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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2026

A transcriptomic and spatial map of serotonin autoreceptor expression in Drosophila

Serotonin is an evolutionarily ancient neurotransmitter that modulates an array of behaviors such as mood, sleep, and appetite across species. Serotonin acts primarily by binding to serotonin receptors, which are expressed in post-synaptic neurons (heteroreceptors) and serotonergic neurons themselves (autoreceptors). Serotonin autoreceptors modulate serotonergic tone, the foundational principles of which have been excellently demonstrated in vertebrate and invertebrate models. However, many aspects of the mechanisms and contexts in which this modulation occurs are still unclear. Drosophila melanogaster is a powerful model organism that can provide unique insights into autoreceptor function by the ability to perform precise spatial and temporal genetic manipulation with structural and functional readouts / behaviors of serotonin systems. However, a systematic characterization of serotonin autoreceptor expression in Drosophila has not been conducted. Here we use single-cell sequencing and genetic labeling to show that all five serotonin receptors are expressed in serotonergic neurons and map their expression at both the larval and adult stages of development. This is the first evidence of 5-HT2A and 5-HT7 expression in serotonergic neurons in any organism. Moreover, the unique combinations of autoreceptor expression in specific neuronal clusters will aid in the development of novel hypotheses for autoreceptor function, and demonstrates the utility of Drosophila as a model organism to study the function of serotonin autoreceptors.

neuroscience↗

bioRxiv2026

Low-Density Lipoprotein Modulates Plasma Fibrin Network Architecture and Impairs Fibrinolysis

Low-density lipoprotein (LDL) is a major atherogenic lipoprotein, yet its potential to directly modify the fibrin scaffold of blood clots is incompletely understood. Here, we investigated how LDL alters plasma fibrin network architecture and internal fibrinolysis across defined fibrinogen/thrombin conditions. Pooled normal human plasma was supplemented with LDL and clotted with controlled concentrations of fibrinogen and thrombin. Fibrin architecture was visualized by confocal microscopy and quantified by pore-size analysis; clot formation and lysis were monitored turbidimetrically in the presence of tissue plasminogen activator (tPA). Increasing LDL produced a pronounced reduction in fibrin-network pore size across the tested fibrinogen/thrombin conditions. The LDL dependence of pore diameter was well described by a power-law relationship, D_pore=(6.54 +/- 0.11)[LDL]^(-0.12 +/- 0.02) , (R^2 = 0.90), with a significant negative LDL exponent (p = 4 x 10^5). Increasing LDL also prolonged clot lysis time and altered turbidity kinetics. These findings extend epidemiologic and clinical associations between ApoB-containing lipoproteins and hypofibrinolytic clot phenotypes by demonstrating, in a controlled plasma system, that LDL itself can modify fibrin network architecture and fibrinolytic susceptibility. The results support a structure-function role for LDL within the fibrin biomaterial and motivate direct tests of LDL incorporation, protofibril packing, fibrinolytic-protein binding, and single-fiber mechanics.

biophysics↗

bioRxiv2026

DIFFERENTIAL PHOTOSYNTHETIC RESPONSES TO GLUFOSINATE AMMONIUM IN TWO GRASS WEEDS: Lolium multiflorum AND Echinochloa crus-galli.

Background: Weed control is one of the main challenges in agriculture today, particularly due to the increasing occurrence of herbicide-resistant populations. Among the most problematic species are Lolium multiflorum (L.) and Echinochloa crus-galli (L.) Beauv., for which glyphosate-resistant populations have been reported. In this context, glufosinate ammonium has emerged as an alternative for their control; however, its efficacy may vary depending on species and photosynthetic metabolism. Objective: The objective of this study was to evaluate the differential sensitivity of ryegrass (C3) and barnyardgrass (C4) to ammonium glufosinate by analyzing physiological responses associated with leaf senescence and photosystem II activity. Methods: Visual injury, chlorophyll fluorescence, and ammonium accumulation were assessed. Results: Results revealed a differential response between species. Barnyardgrass exhibited earlier symptom onset and a greater reduction in the quantum yield of photosystem II ({Phi}PSII), whereas ryegrass showed a slower senescence process. These differences indicate a higher sensitivity of barnyardgrass to glufosinate ammonium, possibly associated with its C4 photosynthetic metabolism. Conclusions: It is concluded that the effectiveness of glufosinate ammonium depends on the type of photosynthetic metabolism and on the ability of each species to cope with herbicide-induced oxidative stress. This information contributes to optimizing glufosinate ammonium use and to the development of management strategies aimed at delaying the evolution of herbicide resistance.

