to Drosophila motoneurons to block TOM-TIM23-mediated import with temporal control. Sustained import stress converts somatic mitochondria into donut-shaped structures, depletes functional mitochondria from synaptic terminals, and causes progressive neurodegeneration with impaired neurotransmitter release and locomotor dysfunction. This neurodegeneration is mechanistically distinct from mitochondrial absence, as miro mutant neurons that completely lack presynaptic mitochondria do not degenerate. Import-stressed motoneurons activate multiple protective programmes, including chaperone remodelling, metabolic repression, and translational control through the eIF2 kinase PERK. Both pharmacological PERK inhibition and reversal of translational attenuation via ISRIB accelerate neurodegeneration, whereas PERK overexpression alone is sufficient to cause it, defining a protective range of eIF2-dependent translational control. The observation that PERK inhibition is protective in protein misfolding models but detrimental during import stress shows that the nature of mitochondrial dysfunction determines the molecular consequence of translational control in neurodegeneration.

neuroscience↗

bioRxiv2026

Syncytial coupling of mid-capillary pericytes underlies seizure-associated electro-metabolic signaling

Disturbances of neurovascular coupling (NVC) contribute to metabolic derailment and neurological symptoms associated with epilepsy. While postictal arterial constriction can be alleviated by inhibitors of voltage gated calcium channels (VGCCs), less is knownregarding seizure-associated electrical signals in higher-order capillaries and their role in determining pericyte tone during seizures. Here we investigated electrical signaling within the ex vivo neurovascular unit (NVU) derived from rat and human brain tissue. We focused on electrical signal transduction between pericytes and endothelial cells and the potential role of VGCCs in vasomotion. Using dye coupling and paired patch-clamp recordings, we showed that morphologically heterogeneous groups of mid-capillary pericytes build a functional syncytium with endothelial cells. Coupling was asymmetric, allowing for directed propagation of electrical signals. Regardless of their morphology, mid-capillary pericytes responded with depolarization and constriction to metabotropic receptor (GPCR) activation (by thromboxane, norepinephrine and UDP-glucose). However, depolarization via the patch pipette induced neithe r Ca2+-influx nor constriction, suggesting lack of contribution of VGCCs to vasomotion. On inducing epileptiform activity, A2a adenosine receptors and inwardly rectifying potassium channels hyperpolarized the capillary syncytium, followed by repeated depolarizations due to seizure-associated potassium increase in the parenchyma. Thus, while mid-capillary pericytes are contractile, their tone does not rely on their membrane potential and VGCCs. However, syncytial coupling allows for transmission of seizure-associated hyper- and depolarizing signals to upstream feeding arterioles.

neuroscience↗

bioRxiv2026

Mind the translational gap: human microglia differ from mouse microglia in their regulation of Kv and Kir2.1 channels

K+ channels are important for controlling membrane potential and regulating functional properties of microglia. Whereas the inward-rectifying K+ (Kir) channel 2.1 modulates proliferation, voltage-gated K+ channels (Kv) are linked to inflammatory response in mouse microglia (mMG). These channels serve as possible drug targets but little is known regarding their activity in human microglia. We used patch-clamp recording to study membrane currents of primary human microglia (hMG) and human induced pluripotent stem cell-derived microglia-like cells (hiPSC-MGL) and compared them with mMG. Unlike mMG, hMG and hiPSC-MGL exhibited Kir2.1 currents only after LPS+IFN-{gamma} stimulation. Interestingly, Kv currents were not observed in hMG or hiPSC-MGL under any condition. While mMG had a progressively ameboid morphology after stimulation, hMG showed few morphological changes and hiPSC-MGL increased ramification. Overall, the activity of Kir2.1 and Kv channels in hMG and hiPSC-MGL differs fundamentally from mMG. Our findings highlight differences between species and underscore the need for translational approaches.

neuroscience↗

bioRxiv2026

Combination of 3D and 2D small and wide angle X-ray scattering imaging reveals diminished bone quality in the superior human femoral neck cortex

The human femoral neck is particularly vulnerable to fracture, with failure most often initiating in the superior region. While age-related microstructural changes such as cortical thinning and increased porosity are well established, the contribution of material properties at the lamellar and mineralised collagen fibril (MCF) levels remains poorly understood. Here, regional differences in nanostructural properties of cortical bone from 78 femoral necks obtained from 44 donors aged 54-96 are investigated using a combined 2D and 3D X-ray scattering imaging approach. This approach quantifies MCF orientation and structure averaged over multiple lamellae in large fields of view, capturing tissue heterogeneity through the hierarchical scales. We identified misalignment between the scattering signals arising from the MCF bundles -- specifically those associated with mineral inclusions in the collagen fibril gap regions, the mineral nanostructure, and the mineral crystal lattice -- suggesting the presence of distinct mineral phases within and around the collagen fibers. Despite substantial intra-sample variability, the superior region displays on average more oblique MCF orientations, larger and thicker mineral platelets arranged in a less-ordered structure, greater misalignment between mineral and collagen at the MCF level, and possibly stiffer collagen fibres, with no significant trends observed with donor age or sex. The cumulative effect of these material property differences may contribute to the increased susceptibility of the superior cortex to compressive failure.

