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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Optic Nerve Tortuosity and Globe Proptosis in Normal and Glaucoma Subjects

PurposeTo assess the difference in optic nerve tortuosity during eye movements and globe proptosis between primary open angle glaucoma and normal subjects using orbital magnetic resonance imaging.\n\nMethods10 Chinese subjects matched for age, ethnicity and refractive errors were recruited, including five normal controls and five patients with primary open angle glaucoma. All subjects underwent magnetic resonance imaging to assess their optic nerves and globes for three eye positions: primary gaze, adduction and abduction. Optic nerve tortuosity (optic nerve length divided by the distance between two ends) and globe proptosis (maximum distance between cornea and interzygomatic line) were measured from magnetic resonance imaging images.\n\nResultsIn adduction, the tortuosity of normal eyes was significantly larger than that of the glaucomatous eyes. Optic nerve tortuosity in adduction in the control and glaucoma groups were 1.004{+/-}0.003 (mean {+/-} standard deviation) and 1.001{+/-}0.001, respectively (p=0.037). Globe proptosis (primary gaze) in glaucoma subjects (19.14{+/-}2.11 mm) was significantly higher than that in control subjects (15.32{+/-}2.79 mm; p = 0.046).\n\nConclusionsIn this sample, subjects with glaucoma exhibited more taut optic nerves and more protruding eye globes compared to normal eyes. This may impact optic nerve head deformations in anatomically predisposed patients.\n\nPrecisEyes with glaucoma have tauter optic nerves compared with normal eyes, which may exert more force on the optic nerve head tissues during eye movements.

pathology↗

bioRxiv2018

Establishment of baseline sensitivity of Rhizoctonia solani to thifluzamide in corn and its field application

In recent years, banded leaf sheath blight in corn has become an important disease in corn that seriously affects quality and yield. This paper aims to evaluate the sensitivity of Rhizoctonia solani to thifluzamide in corn, to clarify the effect of seed coating using a thifluzamide suspension agent on safety and physiological indicators and to determine banded leaf sheath blight in corn control effectiveness in the field, thereby providing a basis for the application of thifluzamide suspension agent as a seed coating. In this study, the thifluzamide sensitivity of 102 strains of R. solani in corn in different regions of Shandong was determined using the mycelial growth rate method, and the average half-maximal effective concentration value (EC50) was 0.086{+/-}0.004 g/mL. The sensitivity was consistent with a continuous and skewed normal distribution, and the sensitivity distribution frequency exhibited a continuous, unimodal curve, indicating that thifluzamide had strong inhibitory activity on the mycelial growth of R. solani in corn. The impacts of using a thifluzamide suspension agent for seed coating on safety and physiological indicators as well as the control effect in corn were evaluated by combining seed coating, an indoor pot test, and a field trial. The root activities under 24 g a.i. 100 kg-1 seed and 12 g a.i. 100 kg-1 seed were found to increase by 78.01% and 77.40%, respectively, compared with that under the blank control; the chlorophyll content of corn increased most significantly at a dosage of 24 g a.i. 100 kg-1, which was a 32.32% increase compared to the blank control. Thifluzamide (FS) could significantly increase the hundred-grain weight of corn and the per-plot yield. Among the examined dosages, 24 g a.i. 100 kg-1 seed had the most significant treatment effect, with the hundred-grain weight increasing by 12.47% and the yield rate increasing by 15.72% compared to the control in 2016, Simultaneously, the hundred-grain weight increasing by 13.44% and the yield rate increasing by 14.11% compared to the control in 2017. Three dosages of 24% thifluzamide (FS) increased the emergence rate and seedling growth of corn to varying extents. The field control effectiveness against banded leaf sheath blight in corn was best at the dosage of 24 g a.i. 100 kg-1 seed for seed dressing with thifluzamide (FS); in 2016 and 2017, the control effects in the small bell stage, large bell stage, tasseling and pollen-shedding stage, silking stage, milk-ripening stage, and wax-ripening stage were 100%, 66.73%, 52.8%, 67.81%, 68.48%, and 62.68% (2016), respectively, and 74.97%, 63.17%, 50.90%, 53.60%, 61.42%, and 55.88% (2017). These results indicated that thifluzamide had enormous potential for controlling banded leaf sheath blight in corn.

