Biology subjects

Adam, M.

Publications and source records attributed to Adam, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Concurrent cognitive, behavioral and systemic physiological features mark preclinical Alzheimer's disease

Alzheimer's disease (AD) pathology accumulates years before overt cognitive impairment, yet its multidomain phenotype remains poorly defined. To limit confounding by uncontrolled comorbidities, we assembled a cohort of 644 older adults self-reporting intact cognition, free of systemic or neurological diseases and managed medically for risk factors. Plasma p-tau217 was elevated in 20%, and 93 of these were cognitively unimpaired. This biomarker-defined, risk factor -controlled preclinical AD subgroup showed subtle, concurrent cognitive and behavioral differences, accompanied by modest differences in physiological measures within clinical reference ranges, and alongside higher biomarkers of astrogliosis (GFAP) and neurodegeneration (NfL). Reported modifiable risk factor histories were not associated with p-tau217 when effectively managed. A proof-of-concept AI classifier integrating routine multidomain clinical data improved identification of p-tau217-high individuals relative to cognitive screening alone. These findings indicate preclinical AD is not phenotypically silent at the group level and support multidomain-based screening for biomarker testing and early-detection.

neuroscience↗

bioRxiv2026

A cell death-independent role for MLKL in TGF-β receptor recycling in Marfan syndrome

Marfan syndrome (MFS) causes thoracic aortic aneurysm through mutations in the fibrillin-1 gene and subsequent dysregulated TGF-{beta} signalling. Mixed lineage kinase domain-like protein (MLKL) executes necroptosis after RIPK3-dependent phosphorylation, but also functions in endosomal trafficking. Here we show that MLKL phosphorylation sustains TGF-{beta} receptor recycling and aortic wall integrity without causing cell death. Phosphorylation-dead MLKLS345A/S347A (MlklAA) mice developed aortic root dilation with disorganised collagen architecture and a secretory-pathway proteomic signature. Crossing them with Fbn1C1039G/+ MFS mice aggravated aortic dilation, disrupted collagen fibril ultrastructure and prolyl/lysyl hydroxylation, and caused lethal rupture under angiotensin II. Complete MLKL deficiency reproduced this phenotype. Phosphorylated MLKL was increased in MFS aortas, yet cleaved caspase-3, TUNEL positivity, smooth muscle cell content and leukocyte infiltration were unchanged. In smooth muscle cells, MLKL depletion dysregulated collagen-modifying enzymes, altered TGF-{beta}-driven matrix remodelling and impaired RAB11-dependent TGF{beta}R1 recycling. These findings suggest that phosphorylation-dependent, non-lytic functions of MLKL may contribute to the maintenance of thoracic aortic integrity in MFS.

cell biology↗

bioRxiv2026

Functional Characterization of Myeloid Neoplasm-associated DDX41 Variants Reveals Pathogenic Interaction with Acquired Hotspot Mutation

Germline variants in DDX41 are the most frequent genetic predisposition to adult hematologic malignancies. The most common variants are truncating, implicating loss of function in the pathogenesis. However, non-truncating variants account for 30-40% of cases, and their impact on essential DDX41 functions remains unknown. We utilized a genetic complementation assay to assess the functionality of 10 recurrent germline non-truncating variants of DDX41. All variants restored viability to Ddx41-deficient hematopoietic progenitor cells at exogenous expression levels. In contrast, the hotspot mutant p.R525H, which is somatically acquired at disease onset in >50% of patients, failed to restore viability. CRISPR-based modeling in cell lines and mice revealed heterogeneity: some variants were non-functional at endogenous expression levels whereas others maintained complete functionality, supporting normal cell proliferation and even lifelong hematopoiesis in a homozygous setting. Notably, co-expression of p.R525H with some variants caused impaired hematopoietic progenitor cell viability, indicating a dominant-negative effect of p.R525H. In contrast, other variants, all classified as variants of unknown significance, were unaffected by the presence of p.R525H. A screen of 100 disease-associated variants confirmed that many non-truncating germline variants are susceptible to p.R525H-mediated dominant-negative effects, whereas wild-type DDX41 is not. These findings indicate that DDX41 variant curation is complicated by variable effects on functionality and variant-specific interactions with somatically-acquired DDX41 mutations. The dominant-negative effect of p.R525H provides a mechanistic basis for the conclusion of recent patient cohort analyses that co-occurrence with a somatic hotspot mutation is a reliable indicator of DDX41-driven disease in carriers of non-truncating variants.