plant biology↗

bioRxiv2026

Using sequence-to-function models to interpret archaic hominin introgression

Understanding the functional impact of archaic hominin introgression remains challenging due to the poor representation of global introgression in publicly available genomics resources. Sequence-to-function models can predict the effects of any possible variant in the human genome and may fill this gap. Here, we used AlphaGenome to predict the effects of 144,139 introgressed SNPs segregating in present-day individuals of Papuan genetic ancestry. AlphaGenome's chromatin accessibility predictions recapitulate experimentally observed effects, but gene expression performs no better than chance. Predictions correlate more strongly with an independent reporter assay of single-variant activity than with the same variants' effects in live cells, indicating that AlphaGenome captures the regulatory potential of individual variants more reliably. Predictions carry tissue specificity, allowing us to predict specific tissues potentially impacted by introgressed haplotypes. We identify genes, including JAK1 and TAB2, that are associated with haplotypes that contain an excess of variants predicted by AlphaGenome to have large impacts on chromatin accessibility. Finally, we highlight the challenges and limitations associated with using sequence-to-function models for introgressed variant effect prediction, and show that while AlphaGenome's chromatin accessibility predictions can aid in prioritising candidate functional regions, expression predictions and the assignment of variants to target genes remain as open challenges.

genomics↗

bioRxiv2026

Entorhinal grid coding as a functional link between tau accumulation and episodic memory in human aging

Episodic memory decline is a common feature of cognitively normal aging, but its extent varies markedly across individuals. Although entorhinal tau pathology is thought to be a key contributor to episodic memory impairment, the neural mechanisms linking early tau accumulation to memory differences remain unclear. Grid-cell computations in the entorhinal cortex, which provide scaffolds for organizing experiences into episodic memories, offer one candidate mechanism. Here, we combined virtual-reality functional MRI, multivariate analysis, tau PET, and delayed word-list recall in cognitively normal older adults to test whether tau-related alterations in entorhinal coding are associated with worse episodic memory. Weaker left entorhinal grid-cell-like signal was associated with poorer memory performance, and individuals with higher left entorhinal tau burden showed weaker grid-cell-like signal. This association was specific to the canonical six-fold signal and was not explained by entorhinal volume, mean diffusivity, or intracortical myelination. A cross-sectional Bayesian mediation analysis further demonstrated that bilateral medial temporal tau burden is related to memory indirectly through left entorhinal grid-cell-like signal. Together, these findings provide evidence that entorhinal grid codes may constitute a functional pathway linking tau accumulation to memory variability in normal aging.

neuroscience↗

bioRxiv2026

Pallidal beta oscillations underlying locomotor adaptation in Parkinsons disease

BackgroundLocomotor adaptation is essential for adjusting walking patterns to complex environments. This study investigated locomotor adaptation deficits in people with Parkinsons disease (PD) and examined oscillatory activity in the globus pallidus internus (GPi) during walking adaptation. We hypothesized that elevated beta-band activity in the GPi is associated with reduced locomotor adaptability in PD. MethodsTwelve PD patients with GPi deep brain stimulation (DBS) (eleven bilateral and one unilateral) were included. Local field potentials (LFPs) were recorded from DBS electrodes during split-belt treadmill walking. Patients were tested in the medication-off, DBS-off state. Locomotor adaptation was measured as the change in step length asymmetry during split-belt walking, with smaller changes indicating greater adaptation deficits. ResultsWe found that GPi high beta (20-30 Hz) and low gamma (30-60 Hz) oscillations were modulated during split-belt walking. Compared to adapters, non-adapters showed decreased movement-related beta suppression during walking. Across participants, beta activity in the GPi contralateral to the fast leg was negatively associated with adaptation magnitude (Spearmans {rho} = -0.65 to -0.75). ConclusionsGPi oscillations are dynamically modulated during locomotor adaptation in PD. Increased beta activity may underlie impaired sensorimotor adaptation during walking. These findings provide novel insight into basal ganglia mechanisms of gait adaptation in PD and suggest that elevated GPi beta activity may serve as a marker of locomotor adaptation deficits.