pathology↗

bioRxiv2018

Tenuivirus uses a molecular bridge strategy to overcome insect midgut barriers for virus persistent transmission

Many persistent transmitted plant viruses, including Rice stripe tenuivirus (RSV), cause serious damages to crop productions in China and worldwide. Although many reports have indicated that successful insect-mediated virus transmission depends on proper virus-insect vector interactions, the mechanism(s) controlling interactions between viruses and insect vectors for virus persistent transmission remained poorly understood. In this study, we used RSV and its small brown planthopper (SBPH) vector as a working model to elucidate the molecular mechanism controlling RSV virion entrance into SBPH midgut for persistent transmission. We have now demonstrated that this non-enveloped Tenuivirus uses its non-structural glycoprotein NSvc2 as a helper component to bridge the specific interaction between virion and SBPH midgut cells, leading to overcome SBPH midgut barriers for virus persistent transmission. In the absence of this glycoprotein, purified RSV virion is not capable of entering SBPH midgut cells. In RSV-infected cells, glycoprotein NSvc2 is processed into two mature proteins: an amino-terminal protein NSvc2-N and a carboxyl-terminal protein NSvc2-C. We determined that NSvc2-N interacted with RSV virion and bound directly to midgut lumen surface via its N-glycosylation sites. Upon recognition by midgut cells, the midgut cells underwent endocytosis followed by compartmentalizing RSV virion and NSvc2 into early and then late endosomes. The acidic condition inside the late endosome triggered conformation change of NSvc2-C and caused cell membrane fusion via its highly conserved fusion loop motifs, leading to the release of RSV virion from endosome into cytosol. In summary, our results showed for the first time that a rice Tenuivirus uses a molecular bridge strategy to ensure proper interactions between virus and insect midgut for successful persistent transmission.\n\nAuthor summaryOver 75% of the known plant viruses are insect transmitted. Understanding how plant viruses interacted with their insect vectors during virus transmission is one of the key steps to manage virus diseases worldwide. Both the direct and indirect virus-insect vector interaction models have been proposed for virus non-persistent and semi-persistent transmission. However, the indirect virus-vector interaction mechanism during virus persistent transmission has not been reported previously. In this study, we developed a new reverse genetics technology and demonstrated that the circulative and propagative transmitted Rice stripe tenuivirus utilizes a glycoprotein NSvc2 as a helper component to ensure a specific interaction between Tenuivirus virion and midgut cells of small brown planthopper (SBPH), leading to conquering the midgut barrier of SBPH. This is the first report of a helper component mediated-molecular bridge mechanism for virus persistent transmission. These new findings and our new model on persistent transmission expand our understanding of molecular mechanism(s) controlling virus-insect vector interactions during virus transmission in nature.

pathology↗

bioRxiv2018

Differences in Therapeutic Efficacy in Pancreatic Cancer Between Interstitial and Superficial Light Delivery Strategies in Targeted Photo Therapy

The purpose of this study was to determine if therapeutic efficacy of a Cetuximab based near-infrared (NIR) targeted photo therapy (TPT) was dependent on light delivery strategies. We examined the cytotoxic effects of TPT in a pancreatic cancer mouse model, when administered to tumors interstitially and superficially.\n\nA subcutaneous mouse model of pancreatic cancer using BXPC-3 -GFP cells was established in male athymic (nu/nu) mice. The mice received intravenous (IV) injection of Cetuximab-IR700DX, 24 hours prior to near-infrared light irradiation. Interstitial illumination was administered at a 400mW/cm fixed power output, at a light dose of 100 J/cm to half the mice and at 300 J/cm to the remaining mice. Superficial illumination was administered at a 150mw/cm2 fixed power density at a dose of 50 J/cm2 to half the mice, and at 250 J/cm2 to the other half. Cellular damage and decrease in cell viability was determined by the decrease in GFP fluorescence intensity levels in whole animal images and in relative intensity measurements.\n\nInterstitially administered TPT resulted in greater long-term permanent damage (72 hours post treatment) to tumor cells (0% recovery at low dose, and 11% recovery at high dose) compared to superficially administered TPT (1% recovery at low dose, and 44% recovery at high dose). While these results demonstrated that near-infrared targeted photo therapy efficacy was dependent on the type of light delivery strategy, overall, both superficial and interstitial Cet-IR700DX based near-infrared targeted photo therapy can effect significant long-term damage (less signal recovery) to pancreatic cancer cells in vivo at lower doses regimens, compared to higher dose regimens (higher signal recovery).