cancer biology↗

bioRxiv2026

ArchiCrop: a 3D+t architectural model driven by crop model dynamics

Evolving agricultural practices and contexts invite to reconsider the way crop and plant models represent agroecosystem processes. Crop models assume spatial homogeneity, which reduces confidence in their predictions for structurally heterogeneous systems, whereas FSPMs complexity limits their application to field-scale or large-scale studies. To benefit from strengths of both approaches, we introduce ArchiCrop, a parametric 3D architectural model of cereals that generates plant geometries constrained by crop model dynamics and coordination rules. Inspired by the concept of equifinality, ArchiCrop generates a morphospace of architecturally diverse morphotypes which remain equivalent at crop scale in terms of LAI and height. This multiscale approach enables the comparison of processes computed at different scales on wheat, rice, maize and sorghum. We demonstrate its application evaluating light interception Beers formalism in STICS soil-crop model relying on the leaf-resolved radiosity model Caribu for the 3D reference simulations, for a sorghum monocrop. We show that the consideration of the variability of only two plant architectural traits, leaf insertion angle and leaf number, introduces up to 27% of uncertainty in the cumulated absorbed light at the end of the season. A possible outcome from this method is also the definition of metamodels for crop model processes, as exemplified for extinction coefficient of Beers law. ArchiCrop can support a range of applications, including crop model uncertainty analysis, model-assisted phenotyping, and ideotype design. HighlightsO_LIArchiCrop is the first 3D+t botany-based parametric generative model for cereals. C_LIO_LIArchiCrop downscales crop model dynamics to 3D+t architecture canopies efficiently. C_LIO_LIArchiCrop compares big leaf versus leaf-resolved light interception. C_LIO_LIPlant architectures with same leaf area intercept light with up to 27% variability. C_LIO_LIArchiCrop helps ideotyping, crop model evaluation and error propagation analysis. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/716970v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@6534b3org.highwire.dtl.DTLVardef@66df41org.highwire.dtl.DTLVardef@1cb4c9dorg.highwire.dtl.DTLVardef@12fa30_HPS_FORMAT_FIGEXP M_FIG C_FIG

plant biology↗

bioRxiv2026

Disruption of the Brain-Spleen Axis Impairs Monocyte-Microglia Communication and Accelerates Disease Progression in a Model of Amyloidosis

Alzheimers disease (AD) is characterized by a prolonged asymptomatic phase before cognitive decline emerges, yet the mechanisms driving symptom onset remain unclear. Here, we hypothesized that the transition from asymptomatic to symptomatic disease is linked to dysfunction of brain-immune communication. Retrograde neuronal tracing in the 5xFAD mouse model of amyloidosis revealed reduced brain-spleen connectivity at advanced disease stages. To probe the functional role of the brain-spleen axis in coping with disease, we denervated the splenic nerve at an early presymptomatic stage. This intervention accelerated cognitive decline, impaired splenic hematopoiesis, diminished monocyte recruitment to the brain, disrupted monocyte-microglia signaling networks, and reduced the transition of microglia from a homeostatic to the disease-associated (DAM) state. Conversely, enhancing splenic noradrenergic input increased hematopoiesis, restored monocyte homing to the brain, and delayed cognitive impairment. The protective role of splenic monocytes was independently validated in a retinal cytotoxic injury model, in which splenic denervation impaired post-insult retinal ganglion cell survival. Together, these findings identify an active brain-spleen circuit in regulating monocyte recruitment and establish peripheral monocytes as key drivers of microglial state transitions and disease progression.

neuroscience↗

bioRxiv2026

Adult human ex vivo brain slices for dissecting glial biology and multicellular communication