neuroscience↗

bioRxiv2026

Sensory neuron dysfunction and hyperexcitability in dorsal root ganglia at disease onset in the SOD1G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder traditionally characterized by motor neuron degeneration, but emerging evidence indicates sensory system involvement. Despite reports of sensory abnormalities in some patients, the molecular and functional alterations in dorsal root ganglion (DRG) neurons remain insufficiently characterized. We investigated DRG pathology at disease onset in 12-week-old SOD1G93A mice using an integrated transcriptomic, morphological, and electrophysiological approach. RNA sequencing of lumbar DRG identified 35 differentially expressed genes, predominantly upregulated, enriched in oxidative stress-related and phagosome pathways. Comparative analysis with motor neuron transcriptomes revealed distinct gene expression profiles, indicating sensory neuron-specific molecular responses. Immunohistochemistry demonstrated reduced soma diameter in both A- and C-fiber DRG neurons. Nav channel colocalization increased for Nav1.7 in A fibers and Nav1.8 in both fiber types, whereas Nav1.6 was unchanged. Whole-cell patch-clamp recordings showed depolarized resting membrane potential, increased spike amplitude, and enhanced repetitive firing in A-fiber neurons, consistent with hyperexcitability, while C fibers showed no significant functional changes. These findings demonstrate early molecular, structural, and functional alterations in primary sensory neurons in ALS, supporting pathology beyond motor neurons and identifying sensory neuron excitability as a potential therapeutic target.

neuroscience↗

bioRxiv2026

CpxR and HicB exert independent regulatory action on the gonococcal hicAB-encoded toxin-antitoxin system

The continued emergence of Neisseria gonorrhoeae (Ng) isolates resistant to front-line antibiotics has focused efforts on understanding how alternative therapies, such as the expanded use of gentamicin (Gen), might counteract this global public health problem. Focusing on Gen as a viable alternative antibiotic for the treatment of gonorrheal infections, we previously used RNA-seq to determine if sub-lethal levels of Gen might impact gonococci on a transcriptional level and showed that expression of the putative HicA-HicB toxin-antitoxin (TA) system was increased in response to sub-lethal Gen. Importantly, loss of this TA system resulted in reduction of Ng biofilm formation in a strain specific manner. Focusing on this strain specificity, we found that the CpxR/CpxA two-component system (TCS) influences expression of the hicAB operon independently of HicB autoregulation. We now report that CpxR selectively binds to the hicAB operon to enhance expression of hicAB but does not interfere with binding of HicB to the promoter region. Furthermore, we show that single base pair differences in the intergenic region between hicA and hicB impact regulation by CpxR. Hence, the regulation of the HicAB TA in gonococcal strains is a highly coordinated response that can involve autoregulation by HicB and the CpxRA TCS. We propose that this dual regulatory scheme maximizes the ability of Ng to respond to Gen and hostile environmental conditions.

microbiology↗

bioRxiv2026

POU2AF2/OCA-T1 coactivates POU2F2 and defines a lineage-specific dependency in diffuse large B-cell lymphoma

Lineage-restricted transcriptional programs establish cell identity and can create selective dependencies in cancer. Here, we identify POU2AF2, encoding the transcriptional co-activator OCA-T1, as a critical lineage-specific dependency in a subset of diffuse large B-cell lymphoma (DLBCL). Pan-cancer dependency analyses and patient cohorts reveal elevated POU2AF2 expression in genetically aggressive DLBCL, where its depletion markedly suppresses tumor growth in vitro and in vivo. Mechanistically, POU2AF2 cooperates with the B-cell lineage-defining transcription factor POU2F2 (OCT2) to activate lymphocyte activation gene programs through direct chromatin engagement, thereby sustaining malignant transcriptional networks. We further identified a key epigenetic regulatory axis composed of the lineage-specific transcription factor TCF3 and the histone methyltransferase SET1A-COMPASS that drives POU2AF2 expression downstream of B-cell receptor signaling. Single-cell transcriptomic analysis reveals that POU2AF2 marks and sustains an innate-like B1 B-cell population in vivo, a candidate cell of origin for lymphoma. Together, these findings define a lineage-restricted POU2AF2/POU2F2 transcriptional module, controlled by a TCF3/SET1A epigenetic network, that sustains both innate-like B-cell identity and malignant fitness in DLBCL. Our study uncovers a previously unrecognized lineage-specific transcriptional dependency and highlights POU2AF2 and its associated regulatory circuitry as potential therapeutic targets in aggressive B-cell malignancies.

