Biology subjects

Schneider, K.

Publications and source records attributed to Schneider, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Simulated microgravity induces aging phenotypes in human organoids

Simulated microgravity provides a controlled perturbation for testing how loss of mechanical load affects human tissues. After 24 hours in rotating-wall vessels, neural, cardiac and tonsil organoids developed tissue-specific transcriptional responses that overlapped published spaceflight datasets, accompanied by higher transcriptomic-age estimates in neural and cardiac models, altered cardiac-organoid contraction dynamics and modified tonsil-organoid antiviral gene-expression signatures. These findings establish a multi-organoid framework for studying acute responses to gravitational unloading.

molecular biology↗

bioRxiv2026

Cyclic uremia without kidney injury drives cardiovascular disease with rapid onset of immunosenescence and heart failure

End-stage kidney disease (ESKD) is a major driver of cardiovascular disease (CVD) and requires dialysis treatment leading to a unique metabolic phenotype with cyclic transitions between accumulation and clearance of uremic toxins. Although ESKD patients display the highest cardiovascular mortality among CKD patients, the effect of cyclic uremia on cardiovascular disease remains subject to discussion. Existing mouse models rely on induction of kidney injury and do not resolve the interconnected pathophysiological effects of metabolic, hypertensive and endocrine renal failure. They are therefore unable to distinguish uremia-driven effects from well-established drivers of cardiovascular disease such as hypertension. Here, we established a simple, reproducible, and sex-inclusive mouse model of uremia in absence of kidney injury or hypertension leveraging a bistable vesico-peritoneal shunt (VPS). Strikingly, we identify cyclic uremia as an independent driver of ESKD-induced CVD, that induces heart failure with preserved ejection fraction (HFpEF), vascular inflammation and immunosenescence. As such, the VPS represents the first preclinical model that enables investigation of cyclic uremia as a driver of cardiovascular disease.

systems biology↗

bioRxiv2026

Glycine betaine-mediated transcriptional stimulation links its catabolism and vitamin B12 biosynthesis in Rhizobiaceae

Glycine betaine (GB) is a trimethylated ammonium compound widely used as a compatible solute, and serves as a carbon, nitrogen, and methyl group source in many members of the Rhizobiaceae. GB is critical for high-level vitamin B2 production, a cofactor synthesized exclusively by microorganisms. Vitamin B2 formation requires multiple methylation steps. In the industrial vitamin B2 production strain Pseudomonas denitrificans, GB has been shown to serve as a methyl group donor through its successive demethylation to glycine and to provide the carbon backbone for the universal porphyrin precursor 5-aminolevulinic acid. Moreover, previous proteomics studies have revealed increased levels of vitamin B2 biosynthetic enzymes in the presence of GB. However, it has remained unclear at what level of gene expression this regulation occurs. Here, using promoter-reporter fusions in the vitamin B2 overproducer Ensifer adhaerens LU2703 and in the low-producer Sinorhizobium meliloti 102F34, we demonstrate that GB activates promoters of both its own catabolic pathway and of major cob operons. Two of these operons encode the complete set of S-adenosylmethionine-dependent methyltransferases required for corrin ring biosynthesis, the foundational, rate-limiting stage in vitamin B12 production. Stimulation of cobE and cobH promoters as well as vitamin B2 production yields followed sigmoidal dose-response curves with saturation in a similar concentration range, suggesting a tight coupling between GB supply and biosynthetic output. Our findings uncover a novel regulatory layer in vitamin B2 biosynthesis and provide promoter-probe set-ups for further exploration of GB-mediated transcriptional control.

microbiology↗

bioRxiv2026

Single-nucleus profiling reveals age-associated remodeling opposed by parity in the postmenopausal human ovary