Glial cells are critical modulators of brain function in health, aging, and disease, emerging as promising therapeutic targets. However, exploring their roles and therapeutic potential is limited by the lack of experimental systems that faithfully capture the repertoire of mature human glial cells while permitting controlled perturbations. Here, we establish a robust ex vivo platform for cell-type specific interrogation of glial responses and multicellular crosstalk, based on adult human organotypic brain slice cultures, obtained from neurosurgical resections. We show that slice cultures preserve tissue architecture, maintain all major cell types and mature cellular identities over weeks in culture. These cultures elicit robust, stimulus-specific transcriptional programs to diverse stressors and inflammatory stimuli, demonstrating sensitivity to distinguish closely related signals and reproducibility despite biological and technical variation. Moreover, we resolved coordinated glial cell type-specific responses to TNF, a key mediator of neuroinflammation, uncovering distinct and physiologically relevant functional roles validated in postmortem human brains. Network analyses discovered balanced pro- and anti-inflammatory loops among microglia and astrocyte cells, which notably also involved oligodendrocyte precursor cells (OPCs), confirming their suggested role in regulation of the tissue level inflammatory response in human brains. We experimentally validated that glial activation in slice cultures is orchestrated not only by direct stimulation but also through intercellular signaling across cell types, mirroring natural multicellular dynamics in brain tissue. Together, organotypic brain slice cultures emerge as a sensitive and robust platform for dissecting adult human glial biology, paving the way for deeper mechanistic insights and advanced drug-screening applications.

neuroscience↗

bioRxiv2025

Discovery of an orally available potent ER aminopeptidase 1 (ERAP1) inhibitor that enhances anti-tumor responses and limits inflammatory autoimmunity in vivo.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that can regulate immune responses primarily by proteolytically processing peptides before loading and presentation on the cell surface by major histocompatibility class I molecules (MHC-I). ERAP1 activity can either reduce the immunogenicity of cancer cells by over-trimming cancer-associated antigenic peptides or contribute to autoimmunity by generating self-antigenic peptides. As a result, ERAP1 inhibition has emerged as a tractable approach for cancer immunotherapy and specific classes of autoimmunity. Here, we describe the discovery, after hit-to-lead optimization, of a potent and selective ERAP1 inhibitor based on the pyrrolidine 3-carboxylic acid scaffold that targets the regulatory allosteric site. The compound has favourable in vivo pharmacokinetics, including oral bioavailability, and can regulate the immunopeptidome of cancer cells and enhance cancer cell antigenicity in vivo in a dose-dependent manner, controlling tumor growth. In addition, when administered in the murine collagen-induced arthritis model, it does not induce any exacerbation of autoimmune responses but rather results in a dose-dependent therapeutic benefit. Our results demonstrate that ERAP1 inhibition can constitute a tractable approach to modulating immune responses for therapeutic applications, providing mechanistic insight and a valuable lead and in vivo tool for further drug development efforts and for interrogating ERAP1 biology.

immunology↗

bioRxiv2025

Single-cell and Spatial Omics Reveals Region-Specific Plasticity and Therapeutic Vulnerabilities in Metastatic High-Risk Neuroblastoma

Neuroblastoma, a deadly pediatric cancer derived from sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes. Primary neuroblastomas are well-characterized, but the mechanisms underlying metastasis remain poorly understood. Here, by applying single-cell and spatial multi-omics analyses to primary and metastatic tumors, we found that lymph-node metastases in high-risk neuroblastomas display distinctive cellular heterogeneity and plasticity, marked by mesenchymal-like and stem-like states and heightened epithelial-to-mesenchymal transition activity compared to primary adrenal tumors. Additionally, compared to primary adrenal masses, the metastatic niche display increased immunosuppressive myeloid programs, heightened immune checkpoint signaling, and lymphocyte exhaustion, which are indicative of immune evasion and dysfunction. Notably, metastatic neuroblastomas show elevated eIF4F translation machinery and XPO1 levels. Dual inhibition of eIF4A and XPO1 synergistically halted tumor growth and prolonged survival in xenograft models. Together, our multi-omics studies reveal the molecular and cellular plasticity that contributes to therapy resistance and highlight exploitable therapeutic vulnerabilities in high-risk metastatic neuroblastomas.

cancer biology↗

bioRxiv2025

Early neuronal reprogramming and cell cycle reentry shape Alzheimer's disease progression