pathology↗

bioRxiv2018

Single fiber proteomics of respiratory chain defects in mitochondrial disorders

Mitochondrial DNA mutations progressively compromise the respiratory chain of skeletal muscle, resulting in a mosaic of metabolically healthy and defective fibers. The single fiber investigation of this important diagnostic feature has been beyond the capability of large-scale technologies so far. We used laser capture microdissection (LCM) to excise thin sections of individual muscle fibers from frozen biopsies of patients suffering from chronic progressive external ophthalmoplegia. We then applied a highly sensitive mass spectrometry (MS)-based proteomics workflow to analyze healthy and defective muscle fibers within the same biopsy. We quantified more than 4000 proteins in each patient, covering 75% of all respiratory chain subunits, and compared their expression in metabolically healthy and defective muscle fibers. Our findings show that mitochondrial disease causes extensive proteomic rearrangements, affecting the OPA1-dependent cristae remodeling pathway and mitochondrial translation. We provide fiber type-specific information showing that increased expression of fatty acid oxidation enzymes occurs in defective slow but not fast muscle fibers. Our findings shed light on compensatory mechanisms in muscle fibers that struggle with energy shortage and metabolic stress.

pathology↗

bioRxiv2018

A novel method for comparison of arterial remodeling in hypertension: quantification of arterial trees and recognition of remodeling patterns on histological sections

Remodeling of spatially heterogeneous arterial trees is routinely quantified on tissue sections by averaging linear dimensions, with lack of comparison between different organs and models. The impact of experimental models or hypertension treatment modalities on organ-specific vascular remodeling remains undefined. A wide variety of arterial remodeling types has been demonstrated for hypertensive models, which include differences across organs. The purpose of this study was to reassess methods for measurement of arterial remodeling and to establish a morphometric algorithm for standard and comparable quantification of vascular remodeling in hypertension in different vascular beds. We performed a novel and comprehensive morphometric analysis of terminal arteries in the brain, heart, lung, liver, kidney, spleen, stomach, intestine, skin, skeletal muscle, and adrenal glands of control and Goldblatt hypertensive rats on routinely processed tissue sections. Mean dimensions were highly variable but grouping them into sequential 5 m intervals permitted creation of reliable linear regression equations and complex profiles. Averaged arterial dimensions demonstrated seven remodeling patterns that were distinct from conventional inward-outward and hypertrophic-eutrophic definitions. Numerical modeling predicted at least twenty variants of arterial spatial conformations. Recognition of remodeling variants was not possible using averaged dimensions, their ratios, or the remodeling and growth index. To distinguish remodeling patterns, a three-dimensional modeling was established and tested. The proposed algorithm permits quantitative analysis of arterial remodeling in different organs and may be applicable for comparative studies between animal hypertensive models and in human hypertension. Arterial wall tapering is the most important factor to consider in arterial morphometry, while perfusion fixation with vessel relaxation is not necessary. Terminal arteries in organs undergo the same remodeling pattern in Goldblatt rats, except for organs with hemodynamics affected by the arterial clip. The existing remodeling nomenclature should be replaced by a numerical classification applicable to any type of arterial remodeling.\n\nAuthor summaryArterial hypertension effects modern nations and is characterised by systemic hypertensive angiopathy that affects all organs. Arterial remodeling is a main factor to be analyzed in animal models and human. Despite abundant data, there is a significant lack of comparative analysis on arterial remodeling. The data from the present study have established a novel methodological approach to assess and compare arterial remodeling in hypertension. We have developed an effective algorithm for morphometry of intra-organ arteries to standardize remodeling assessment and allow comparisons between different hypertensive models, organs and species. Our study opens the possibility to assess remodeling using conventional widely used histological tissue sections with no need for special perfusion-fixation. The method will elucidate the improvement and development of animal models of hypertension, and enhance the assessment of experimental therapeutic modalities.

pathology↗

bioRxiv2018

Precision identification and prediction of high mortality phenotypes and disease progression pathways in severe malaria without requiring longitudinal data