The postmenopausal ovary is commonly viewed as a passive organ, and its biology and cell composition remain incompletely characterized. Here, we generated a single-nucleus atlas of the aging postmenopausal human ovary comprising 439,011 nuclei across 64 ovarian samples from 28 donors. We resolved 37 fine cell states, revealing extensive stromal, vascular, and immune heterogeneity in the postmenopausal ovary. Aging was associated with stromal stress-state expansion, vascular and immune depletion, and enrichment of steroidogenic programs consistent with ovarian androgenization. Several major age-associated compositional shifts were supported in an independent GTEx ovary bulk RNA-seq cohort. Notably, the number of live births broadly opposed age-associated transcriptional and compositional remodeling. Together, our findings show that the postmenopausal ovary remains an actively remodeled aging tissue and that reproductive history leaves durable molecular and cellular imprints on ovarian aging.

genomics↗

bioRxiv2026

Cellular senescence dysregulates antiviral interferon responses in idiopathic pulmonary fibrosis

Patients with idiopathic pulmonary fibrosis (IPF) are highly vulnerable to respiratory virus infections, but the cellular mechanisms linking fibrotic remodeling to impaired local antiviral defense remain unclear. Here, we investigated how cellular senescence shapes the response of patient-derived healthy and IPF primary lung fibroblasts to influenza A virus (IAV) infection. Transcriptomic profiling identified infection as the driver of gene expression in both DNA damage-induced senescent healthy and IPF fibroblasts and revealed induction of canonical antiviral pathways in both cell states. However, senescent IPF fibroblasts adopted a distinct antiviral response state characterized by a broader set of uniquely induced genes and differential coordination of antiviral transcriptional networks. Functionally, senescence increased viral titers in healthy and IPF fibroblasts, while senescent IPF fibroblasts displayed an altered inflammatory response. Network analysis linked viral response- and cell cycle-associated modules specifically to the senescent healthy infected state, whereas these programs were weaker in senescent IPF fibroblasts. Transcription factor inference identified IRF3 and STAT1 as candidate regulators of this altered antiviral state in both senescent healthy and IPF fibroblasts. Consistent with the network and transcription factor analyses, siRNA-mediated depletion of IRF3 or STAT1 significantly reduced IFN-{beta} secretion in senescent healthy fibroblasts, whereas IPF fibroblasts showed only milder effects, indicating a disease-specific dependence on these pathways for antiviral control. Together, these findings show that the combination of cellular senescence and fibrotic fibroblast identity creates a dysfunctional antiviral state that may help explain the high susceptibility of IPF patients to virus-associated acute exacerbations and disease worsening.

cell biology↗

bioRxiv2026

DNA damage drives a unique, Alzheimer's disease-relevant senescent state in neurons

Alzheimers disease (AD) shares molecular hallmarks with the canonical drivers of cellular senescence. Senescent cells have also been shown to accumulate in the brain with age, yet the mechanisms linking AD pathology to the accumulation of senescent cells in the brain remain unclear. Here, we demonstrate that DNA damage in patient-derived directly induced neurons (iNs) drives a senescent-like cell state with relevance to AD. DNA damage-induced senescent iNs show significant transcriptional concordance with human AD neurons and a weighted gene co-expression network analysis (WGCNA) uncovers candidate regulators associated with the senescent-like state in neurons. Direct comparison of iNs to the original patient fibroblasts reveals striking cell-type specific senescence signatures following DNA damage. iNs adopt a p21-associated senescent-like state characterized by a senescence-associated secretory phenotype (SASP) and predicted activation of NF-{kappa}1. In contrast, fibroblasts develop a p16-associated senescent state lacking a SASP phenotype and show a predicted repression of NF-{kappa}1. Early responses to DNA damage further reveal divergent DNA damage response (DDR), with neurons exhibiting higher accumulation of damage lesions relative to fibroblasts. Together, these findings demonstrate that DNA damage drives a unique senescent-like neuronal state that models molecular features of AD, while also revealing fundamental cell-type specific differences in senescent-like phenotypes and DDR.

cell biology↗

bioRxiv2026

ELMO1 dependent efferocytosis protects from nephrotoxin induced acute kidney injury