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by hallmark pathologies, synaptic dysfunction, neuronal loss, gliosis and cognitive decline-dementia. Recent large-scale cell atlases of human AD brains exposed vulnerability of specific neuronal subtypes and highlighted early, coordinated glial responses, suggesting glial involvement in disease progression. However, the timing and nature of neuronal changes, differences between neuronal subtypes, and their coordination with glia remain unclear. Here, we used non-negative matrix factorization to identify co-expression gene programs in single-nucleus RNA profiles from the prefrontal cortex of 437 samples from donors whose clinical symptoms ranged between no cognitive impairment and AD dementia. This approach identified early coordinated transcriptional changes across all neuronal subtypes, preceding clinical symptoms of cognitive decline, and validated in independent snRNA-seq, proteomics, and ELISA datasets. We found neurons in AD undergo rapid modulation of synaptic genes, accompanied by convergence of neurons into two distinct programs: An oxidative stress and apoptosis program abundant in vulnerable neuronal subtypes, and a DNA damage and cell-cycle reentry program associated with resilient subtypes. Moreover, neuronal reprogramming was closely tied to glial responses, and diverged between AD to non-AD brain aging, suggesting neuro-glial coordinated reprogramming shapes the AD cascade and influences disease outcomes.

neuroscience↗

bioRxiv2025

Specific cell states underlie complex tissue regeneration in spiny mice

SUMMARY STATEMENTComparing regenerative vs. fibrotic healing, we identify injury-induced cell states associated with persistent cell cycle progression and complex tissue regeneration in mammals. Cell proliferation is an elemental feature of epimorphic regeneration in vertebrate taxa. We previously reported that in contrast to fibrotic repair observed in laboratory mouse (Mus) strains, highly regenerative spiny mice (Acomys spp.) exhibit cell cycle progression and cell proliferation to faithfully replace missing tissue. However, little is known about proliferation dynamics, and specific cell types and states that may contribute to complex tissue regeneration in mammals. Using temporal pulse-chase experiments, we show that stromal cells in Acomys dimidiatus rapidly re-enter the cell cycle in response to injury and maintain tight spatiotemporal control of cell cycle progression to restrict the proliferative population to a distal area relative to the injury. Conversely, Mus stromal cells incorporate thymidine analogs without cell division supporting an S-phase arrest after D10. Deploying immunostaining and scRNA-seq, we identify several key cell types (CRABP1+, SMA+) differentially associated with regenerating versus scar tissue. Importantly, our single cell data revealed distinct gene expression profiles for cross-species stromal cell types, identifying cell states specific for regenerative or fibrotic healing. While CRABP1+ fibroblasts are enriched in Acomys ears before and after injury, similar fibroblasts enriched in young, postnatal Mus ears remain unable to promote regeneration. Our data underscore the finely regulated dynamics of proliferating cells during regeneration and emphasize that regeneration depends on multiple factors including the presence of specific cell types and the ability of cells to acquire specific states. Key Conclusions-Differentiated cells in Acomys, Mus and Danio re-enter the cell cycle in response to injury, while homeostatic cycling cells contribute to blastema formation in Ambystoma -Pulse-chase thymidine analog labeling shows tight spatiotemporal control of proliferating stromal cells during regeneration in Acomys. -Following injury, CRABP1 and SMA are expressed in distinct stromal cell populations in Acomys but are co-expressed in Mus stromal cell populations. -Species-specific cell states underlie regenerative and fibrotic repair -CRABP1+ cells are lost during embryonic development in Mus ear pinna but are retained in Acomys to adulthood. -Young neonatal Mus with abundant CRABP1+ cells still fail to execute regenerative healing

developmental biology↗

bioRxiv2025

The thin descending limb of the loop of Henle originates from proximal tubule cells during mouse kidney development