cell biology↗

bioRxiv2026

An agent-based 3D model of non-genetic adaptation in cancer tissues under electrical, mechanical, and hypoxic stress

Non-genetic adaptation enables cancer cells to alter their phenotype under stress without requiring new mutations. However, the mechanisms by which electrical, mechanical, and hypoxic cues combine to shape this process in 3D tissues remain poorly understood. This work presents an agent-based tumor model that integrates vascular oxygen supply, a globally imposed electric field, mechanically mediated crowding and compression cues, phenotype transitions, cell growth, mitosis, death, and inheritance of adaptive memory across division. The simulated tumors exhibit a three-stage trajectory consisting of necrosis onset, transient collapse of live mass, and partial regrowth accompanied by progressive accumulation of adapted cells. Continuous electrical stimulation produces a dose-dependent reduction in live mass while markedly increasing the adapted fraction, with comparatively limited changes in final necrotic burden. This response is strongly conditioned by mechanics and reshapes (and is reshaped by) adaptive capacity. Pulsed stimulation further shows that, in the model, electric field amplitude and temporal schedule jointly determine memory phenomena, phenotypic diversification, and growth recovery. These results show that coupling local oxygen availability, mechanical constraints, electrical forcing, and history-dependent phenotype transitions can generate distinct tissue-level patterns of phenotypic heterogeneity. Both stimulus magnitude and temporal protocol influenced the resulting population structure, suggesting that the history of physical stress may be an important determinant of adaptive dynamics in spatially organized tumor models.

biophysics↗

bioRxiv2026

Programmable Antibody-DNA Conjugation via HUH-Tags Enables Quantitative Measurement of Receptor-Specific Adhesion Dynamics

Antibody-DNA oligonucleotide conjugates (AOCs) are widely used for molecular assembly and cellular analysis, yet current approaches for generating these conjugates often rely on nonspecific chemistries that produce heterogeneous products. Here, we present two complementary strategies for generating site-specific AOCs using covalent DNA-linking HUH endonucleases. In one approach, recombinant antibodies are genetically fused to HUH-tags to enable direct, site-specific DNA conjugation. In the second, off-the-shelf antibodies are indirectly linked to HUH-tags using a photocrosslinkable Protein G-HUH fusion, enabling covalent Fc-directed attachment. Both strategies yield homogeneous AOCs while preserving antigen binding affinity. We apply these conjugates to a DNA-based mechanochemical assay, termed rupture-and-deliver tension gauge tethers (RAD-TGTs), which converts receptor-mediated adhesion forces into intracellular delivery of a fluorescent oligonucleotide payload. By tuning duplex stability, we define adhesion dynamics across multiple mechanical regimes. Using HER2- and beta1-integrin-targeting AOCs, we identify receptor-specific adhesion signatures and uncover cooperative interactions between receptor systems in a panel of cancer cell lines. Dual-color probes enable multiplexed single-cell mechanical phenotyping, and application to primary NK cells reveals dose-dependent responses to integrin modulators. These results establish a generalizable platform for site-defined AOC generation and for quantitative, high-throughput measurement of receptor-mediated adhesion dynamics.

bioengineering↗

bioRxiv2026

Embedding wear assessment in musculoskeletal simulation: A proof-of-concept application to total hip arthroplasty

Predicting wear in artificial joints requires integrating joint dynamics, contact mechanics and progressive surface evolution, yet these processes are often treated separately. In total hip arthroplasty (THA), finite-element approaches remain the reference standard, but they are computationally demanding and usually rely on boundary conditions from independent musculoskeletal (MSK) models, hindering consistent coupling and feedback between wear progression and movement dynamics. As a single-subject proof of concept, we present a computational framework that embeds wear estimation within forward MSK simulations through OpenSim-MATLAB integration. Contact variables are computed using an elastic-foundation formulation, and wear is updated through the Archard law, enabling cyclic prediction of contact mechanics and surface evolution within a single workflow at practical computational cost. The framework was evaluated in one subject with right THA during five activities of daily living and numerically benchmarked against finite-element simulations. A long-term walking analysis of 4 million cycles was also performed to assess geometry updating. Across tasks, peak contact pressures remained within 7% of finite-element predictions. Linear wear depth and volumetric loss showed maximum deviations of 16% and 13%, respectively. Accounting for progressive geometry changes yielded a maximum wear depth about 31% lower than linear extrapolation. These preliminary results support the framework's computational feasibility and numerical consistency for the tested case; nevertheless, multi-subject evaluation is required before broader predictive or clinical use.