The parasite Plasmodium falciparum is the main cause of severe malaria (SM). Despite treatment with antimalarial drugs, more than 450,000 SM deaths are reported every year, mainly in African children. The diversity of clinical presentations associated with SM indicate important differences in disease pathogenesis that often require specific treatment, and this clinical heterogeneity of SM is largely unresolved. In this study, we apply new machine learning and inference tools for large-scale data analysis to dissect the heterogeneity in patterns of clinical features associated with SM in 2,695 Gambian children admitted to hospital with Plasmodium falciparum malaria. This quantitative analysis, including the powerful HyperTraPS algorithm for inference of progressive processes, reveals pathways of SM symptom progression and features predicting the severity of individual patient outcomes. Notably, our approach allows the identification and dissection of disease progression pathways without the need for longitudinal observations. Learning these pathways and features from this rich dataset allows us to construct several quantitative measures of the mortality risk associated with a patient presenting with a given set of symptoms. By independently surveying expert practitioners, we show that this data-driven approach agrees with and expands the current state of knowledge on malaria progression, while simultaneously providing a data-supported framework for predicting clinical risk.

pathology↗

bioRxiv2018

Cyclophosphamide immunosuppressed Xid mice model clarify the protective role of B cells in experimental encephalitozoonosis

Encephalitozoon cuniculi is an intracellular pathogen that stablishes a balanced relationship with immunocompetent individuals, which is dependent of T lymphocytes activity. We previously showed X-linked immunodeficiency (XID - B cell deficient) mice are more susceptible to encephalitozoonosis and B-1 cells presence influences in the immune response. Because XID mice are deficient both in B-1 and B-2 cells, here we investigate the role of these cells against E. cuniculi infection using cyclophosphamide (Cy) immunosuppressed murine model to exacerbate the infection. XID mice presented lethargy and severe symptoms, associated with encephalitozoonosis and there was an increase in the peritoneal populations of CD8+ and CD4+ T lymphocytes and macrophages and also in the proinflammatory cytokines IFN-{gamma}, TNF- and IL-6. In BALB/c mice, no clinical signs were observed and there was an increase of T lymphocytes and macrophages in the spleen, showing an effective immune response. B-2 cells transfer to XID mice resulted in reduction of symptoms and lesion area with increase of B-2 and CD4+ T populations in the spleen. B-1 cells transfer increased the peritoneal populations of B-2 cells and macrophages and also reduced the symptoms. Therefore, the immunodeficiency of B cells associated to Cy immunosuppression condition leads to disseminated and severe encephalitozoonosis in XID mice with absence of splenic immune response and ineffective local immune response, evidencing the B-1 and B-2 cells role against microsporidiosis.\n\nAuthor summaryThe adaptive immune response plays a key role against Encephalitozoon cuniculi, an opportunistic fungus for T cells immunodeficient patients. The role of B cells and antibody play in natural resistance to Encephalitozoon cuniculi remains unresolved. Previously, we demonstrated that B-1 deficient mice (XID), an important component of innate immunity, were more susceptible to encephalitozoonosis, despite the increase in the number of CD4+ and CD8+ T lymphocytes. In order to better understand the role of B-1 and B-2 cells and the relationship with the other cells of the immune response in encephalitozoonosis, we infected with E. cuniculi in cyclophosphamide immunosuppressed mice. Here we demonstrate that infected XID mice showed reduction of T cells and macrophages and increase of proinflammatory cytokines associated with disseminated and severe encephalitozoonosis with presence of abdominal effusion and lesions in multiple organs. This pattern of infection observed in mice with genetic deficiency in T cells, so we suggest that the absence of B-1 cells affects the cytotoxic capacity of these lymphocytes. When we transfer B-2 cells to XID mice, the lesion areas caused by the fungus, the populations of T lymphocytes in the peritoneum and the proinflammatory cytokines decrease, indicating a better resolution of the infection. We speculate that B-1 and B-2 cells participate in the immune response against E. cuniculi, interacting with the other components effective in immunity. The results shown here indicate that B-1 cells as a constituent of the innate response to microsporidia.

pathology↗

bioRxiv2018

StPOPA, encoding an anionic peroxidase in Solanum tuberosum, enhances resistance against Phytophthora infestans