Acute kidney injury (AKI) is a sudden episode of kidney failure linked to a wide range of health conditions. High mortality in AKI highlights the need to identify new therapeutic approaches. Homeostasis in multicellular organisms is exquisitely regulated by phagocytosis of apoptotic cells, also known as efferocytosis. Apoptotic cells are frequently observed at sites of inflammation, including in AKI. Engulfment and cell motility protein-1 (ELMO1) is a regulator of the actin cytoskeleton that promotes apoptotic cell removal by phagocytes during efferocytosis. Mutations in the human ELMO1 gene are linked with diabetic nephropathy and, in animal models of this disease, high ELMO1 levels promote renal dysfunction. However, the role of ELMO1 in AKI was not known. Here, we describe the links between ELMO1 and kidney pathology and test global and tissue-specific ELMO1-deficient mice in models of AKI. While global loss of Elmo1 expression did not impact the immediate loss of renal function after ischemia-reperfusion elicited AKI, ELMO1 deficiency resulted in increased tissue injury in AKI caused by cisplatin injection. Cisplatin induced robust renal cell apoptosis that was significantly elevated in mice with the global loss of ELMO1, but not in mice with the macrophage-specific Elmo1 deletion. Using primary cell culture and immunofluorescence approaches, we highlight the role of ELMO1 in efferocytosis by several renal cell types, suggesting possible additive effects during nephrotoxic injury.

pathology↗

bioRxiv2026

Neuroprotective Effect of Intraperitoneal Humanin-G in Retinal Degeneration of Royal College of Surgeons Rats

This study aimed to examine whether Humanin-G (HNG), a mitochondrial derived peptide with cytoprotective properties, could improve the retinal function and gene expression profiles after intraperitoneal injections to Royal College of Surgeons (RCS) rats with Retinal Pigment Epithelium (RPE) dysfunction and retinal degeneration. Starting at postnatal day 21 (p21), RCS rats received twice a week intraperitoneal injections of either Low Dose HNG (0.4 mg/kg), High Dose HNG (4mg/kg), or sham-saline for 1 or 4 weeks. Visual function was tested with full field scotopic & photopic electroretinography (ERG) and optokinetic testing (OKT) 1 and 4 weeks after first injection (WAFI). The rats were euthanized after the ERG and OKT (1 or 4 WAFI) and the dissected retinas and RPE were collected for RNA, cDNA and Quantitative Real-time PCR (qRT-PCR) analysis. The results of our study showed that high dose (4mg/kg) HNG at 4 WAFI was associated with the largest change in gene expression in the RPE and retina of treated animals, altering expression of genes involved in apoptosis, oxidative stress, inflammation and retinal/RPE function. Analysis of a and b waves from scotopic and photopic ERG showed no difference between either low or high dose of HNG and sham injection at 4 WAFI. However, at 4 WAFI, the visual acuity in rats treated with high dose HNG showed significant improvement as compared to the rats treated with low dose of HNG or saline. Most significantly, our findings support that HNG administered IP can modulate RPE/neuroretina cells and improve vision, thus may be a potential treatment for retinal degeneration diseases.

neuroscience↗

bioRxiv2026

Simulated Microgravity Recapitulates Aspects of Biological Aging in Humans

Spaceflight and microgravity profoundly affect human physiology and have been proposed to recapitulate key features of biological aging, yet the underlying mechanisms remain incompletely understood. Here, we performed whole-genome transcriptomic profiling to define immune cell alterations associated with both natural aging and simulated microgravity. Leveraging the longitudinal nature of the Stanford 1,000 immunomes Project, we compared peripheral blood mononuclear cells (PBMCs) exposed to rotating wall vessel bioreactor with matched samples collected up to 9 years later from the same individuals. We quantified changes across aging hallmarks, molecular pathways, gene modules, cellular energetics, disease risk and vaccine-response signatures. Microgravity-induced transcriptional closely tracked subject-level aging trajectories spanning across disease risk domains including those affecting the metabolic, musculoskeletal and circulatory systems, and multiple aging hallmarks involving nutrient sensing, intrinsic capacity, chronic inflammation, proteostasis, cellular senescence and metabolic regulation. Independent validation using Single-Cell Energetic Metabolism by Profiling Translation Inhibition (SCENITH) profiling confirmed these observed metabolic adaptations and revealed reduced mitochondrial dependence with minimal compensatory glucose dependence across immune cell subsets, features that strongly parallel aging biology. Consistent with previous findings, longitudinal changes indicated that close of 1/3 of participants do not follow population trajectories but these can be partly predicted with simulated microgravity exposure. Together, this within-donor framework establishes simulated microgravity as a scalable and experimentally tractable platform to model aspects of biological aging in humans and accelerating the prioritization of candidate countermeasures for spaceflight and aging on Earth.