BackgroundThe thin descending limb of the loop of Henle is crucial for urine concentration, as it facilitates passive water reabsorption. Despite its importance, little is known about how this nephron segment forms during kidney development. MethodsWe assembled a large single-cell RNA sequencing (scRNA-seq) dataset by integrating multiple datasets of non-mutant developing mouse kidneys to identify developing thin descending limb cells. To test whether those cells originate from proximal tubule cells, we generated a proximal tubule-specific Cre line, Slc34a1eGFPCre, and conducted lineage tracing. Additionally, given that the transcription factor Hnf4a directly binds to the Aqp1 gene, we examined whether the loss of Hnf4a affects Aqp1 expression in thin descending limb cells. ResultsFrom our scRNA-seq dataset, we identified a small cluster of cells distinct from both the proximal tubule and the thick ascending limb of the loop of Henle. Those cells exhibited high expression of thin descending limb marker genes, including Aqp1 and Bst1. Notably, a subset of proximal tubule cells also expressed thin descending limb marker genes, suggesting that proximal tubule cells may give rise to thin descending limb cells. Using lineage tracing with the Slc34a1eGFPCre line, we found that, at least, a subset of thin descending limb cells are descendants of proximal tubule cells. Furthermore, the loss of Hnf4a, a transcription factor essential for mature proximal tubule cell formation, disrupted proper Aqp1 expression in thin descending limb cells, providing additional evidence of a developmental link between proximal tubule cells and thin descending limb cells. ConclusionOur findings shed new light on the developmental origin of thin descending limb cells and highlight the importance of Hnf4a in regulating their formation. Key PointsO_LIReference single cell RNA-seq dataset of the developing mouse kidney was assembled and used to identify the thin descending limb of the loop of Henle. C_LIO_LILineage analysis of proximal tubules in the mouse kidney shows that proximal tubule cells give rise to the thin descending limb of the loop of Henle. C_LIO_LIDeletion of Hnf4a disrupts the expression of Aqp1 in the thin descending limb of the loop of Henle, highlighting a developmental link between proximal tubules and the loop of Henle. C_LI

developmental biology↗

bioRxiv2024

MCM2 mediates post-MI cardioprotection by promoting the pro-angiogenic cardiosome signaling

AbstractO_ST_ABSBackgroundC_ST_ABSIn the past decade, induced cardiac rejuvenation has emerged as a leading approach to repair cardiac injury. Recent studies demonstrate that promoting cell cycle reentry in adult cardiomyocytes (CM) enhances cardiac rejuvenation by influencing paracrine signaling. We previously demonstrated that the inhibition of two cell cycle inhibitors, Retinoblastoma 1 (Rb1) and Meis homeobox 2 (Meis2), in the adult CM enhances angiogenesis and cardiac function following ischemic injury, but the underlying mechanisms have yet to be elucidated. The goal of this study is to determine the mechanisms by which inhibition of Rb1 and Meis2 promotes cardiac rejuvenation in a mouse model of myocardial infarction. MethodsMyocardial infarction was induced in adult C57/Bl6 mice via permanent LAD occlusion followed by direct injection of either control or Rb1+Meis2 siRNA cocktail to the ischemic myocardium. MCM2 overexpression done via direct myocardial injection of an MCM2-plasmid DNA expression cassette. Cardiac function and LV wall motion was assessed via echocardiography, and fibrosis and CM hypertrophy were assessed via histology. RNA-sequencing was performed on isolated adult murine CMs with siRNA-mediated Rb1+Meis2 knockdown to delineate the downstream mechanisms. Further identification of Rb1, Meis2, and MCM2-dependent mechanisms were done using in vitro techniques in isolated CMs and HUVEC cells. ResultsWe show that siRNA-mediated knockdown of Rb1 and Meis2 in vivo reduces pathological LV remodeling and preserves cardiac structure and function in adult mouse hearts post-MI. RNA-seq analyses revealed MCM2 as a potential downstream target of Rb1/Meis2 to enhance protective paracrine signaling in primary adult CMs. Indeed, re-expression of MCM2, which is developmentally lost from neonatal to adult CM in the heart, improves cardiac function and LV wall motion while reducing myocyte hypertrophy and fibrotic scar size post-MI. Mechanistically, re-expression of MCM2 promotes the secretion of pro- angiogenic factors from adult CM, and transfer of conditioned media from MCM2 expressing CM induced vasculogenesis in HUVEC cells. Proteomic analysis of the MCM2 interactome confirmed a significant enrichment of angiogenic mediators and suggests an MCM2-dependent protein packaging of pro- angiogenic factors in CM-derived small extracellular vesicles (cardiosomes). ConclusionRe-expression of MCM2 in adult CM promotes the secretion of pro-angiogenic cardiosomes that induce paracrine revascularization of endothelial cells and mitigates cardiac injury post-MI. SUMMARY DIAGRAM O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/628232v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@17eaeforg.highwire.dtl.DTLVardef@40f0f5org.highwire.dtl.DTLVardef@18b7664org.highwire.dtl.DTLVardef@109cb1c_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Reversal of vein of Galen aneurysmal malformation by stimulation of flow-mediated vessel fusion