Potato late blight, caused by Phytophthora infestans, is one of the major threats affecting the quality and output of potato all over the world. Reactive oxygen species (ROS) acted as a signal molecule to transmit signals in plants at the early stage of disease infection, and it could induce disease resistance of the plant, including potato late blight. Anionic peroxidases in many plants were reported to be involved in defense to disease. However, limited information about anionic peroxidase genes is available for the potato. Here, we reported that the expression of the StPOPA, a gene encoding a suberization-associated anionic peroxidase, was associated with resistance in potato against P. infestans. The StPOPA gene was induced by P. infestans infection, mechanical damage, jasmonic acid and ethylene treatment. Overexpression of the StPOPA gene in potato enhanced the resistance against P. infestans via promoting the accumulation of callose in the cell wall and ROS in the cytoplasm, which restricted the infection and spreading of the disease possibly by purposeful programmed cell death. Taken together, our results suggested that the StPOPA gene contributed to potato immunity against P. infestans and this gene could be used for the genetic improvement of resistance against potato late blight.

pathology↗

bioRxiv2018

Erythrocyte indices, anaemia levels and types in Kenyan injection and non-injection substance users

The impact of injection and non-injection substance use in HIV infections is an area of great public importance especially with respect to hematologic and immune profiles. Evaluations of hematologic and immune status are critical for better disease classification and clinical management especially of HIV positive substance users. However, not much information is known about the hematologic and immune derangements in HIV infected injection and non-injection substance users. This study, therefore, aimed at determining the laboratory markers of hematologic and immune derangements in HIV infected substance users. Hematologic and immune profiles were evaluated on venous blood specimens obtained from injection substance users, ISU (HIV-infected, n=62 and -uninfected, n=213) and non-injection substance users (HIV-infected, n=33 and -uninfected, n=186); and non-substance using controls (n=56) from Mombasa, coastal town of Kenya. The prevalence of anemia was higher in HIV infected ISU (48.4%) and non-ISU (63.6%) (p<0.0001); and HIV uninfected ISUs (56.3%) compared to HIV-uninfected non-ISUs (39.2%) and non-substance using controls (28.6%; p=0.0028). Hypochromic anaemia was more prevalent in the HIV-infected ISU (50.0%) and non-ISU (61.9%), and HIV-negative ISU (63.3%) relative to the HIV-negative non-ISU (39.7%) and non-substance using controls (56.3%; p=0.0007). Mild immunodeficiency dominated in the HIV infected individuals (HIV-infected ISU, 32.3% and non-ISU, 21.2%) versus HIV-uninfected ISU (16.9%); non-ISU (12.9%); and non-substance users (14.3%) while severe immunosuppression prevailed in HIV infected substance users (ISU, 14.5% and non-ISU, 15.2%) against HIV uninfected substance users (ISU, 5.2% and non-ISU, 3.8%); thus immunosuppression in substance users is aggravated with HIV infection. Moreover, drug-induced immunosuppression is associated with a higher likelihood of anaemia in HIV-uninfected substance users; ISU (OR=3.95, CI=1.934-8.077, p<0.0001) and non-ISU (OR=3.63, CI=1.571-8.39, p=0.003). Altogether, hypochromic anaemia, normochromic anaemia and CD4+ T-helper cytopenia are the most prevalent hemocytopenias in HIV infected and uninfected injection and non-injection substance users.

pathology↗

bioRxiv2018

Targeting RyR2 with a phosphorylation site-specific nanobody Reverses Dysfunction of Failing Cardiomyocytes in Rat

Chronic PKA phosphorylation of RyR2 has been shown to increased diastolic SR Ca2+ leak and lead to cardiac dysfunction. Since the change of phosphorylation level of RyR2 is a biomarker of failing heart, we attempted to verify the hypothesis that intracellular gene delivery of a RyR2 targeting phosphorylation site-specific nanobody could preserve contractility of failing myocardium. In present study, we acquired the RyR2-specific nanobodies from a phage display library which are variable domains of camellidae heavy chain-only antibodies (VHH). One of the monoclonal nanobodies, AR185, inhibiting RyR2 phosphorylation in an in vitro assay was then chosen for further investigation. We investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of AR185 against post-ischemic heart failure. Adeno-associated virus gene delivery elevated the intracellular expression AR185 protein in the ischemic heart failure model of rats, and this treatment normalized the systolic and diastolic dysfunction of the failing myocardium in vivo and in vitro by reversing myocardial Ca2+ handling. Furthermore, AR185 gene transfer to failing cardiomyocytes reduced the frequency of sarcoplasmic reticulum (SR) calcium leak, thereby restoring the attenuated intracellular calcium transients and SR calcium load. Moreover, AR185 gene transfer inhibited PKA phosphorylation of RyR2 in failing cardiomyocytes. Our results provided strong pre-clinical experimental evidence of the cardiac expression of RyR2 nanobody with AAV9 vectors as a promising therapeutic strategy for ischemic heart failure.