immunology↗

bioRxiv2026

Proteogenomic Profiling Reveals a Distinct Endogenous p16INK4a-Associated Senescence Signature in the Human Ovary.

The tumor suppressor and cell cycle regulator, p16INK4a (p16), has been extensively linked to cellular senescence, and its accumulation can reflect endogenous senescence within ovarian tissue. However, gene and protein signatures associated with p16 have not been well defined in human tissue. We utilized immunohistochemical (IHC) staining for P16 to identify distinct positive (P16+) and negative (P16-) regions within the ovarian cortex and employed the GeoMx Digital Spatial Profiler for simultaneous proteomic and transcriptomic analyses on cortical tissue cores. Differential expression and translation between p16-positive and p16-negative cores identified genes and proteins that are cellular senescence related (e.g., CDKN1A, GADD45B, GADD45G, and MYC) or key regulators of the extracellular matrix (e.g., collagen I, ADAMTS4, and MMP11). Additionally, the transcriptomic signature identified here was significantly enriched for the spatially derived ovarian p16-associated signature, BuckSenOvary, but not for other senescence gene sets. Lastly, given the association between changes to the extracellular matrix in aged ovaries and ovarian cancer, we compared genes upregulated and downregulated in p16-positive regions relative to p16-negative regions against multiple ovarian cancer transcriptomic datasets. These findings provide new insight into the molecular landscape of naturally occurring ovarian senescence and its possible relationship to age-associated disease processes, including cancer development.

cell biology↗

bioRxiv2025

Senescence-Linked Fibrosis in the Aging Human Ovary Revealed by p16-Based Histological Profiling and Spatial Transcriptomics

Cellular senescence is implicated as a driver of ovarian aging, but senescent cells in the human postmenopausal ovary remain poorly defined. Using spatially resolved p16INK4a protein expression, a canonical senescence marker, we identified and mapped senescent cells in postmenopausal ovaries. We integrated p16 immunohistochemistry, multiplexed immunofluorescence, spatial transcriptomics, and AI-guided digital pathology to map senescent microenvironments. p16-positive cells formed discrete stromal, vascular, and cyst-associated clusters that increased with age and were enriched for macrophages and myofibroblast-like cells. Wholetranscriptome profiling of 92 spatial regions uncovered a 32-gene p16-associated signature, BuckSenOvary, that distinguished p16-positive regions across cortex and medulla. BuckSenOvary is characterized by suppression of cell-cycle regulators and activation of inflammatory and extracellular-matrix remodelling genes. AI-based collagen matrix analysis confirmed that p16-positive regions exhibit more architecturally complex collagen, demonstrating that focal senescent microenvironments are fibro-inflammatory. These findings position senescent ovarian niches as therapeutic targets to preserve ovarian function.

cell biology↗

bioRxiv2025

Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis

Cellular senescence is a largely heterogeneous state of cell stress that deleteriously accumulates with age. Many types of heterogeneity in senescence have been described; however, cellular senescence within the same cell type has only started to be documented. Here, we show primary, human lung fibroblasts from donors who are healthy or diagnosed with idiopathic pulmonary fibrosis (IPF) exhibit a subtle form of heterogeneity over time after DNA damage. Moreover, senescent IPF lung fibroblasts display a dysregulated transcriptional-protein DNA damage response (DDR). Weighted gene correlation network analysis (WGCNA) reveals unique and known targets linking senescent IPF lung fibroblast heterogeneity to genes associated with DNA damage and repair, cytokine and chemokine responses, and extracellular matrix (ECM) signaling. We combine our healthy and IPF senescent gene expression signatures to develop a novel gene set of senescence-associated genes that identify disease-relevant cells in human single-cell RNA-seq (scRNA-seq) data. Collectively, our results uncover human-relevant senescence signatures, highlight IPF-specific DDR, cytokine and chemokine, and ECM targets, and expand our understanding of how a dysregulated DDR contributes to senescent cell heterogeneity in IPF.