bioengineering↗

bioRxiv2026

Structural characterization the LlaI anti-phage defense system reveals insights into the evolution of nucleotide specificity and the organization of DNA binding in McrBC restriction complexes

Canonical McrBC enzymes are nucleotide-powered, motor-driven endonucleases that bind and cleave modified bacteriophage DNA. Non-canonical McrBC homologs like LlaI and BsuMI are distinguished by a unique three-gene organization and the ability to target DNA site-specifically. Here, we report the atomic-resolution crystal structures of the DNA-binding module LlaI.R1 and AAA+ motor LlaI.R2 from the Lactococcus lactis LlaI anti-phage defense system. The crystallized LlaI.R2 hexamer traps two distinct active site conformations that correlate to different states of the nucleotide hydrolysis cycle and reveal that the organization of the critical catalytic machinery present in canonical McrB homologs is also conserved in non-canonical R2 proteins. Although canonical McrB homologs are strictly GTP-specific, we find that the R2 proteins from LlaI and BsuMI do not discriminate between different nucleotides, even when in complex with their respective R1 partners. Using mutagenesis, we define surfaces on the LlaI.R1 structure that are critical for DNA-binding and interaction with LlaI.R2. These observations support computational modelling of the assembled LlaI restriction system bound to DNA. Together, our data provide new insights into the evolution of nucleotide specificity in McrBC restriction complexes and the molecular mechanisms governing McrBC-catalyzed DNA translocation and cleavage.

biochemistry↗

bioRxiv2026

Automatic bioinformatic software named entity recognition from literature

Bioinformatics software and databases are essential components of modern life science research, yet their mentions in the scientific literature are often inconsistent and difficult to systematically identify at scale. The lack of a comprehensive and up-to-date catalog of bioinformatics resources hinders efforts toward automated biomedical knowledge extraction and streamlined data analysis. Here we present SNAIL, a hybrid named entity recognition framework designed to automatically identify bioinformatics software and database (SW/DB) names from biomedical texts. SNAIL integrates complementary lexical and semantic modeling strategies. The lexical component captures orthographic patterns and contextual cues characteristic of SW/DB names, while the semantic component leverages contextual embeddings generated by transformer-based language models such as SciBERT, combined with an explicit token-masking strategy to enhance entity-focused representations. A large training corpus was constructed automatically through a hybrid pipeline that integrates citation-hinted extraction with large language model-assisted distillation. Evaluation on two independent benchmark datasets and real-world research articles demonstrates that SNAIL substantially outperforms existing approaches, including domain-specific methods such as bioNerDS2 and general-purpose large language models such as ChatGPT, Gemini, Grok and Claude. Applying SNAIL to large-scale literature analysis further reveals distinct journal-level preferences across bioinformatics subfields. These results demonstrate that SNAIL provides an accurate and scalable solution for identifying bioinformatics resources in scientific texts and enables systematic meta-analysis of tool usage and research trends.

bioinformatics↗

bioRxiv2026

Rclade: automated taxonomic collapsing and geological-timescale annotation of time-calibrated phylogenetic trees in R

Background: Reproducible taxonomic collapsing and geological-timescale annotation of time-calibrated phylogenetic trees in R often require coordination among several packages and repeated code for label parsing, clade validation, plotting, and export. Workflow-managed analyses additionally benefit from non-interactive configuration, predictable diagnostics, and machine-readable exit status. Results: We present Rclade, an R package that consolidates the multi-package coordination required for taxonomic collapsing into a streamlined, single-function interface. Rclade provides (1) custom ggproto objects (GeomPolygonStraight/GeomSegmentStraight) that bypass coord_munch() interpolation to achieve straight-edge rendering of collapsed triangles in circular layouts; (2) automatic detection and parsing of four taxonomic-label formats (GTDB, Silva, NCBI, embedded) plus user-supplied custom regex, with explicit input-validation contracts and parsing-accuracy evaluation on real and derived test sets; and (3) workflow embeddability through YAML configuration, library-mode APIs, and standard Unix exit codes. Benchmarks on synthetic and real datasets (200-10,000 synthetic tips and real reference trees up to 10,122 tips; 5 replicates at every scale under a unified fully rendered measurement protocol) show that the full-pipeline overhead is modest for interactive use (median {approx}0.87 s in-session rendering and {approx}8.4 s process-level wall-clock at 10,000 tips). Conclusions: Rclade is a convenience layer over the ggtree/deeptime ecosystem that reduces boilerplate while adding targeted technical improvements for circular-layout rendering and format heterogeneity management.