pathology↗

bioRxiv2018

Sufficient therapeutic effect of cryopreserved frozen adipose-derived regenerative cells on burn wounds

The purpose of this study was to evaluate whether cryopreserved (frozen) adipose-derived regenerative cells (ADRCs) have a therapeutic effect on burn wound healing as well as freshly isolated (fresh) ADRCs.\n\nFull thickness burns were created on dorsum of nude mice and burn wound was excised. The wound was covered by artificial dermis with; (i) fresh ADRCs, (ii) frozen ADRCs, and (iii) PBS (control). The assessment for wound healing was performed by morphological, histopathological and immunohistochemical analyses.\n\nIn vivo analyses exhibited the significant therapeutic effect of frozen ADRCs on burn wound healing up to the similar or higher level of fresh ADRCs. There were significant differences of wound closure, epithelized tissue thickness, and neovascularization between the treatment groups and control group. Although there was no significant difference of therapeutic efficacy between fresh ADRC group and frozen ADRC group, frozen ADRCs improved burn wound healing process in dermal regeneration with increased great type I collagen synthesis compared with fresh ADRCs.\n\nThese findings indicate that frozen ADRCs allow us to apply not only quickly but also for multiple times, and the cryopreserved ADRCs could therefore be useful for the treatment of burn wounds in clinical settings.

pathology↗

bioRxiv2018

Encapsulated mononuclear stem cells: paracrine action for the treatment of acute myocardial infarction

Cell therapy is considered as a treatment option for acute myocardial infarction (AMI). Released molecules by cells paracrine action may promote tissue regeneration. Therefore we used bone-marrow mononuclear cells (BMMNCs) from GFP+ Wistar rats encapsulated in sodium alginate for AMI treatment. Animals were randomly allocated into groups - empty (EC); BMMNC capsules; or sham. AMI was induced by occlusion of left anterior artery and capsules were delivered intrathoracically. Troponin I was measured 24h after AMI and echocardiography was performed at 48h and 7d after AMI. On day 7 animals were euthanized and their hearts were harvested. Tissue levels of TNF-, IL-6, IL-10, cleaved caspase-3, and catalase were measured. Technical procedures were performed by blinded operators. There was no difference in either heart morphofunctional parameters or biochemical analysis between AMI groups. We conclude that the paracrine effects of BMMNCs lacks efficacy to modulate events associated with AMI in the rat.

pathology↗

bioRxiv2018

Rapid, Affordable, Collection and Analysis of Bioaerosol Viral Pathogens (Begomoviruses and Whitefly Vectors)

Detection of pathogens is critical to monitoring their distribution and spread, and is a key component in the prediction and management of disease epidemiology. Monitoring for pathogens as bioaerosols requires developing techniques which are sensitive, affordable, and time saving before they will have widespread impact. This approach also overcomes private property issues, which are a major pitfall in monitoring diseases in complex agricultural and urban settings. In this study, we have applied an emerging technology of electrostatic sampling to the detection of an insect-transmitted plant pathogen as a bioaerosol. Where insects aggregate in large numbers, as with whiteflies, leafhoppers, psyllids and honey bees, the pathogen (ie. virus or bacteria) becoming aerosolized as thousands of excreta droplets fall from the plants during feeding. Agricultural systems have not fully measured the impact of bioaerosols on disease epidemiology. Electrostatic sampling provides a valuable, affordable, method for monitoring for diseases as bioaerosols, which includes plant, animal and human pathogens. This study shows results which successfully used an electrostatic sampling device to collect an aerosolized begomovirus from the air near whiteflies feeding on virus-infected tomato plants.

pathology↗

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