cell biology↗

bioRxiv2025

Facial photographs as proxies for inflammatory aging

Systemic chronic inflammation is a major determinant of aging and disease risk, yet current biomarkers such as the Inflammatory Age (iAge) clock and other proteomic assays remain costly, invasive, and poorly scalable. The skin, as both a visible marker and contributor to age-related inflammation ("inflammaging"), offers a potential non-invasive window into this health metric. Here, we developed Healthy Selfie, a digital predictor of iAge, from simple 2D frontal face photographs. We leveraged data from the Edifice Health Pre-Market trial, a clinical study of 750 participants aged 20 to 90 years, using a subset with available iAge measurements paired to facial images, demographic, clinical, and functional data. Facial embeddings from a pretrained deep learning image model were combined with chronological age, sex and other easily obtainable metadata, and mapped to blood-derived iAge using regression within a leave-one-out cross-validation framework. Photo-predicted iAge values were significantly correlated with blood iAge values (r = 0.536) and were used to identify increased iAge acceleration (accuracy 66.39%, sensitivity 65.61%, specificity 67.24%). Validation on an external dataset containing [~]100,000 images showed no significant demographic bias across ethnicities, including Asian, Black, Indian, Middle Eastern, and Latino populations. Beyond iAge, we also showed that facial features could predict blood levels of individual inflammaging proteins (CXCL9, CXCL1, CCL11, TNFSF10, and IFNG). Our findings suggest that ordinary facial photos can provide information on blood inflammation and can be used as a scalable, ultra low-cost tool for assessing biological aging and advancing precision health.

bioinformatics↗

bioRxiv2025

Pathogenic tau inhibits synaptic plasticity by blocking eIF4B-mediated local protein synthesis

Activity-dependent modulation of synaptic strength is critical for encoding memories and it is inhibited in tauopathies including Alzheimers disease (AD) and Frontotemporal lobar degeneration with tau inclusions (FTLD-tau). Pathogenic tau accumulates in neurons where it obstructs synaptic plasticity. How tau blocks synaptic plasticity leading to memory loss is unclear. Here, we show that FTLD-tau inhibits plasticity by blocking activity-dependent protein synthesis in dendrites. In the plasticity-associated translatome, we identified a subset of downregulated translated mRNAs in FTLD-tau neurons that encode postsynaptic plasticity regulators. Protein synthesis was blocked by FTLD-tau binding to eIF4B which caused eIF4B dissociation from the translation initiation complex and reduced dendritic eIF4B levels. Inhibiting the tau-eIF4B interaction or enhancing eIF4B levels in FTLD-tau neurons restored local protein synthesis and synaptic plasticity. Together, this suggests that pathogenic tau binding to eIF4B disables the local synthesis of plasticity-related proteins that drive synapse strengthening and memory formation.

neuroscience↗

bioRxiv2025

Effects of altered gravity on adrenergic-mediated cAMP signalling in intact cells

Spaceflight-induced cardiac atrophy and rhythm disorders are linked to dysregulation of the adrenergic-cAMP-PKA pathway. Gravity-dependent alterations in adrenergic signaling, particularly cAMP dynamics, remain poorly understood. Using fluorescence biosensors, we studied intact cells under simulated microgravity and hypergravity. We observed shifts in the EC50 of cAMP production: leftward under hypergravity and rightward in microgravity, with faster cAMP accumulation kinetics in hypergravity. Cytoskeletal remodelling, hypothesized to be a determinant of such chances, was negligible, suggesting alternative mechanisms. These findings highlight significant gravity-induced offsets in the pharmacology of a prototypical GPCR, with implications not only for adrenergic signalling but also for other pathways of pharmacological interest, potentially informing countermeasures for astronaut health and pharmacology in altered gravity settings.