bioengineering↗

bioRxiv2026

Balance between DNA repair, LINE1 suppression and lifespan in mice with SIRT6 Serine 10 mutations

Sirtuin 6 (SIRT6) is an important regulator of DNA repair, metabolism, chromatin maintenance and longevity. SIRT6 Serine 10 phosphorylation controls SIRT6 recruitment to the sites of DNA damage. To explore the effect of SIRT6 Serine 10 phosphorylation on lifespan, we generated two SIRT6 mutant mouse strains: phospho-null S10A and phosphomimetic S10E. The S10E mutant mice demonstrated enhanced DNA repair capacity, elevated LINE1 expression and reduced lifespan in male mice compared to the wild-type and S10A mice. This result suggests that SIRT6 S10E mutation enhances DNA repair capacity at the expense of reduced LINE1 silencing leading to shorter lifespan. While both SIRT6 functions in DNA repair and chromatin maintenance are important for longevity, our results suggest that when the balance between these functions is shifted, diminished of LINE1 control has a stronger impact on lifespan than enhanced DNA repair.

molecular biology↗

bioRxiv2025

DINOcell: Learning Generalizable Perturbation Effects through Self-Distillation

AO_SCPLOWBSTRACTC_SCPLOWPredicting cellular responses to therapeutics is a promising approach for novel target discovery. However, state-of-the-art computational models designed to predict perturbation effects struggle to generalize and outperform simple baselines. We present DINOcell, a weakly supervised framework that adapts self-distillation to single-cell transcriptomics for predicting perturbation effects. We demonstrate that DINOcell outperforms baselines in predicting the effects of single gene perturbations. Furthermore, DINOcell accurately predicts non-additive effects of combination perturbations, indicating its capacity to model complex genetic interactions. Finally, we show that DINOcell learns representations that capture biological signals and is a promising, generalizable approach for in silico perturbation modeling, providing a valuable tool for accelerating therapeutic target discovery.

bioinformatics↗

bioRxiv2025

Mesodermal-niche interactions direct specification and differentiation of pancreatic islet cells in human multilineage organoids

Tissues develop and function within a highly complex microenvironment, where diverse cell types interact in tightly regulated spatial and temporal patterns1,2. Through distinct, relay-like waves of activity, these cells collectively shape tissue formation, ensuring that each component emerges in the right place at the right time1,2. Such coordinated cues establish the structural and biochemical framework that drives cell differentiation and tissue organization. Accurately modelling this process in humans requires the development of complex multicellular systems. Here, we pair spatial transcriptomics of the human foetal pancreas with an induced pluripotent stem cell (iPSC)-based multilineage model that faithfully recapitulate the complex, hierarchical processes underlying human pancreatic islet formation. We show that iPSC-derived pancreatic mesodermal lineages direct endocrine commitment from pancreatic progenitors, by suppressing off-target fates and orchestrating niche-mediated spatio-temporal cues that promote beta-cell differentiation. Our results identify a vascular-rich niche, featuring pancreatic pericytes, which is associated with a neural repulsion program and may contribute to shaping the islet microenvironment. We benchmark our in vitro multilineage organoid system against spatial transcriptomics of the human foetal pancreas. Together, these findings identify the key cellular actors and contact-dependent mechanisms that build the human endocrine pancreas, providing a critical model for studying human islet development and disease.

developmental biology↗

bioRxiv2025

Tumor-on-Chip as a Personalised Platform for Rapid Drug-Testing in Breast Cancer

Breast cancer (BC) remains one of the most common malignancies worldwide and continues to pose major therapeutic challenges, emphasizing the need for functional models that can inform fast treatment selection. Currently, patient-derived xenografts (PDXs) and organoids (PDOs) are valuable biological models for functional precision oncology; however, variable success rates of establishment and prolonged timelines limit their clinical application for real-time drug testing. To overcome this, we developed a Tumor-on-Chip (ToC) platform that enables functional drug sensitivity profiling within a clinically actionable 4-day timeframe. We compared ToC models with PDX results, and demonstrated high reproducibility and strong concordance with in vivo PDX responses. Drug sensitivity was correctly identified ex vivo in 88% of PDX-responsive cases, while resistance was detected in 91%, with no false positives at clinically relevant drug concentrations. To facilitate clinical translation, we engineered a custom microfluidic chip optimized for minimal breast cancer biopsy material, yielding results similar to those obtained from resection samples. We ultimately demonstrated the proof-of-concept for applying this platform to patient samples as a further tool for guiding clinical decision-making and discriminated between resistance and sensitive profiles among patients. These findings demonstrate the feasibility and translational potential of ToC models for personalized drug profiling in breast cancer, laying the groundwork for their integration into real-time clinical decision-making workflows.

bioengineering↗