bioinformatics↗

bioRxiv2026

X-inactivation escapee domains are CTCF-cohesin independent chromatin compartments

X-chromosome inactivation involves chromosome-wide gene silencing accompanied by extensive chromatin changes, as well the loss of topologically associating domains. Yet discrete regions of the inactive X chromosome retain activity within localised 3D domains, which contain active genes that variably escape from X inactivation. The transcription factor and architectural protein CTCF has been proposed to be implicated in escape by insulating escape domains or sustaining their topology via cohesin-mediated loop extrusion. Here, we test the role of CTCF and cohesin in escape using acute degron-mediated depletion of CTCF and RAD21 in neural progenitor cells with established escape profiles. Although CTCF occupancy correlates with escape status on the inactive X chromosome, its removal - together with loss of loop extrusion - does not disrupt escapee gene expression, or domain organization, nor does it result in spreading of silencing or activation of genes in cis. Rather, we show that facultative escape regions are self-sustaining compartments of active chromatin enriched in H3K27 acetylation and depleted in H3K27 methylation, with the magnitude of compartment strength scaling up with the degree of transcriptional activity on the inactive X chromosome. These active escapee compartments are propagated independently of CTCF and RAD21-dependent 3D architecture. Our findings identify chromatin compartmentalization as the primary feature of facultative escapee domains.

genetics↗

bioRxiv2026

Dynamic coupling of cell fate specification and cell sorting during mouse preimplantation development

During preimplantation development in mice, cells of the inner cell mass undergo a cell fate decision to become either Epiblast (Epi) or Primitive Endoderm (PrE) cells. Cell fate patterns during this stage range from an alternating pattern at the beginning to the separation of Epi and PrE at the end. Several mechanisms guiding this decision and pattern formation have been proposed, including intra- and intercellular signalling, cell division and cell sorting. The current understanding is that signalling generates the cell fates and subsequent sorting introduces the spatial cell fate separation. We used agent-based modelling to investigate whether cell differentiation and cell sorting can act concurrently and how their relative contributions to pattern formation may change over time. Comparing our model to experimental data for mouse blastocysts and ICM organoids, we find two mechanistic regimes that can produce the experimentally observed spatial separation: (i) simultaneous long-range intercellular signalling and cell sorting, and (ii) a gradual transition from short-range signalling to cell sorting, in which the timing is mediated via reducing cell fate plasticity. While the second agrees better with existing experimental evidence for late blastocysts, the first might still be relevant for early and mid blastocysts. Together, our results refine the sequential view of Epi/PrE patterning by showing that fate specification and cell sorting can be dynamically coupled, with their relative contributions changing over the course of blastocyst development.

developmental biology↗

bioRxiv2026

Arterial Elastin Abundance, Rather Than Orthologue Origin, Modulates Medial Arterial Calcification in Matrix Gla Protein-Deficient Mice

Abstract Calcific deposits in the arterial media have been associated with a number of metabolic and genetic disorders including diabetes, chronic kidney disease and generalized arterial calcification of infancy. While medial calcification and physiologic hard tissue mineralization in the skeleton are both regulated by several common determinants, emerging data suggest that there might be fundamental differences in the mechanisms underlying these two processes. Objective: We previously demonstrated that elastin haploinsufficiency delays medial calcification in MGP-deficient mice. Here, using mice in which a human ELN transgene rescues mouse elastin deficiency, we investigated whether the origin and abundance of arterial elastin differentially affect the initiation and progression of medial calcification. Approach and Results: We pursued a transgenic approach to alter the arterial elastin scaffold in MGP-deficient mice. Our analyses of a humanized MGP-deficient model with 40% reduction of medial elastin content showed a complete absence of the early-stage vascular calcification. Additionally, we showed that mouse and human elastin orthologues affect vascular calcification in a comparable manner. Conclusion: Arterial elastin abundance, rather than orthologue origin, modulates the initiation and progression of medial calcification in MGP-deficient mice. A further reduction in arterial elastin beyond that achieved by elastin haploinsufficiency profoundly delays mineral deposition and maturation, whereas restoration of elastin abundance through transgenic human ELN expression restores arterial calcification.

cell biology↗