cell biology↗

bioRxiv2024

Migrastatic Therapy as a Potential Game-Changer inAdaptive Cancer Treatment

Adaptive therapy, which anticipates and counters the evolution of resistance in cancer cells, has gained significant traction, especially following the success of the Zhang et al.s protocol in treating metastatic castrate-resistant prostate cancer. While several adaptive therapies have now advanced to clinical trials, none currently incorporates migrastatics, i.e. treatments designed to inhibit cancer cell metastasis. In this study, we propose integrating migrastatics into adaptive therapy protocols and evaluate the potential benefits of using a game-theoretic spatial model. Our results demonstrate that combining adaptive therapy with migrastatics effectively delays the onset of metastasis and reduces both the number and size of metastases across most cancer scenarios analyzed. This approach not only extends the time to the first metastasis but also enhances the overall efficacy of adaptive therapies. Our findings suggest a promising new direction for cancer treatment, where adaptive therapy, in combination with migrastatic agents, can target both the evolution of resistance and the metastatic spread of cancer cells.

cancer biology↗

bioRxiv2024

Blood Omics Models for System-Specific Mortality Risk Estimation

Traditional blood-based aging clocks provide an estimate of a persons overall biological age. However, physiological systems and organs age at different rates in an individual, and anti-aging interventions often target specific physiological systems. Therefore, there is a growing need for methods capable of assessing biological age at the level of specific physiological systems. Here, we used blood chemistry and cell count data from 456,180 individuals in the UK Biobank (UKB) to develop mortality-based predictors of biological age across 9 physiological systems matching WHOs International Classification of Disease (ICD-10) chapters (DiseaseAge). We applied DiseaseAge to the Health and Retirement Study (HRS) cohort and validated its ability to identify biologically older systems in individuals diagnosed or deceased from age-related diseases affecting those systems. For instance, individuals diagnosed with high blood pressure, heart attack, congestive heart failure, or angina exhibited a biologically older circulatory system than other systems. Similarly, individuals with accelerated aging in the circulatory, musculoskeletal, or respiratory systems displayed higher risk of mortality from conditions associated with these systems. Additionally, we showed that individuals within the top 5% biologically older metabolic, circulatory, respiratory and mental systems exhibited increased risk of developing diabetes, high blood pressure, lung disease and dementia, respectively. Finally, we used metabolomics and proteomics data in the UKB and epigenomics and transcriptomics in HRS to generate omics surrogates of DiseaseAge for all physiological systems and created an online resource for their calculation.

systems biology↗

bioRxiv2024

STABIX: Summary statistic-based GWAS indexing and compression

Genome-Wide Association Studies (GWAS) are widely used to investigate the role of genetics in disease traits, but the resulting file sizes from these studies are large, posing barriers to efficient storage, sharing, and querying. This issue is especially important for biobanks like the UK Biobank that publish GWAS for thousands of traits, increasing the volume of data that must be effectively managed. Current compression and query methods reduce file sizes and allow for quick genomic position-based queries but do not provide utility for quickly finding loci based on their summary statistics. For example, finding all SNVs in a particular p-value range would require decompressing and scanning the whole file. We propose a new tool, STABIX, which introduces summary-statistic-based queries and improves upon the standard bgzip compression and tabix query tool in both compression ratio and decompression speed. When applied to ten GWAS files from PanUKBB, STABIX created smaller compressed data and indices than tabix for all files, where bgzip and tbi files were an average of 1.2 times the size of STABIX compressed files and indexes. In the same ten files, STABIX per gene decompression was, on average 7x faster than tabix per gene decompression, and achieved faster per gene decompression times for over 99% of nearly 20,000 genes.

bioinformatics↗