Congenital vascular malformations arise from defective homeostatic development of the vascular tree1. The aneurysmal malformation of the Vein of Galen (VGAM) is the most frequent neurovascular malformation in neonates, with limited therapeutic options and poor outcomes in the most severe cases2. This congenital disease is consecutive to germline genetic mutation of RASA1 or EPHB43,4, but little is known about the mechanisms leading to its development. We generated mutant rasa1a and ephb4a deficiency models in zebrafish reproducing the genetic and structural characteristics of the VGAM in the dorsal longitudinal vein of the cerebral vasculature. We link the development of the malformation to a failure of the fusion of precursor blood vessels into a draining vessel for the choroidal type malformations and to a failure to constrict for the mural type malformations. The fusion process is driven by blood flow, sensed and integrated by endothelial cells. RASA1 deficiency destabilizes the homeostatic response to blood flow and contributes to impaired flow-mediated activation of MAPK and PI3K signaling. We targeted these defective mechanotransduction mechanisms pharmacologically in both rasa1a and ephb4a mutant models, successfully reestablishing the fusion and constriction processes in preexisting malformations. This work identifies molecular actors of the flow-mediated blood vessel fusion mechanism, a specific angiogenetic program, and provides ground for treating VGAM and other vascular remodeling disorders.

developmental biology↗

bioRxiv2024

Inter-cellular mRNA Transfer Alters Human Pluripotent Stem Cell State

Inter-cellular transmission of mRNA is being explored in mammalian species using immortal cell lines (1-3). Here, we uncover an inter-cellular mRNA transfer phenomenon that allows for the adaptation and reprogramming of human primed pluripotent stem cells (hPSCs). This process is induced by the direct cell contact-mediated coculture with mouse embryonic stem cells (mESCs) under the condition impermissible for human primed PSC culture. Mouse-derived mRNA contents are transmitted into adapted hPSCs only in the coculture. Transfer-specific mRNA analysis show the enrichment for divergent biological pathways involving transcription/translational machinery and stress-coping mechanisms, wherein such transfer is diminished when direct cell contacts are lost. After 5 days of mESC culture, surface marker analysis, and global gene profiling confirmed that mRNA transfer-prone hPSC efficiently gains a naive-like state. Furthermore, transfer-specific knockdown experiments targeting mouse-specific transcription factor-coding mRNAs in hPSC show that mouse-derived Tfcp2l1, Tfap2c, and Klf4 are indispensable for human naive-like conversion. Thus, inter-species mRNA transfer triggers cellular reprogramming in mammalian cells. Our results support that episodic mRNA transfer can occur in cell cooperative and competitive processes(4), which provides a fresh perspective on understanding the roles of mRNA mobility for intra- and inter-species cellular communications.

cell biology↗

bioRxiv2024

Gucy1α1 specifically marks kidney, heart, lung and liver fibroblasts

Fibrosis is a common outcome of numerous pathologies, including chronic kidney disease (CKD), a progressive renal function deterioration. Current approaches to target activated fibroblasts, key effector contributors to fibrotic tissue remodeling, lack specificity. Here, we report Gucy11 as a specific kidney fibroblast marker. Gucy11 levels significantly increased over the course of two clinically relevant murine CKD models and directly correlated with established fibrosis markers. Immunofluorescent (IF) imaging showed that Gucy11 comprehensively labelled cortical and medullary quiescent and activated fibroblasts in the control kidney and throughout injury progression, respectively. Unlike traditionally used markers platelet derived growth factor receptor beta (Pdgfr{beta}) and vimentin (Vim), Gucy11 did not overlap with off-target populations such as podocytes. Notably, Gucy11 labelled kidney fibroblasts in both male and female mice. Furthermore, we observed elevated GUCY11 expression in the human fibrotic kidney and lung. Studies in the murine models of cardiac and liver fibrosis revealed Gucy11 elevation in activated Pdgfr{beta}-, Vim- and alpha smooth muscle actin (Sma)-expressing fibroblasts paralleling injury progression and resolution. Overall, we demonstrate Gucy11 as an exclusive fibroblast marker in both sexes. Due to its multiorgan translational potential, GUCY11 might provide a novel promising strategy to specifically target and mechanistically examine fibroblasts.

molecular biology↗

bioRxiv2023

Neural and muscular contributions to the age-related loss in power of the knee extensors in men and women

The mechanisms for the loss in limb muscle power in old (60-79 years) and very old ([≥]80 years) adults and whether the mechanisms differ between men and women are not well-understood. We compared maximal power of the knee extensor muscles between young, old, and very old men and women and identified the neural and muscular factors contributing to the age-related loss of power. 31 young (22.9{+/-}3.0 years, 15 women), 83 old (70.4{+/-}4.9 years, 39 women), and 16 very old adults (85.8{+/-}4.2 years, 9 women) performed maximal isokinetic contractions at 14 different velocities (30- 450{degrees}/s) to identify peak power. Voluntary activation (VA) and contractile properties were assessed with transcranial magnetic stimulation to the motor cortex and electrical stimulation of the femoral nerve. The age-related loss in power was [~]6.5 W{middle dot}year-1 for men (R2=0.62, p<0.001), which was a greater rate of decline (p=0.002) than the [~]4.2 W{middle dot}year-1 for women (R2=0.77, p<0.001). Contractile properties were the most closely associated variables with power output for both sexes, such as the rate of torque development of the potentiated twitch (men: R2=0.69, p<0.001; women: R2=0.57, p<0.001). VA was weakly associated with power in women (R2=0.13, p=0.012) but not men (p=0.191), whereas neuromuscular activation (EMG amplitude) during the maximal power contraction was not associated with power in men (p=0.347) or women (p=0.106). These data suggest that the age-related loss in power of the knee extensor muscles is due primarily to factors within the muscle for both sexes, although neural factors may play a minor role in older women. NEW & NOTEWORTHYThe accelerated age-related loss in power relative to the loss in muscle mass of the knee extensors was primarily due to factors altering the contractile properties of the muscle for both old and very old ([≥]80 yr) adults. The mechanisms for the decrements in power with aging appear largely similar for men and women, although neural factors may play more of a role in older women.

physiology↗

bioRxiv2023

Human subcutaneous and visceral adipocyte atlases uncover classical and specialized adipocytes and depot-specific patterns

Human adipose depots are functionally distinct. Yet, recent single-nucleus RNA-sequencing (snRNA-seq) analyses largely uncovered overlapping/similar cell-type landscapes. We hypothesized that adipocytes subtypes, differentiation trajectories, and/or intercellular communication patterns could illuminate this depot similarity-difference gap. For this, we performed snRNA-seq of human subcutaneous and visceral adipose tissue. Whereas the majority of adipocytes in both depots were classical, namely enriched in lipid metabolism pathways, we also observed specialized adipocyte subtypes that were enriched in immune-related, extracellular matrix deposition (fibrosis), vascularization/angiogenesis, or ribosomal processes. Pseudo-temporal analysis suggested a developmental trajectory from adipose progenitor cells to classical adipocytes via specialized adipocytes, suggesting that the classical state stems from loss, rather than gain, of specialized functions. Lastly, intercellular communication routes were consistent with the different inflammatory tone of the two depots. Jointly, these findings provide a high-resolution view into the contribution of cellular composition, differentiation, and intercellular communication patterns to human fat depot differences.

systems biology↗

bioRxiv2023

Remodelling of the endothelial cell transcriptional program via paracrine and DNA-binding activities of MPO

Myeloperoxidase (MPO) is an enzyme that functions in host defence by catalysing the formation of reactive oxygen intermediates. Synthesized majorly by myeloid progenitor cell types and neutrophils, MPO is released into the vascular lumen during inflammation, where it may adhere and subsequently enter endothelial cells coating vascular walls. Here, we show that MPO actually enters the nucleus of these endothelial cells and binds chromatin independently of its enzymatic activity to cause changes in chromatin structure. At its binding sites, MPO drives chromatin decondensation, while enhancing condensation at flanking regions. We further show that MPO binds loci relevant for the activation of the endothelial-to- mesenchymal transition (EndMT) and the migratory potential of ECs. Finally, MPO interacts with the RNA- binding factor ILF3 affecting its relative abundance between cytoplasm and nucleus. This leads to ILF3:MPO- driven transcriptional and post-transcriptional regulation. Accordingly, MPO-knockout mice show reduced EC numbers at scars formed after myocardial infarction, indicating reduced neovascularization. In summary, we describe a non-enzymatic role for MPO in coordinating EndMT and controlling the fate of endothelial cells through direct chromatin binding and association with such co-factors as ILF3.

genomics↗