Biology subjects

Wood, S.

Publications and source records attributed to Wood, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Genome editing of marsupial RSX reveals conserved and divergent principles in mammalian X-inactivation

X-chromosome inactivation balances X-gene dosage between the sexes in eutherians and marsupials. The lncRNA Xist mediates X-inactivation in eutherians but is absent from marsupials. An evolutionarily unrelated lncRNA, RSX, has been identified in marsupials, but its role in X-inactivation is unresolved because genome editing in these mammals has only recently become feasible. Using CRISPR-Cas9 in the opossum, we show that RSX is required for the initiation of X-inactivation in marsupial embryos. RSX deletion later, in differentiated cells, causes modest X-gene de-repression, with repressive chromatin marks H3K27me3 and H3K9me3 retained. H2AK119ub is not enriched on the opossum inactive X, revealing divergent Polycomb-mediated regulation in therians. Our findings reveal stage-specific roles of RSX in marsupial X-inactivation and identify conserved and divergent features of X-dosage compensation in mammals.

genomics↗

bioRxiv2026

Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer

Metastatic castration-resistant prostate cancer (mCRPC) remains lethal as adaptive resistance to standard-of-care therapy develops, often driven by AR splice variants alongside transcriptional and translational reprogramming. To identify strategies capable of overcoming these mechanisms, we performed an unbiased high-throughput screen of 2,480 mechanistically annotated compounds across advanced prostate cancer models. Exportin-1 (XPO1)-mediated nuclear export emerged as a critical dependency, and matrix-based combination screening uncovered robust synergy between inhibitors of XPO1 and the translation initiation factor EIF4A1. Dual inhibition induced coordinated disruption of oncogenic protein networks, including AR/AR-V7, triggering apoptosis and suppressing cell-cycle and metabolic programs. These effects extended to genetically diverse patient-derived organoids and in vivo xenografts at low doses, approximately 8-fold (Eltanexor) and 12-fold (Zotatifin) below established human single-agent regimens. Together, these findings reveal concurrent control of nuclear export and protein translation as a therapeutic vulnerability in mCRPC, providing a strong rationale for clinical evaluation of XPO1-EIF4A1 co-inhibition to overcome AR-driven resistance. STATEMENT OF SIGNIFICANCEUnbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation.

cancer biology↗

bioRxiv2026

DNA methylation signatures of mismatch repair-deficient colorectal cancer

BackgroundColorectal cancer (CRC) is a molecularly heterogeneous disease shaped by both genetic and epigenetic alterations. Approximately 15% of CRCs display widespread CpG island hypermethylation, known as the CpG Island Methylator Phenotype (CIMP). CIMP-high (CIMP-H) tumours frequently exhibit MLH1 promoter hypermethylation, leading to mismatch repair deficiency (MMRd) and microsatellite instability (MSI). However, DNA methylation patterns associated with MSI, independent of CIMP and MLH1 silencing, and the influence of clinical variables such as anatomical location and patient age on the CRC methylome remain poorly characterised. MethodsWe performed epigenome-wide DNA methylation profiling of 259 primary CRC tissue samples using the Illumina EPICv2 array, comparing differential methylation between MSI and microsatellite stable (MSS) CRC, adjusting for tumour purity, MLH1 promoter methylation, CIMP status, and anatomical location, to account for known confounders. We further evaluated the independent effects of anatomical location and patient age on global methylation patterns. ResultsEpigenome-wide differential methylation between MSS and MSI CRC was dominated by MLH1 promoter hypermethylation. After adjusting for MLH1 hypermethylation and CIMP status, we identified a distinct set of 656 CpG sites associated with MMRd independent of MLH1 silencing. These included hypermethylation at LRP6, GSK3{beta}, and CDK12, implicating altered WNT signalling and transcriptional regulation pathways. Comparison of MSI subgroups revealed the co-occurrence of MLH1 hypermethylation with promoter hypermethylation at TXNRD1. Anatomical location showed a strong independent effect on methylation patterns, while we observed only modest effects of patient age on the CRC methylome after adjustment for confounders. ConclusionsWe identified a distinct methylation profile distinguishing MSS and MSI CRC, including MLH1-independent markers of MMRd, as well as novel differentially methylated loci within MSI subgroups. We further showed that anatomical location has a strong independent impact on the CRC methylome. Together, these findings refine the molecular characterisation of CRC and highlight potential epigenetic markers that could inform patient stratification and precision oncology.

cancer biology↗

bioRxiv2026

VesSynth: Tubes Are All You Need for Robust Cross-Scale Cross-Modal 3D Vessel Segmentation

The cerebral vasculature is central to brain function, with alterations linked to numerous cerebrovascular and neurological disorders. Yet, no single imaging modality can capture the entire cerebral vascular network in humans. Instead, an array of techniques are sensitized to different spatial scales, while trading off resolution for coverage. Magnetic Resonance Imaging (MRI) typically resolves only large pial vessels, while high-resolution microscopy allows micrometer-scale vessels to be mapped over limited spatial extents. These techniques must therefore be combined to obtain a complete mapping of the cerebral angioarchitecture, which underscores the need for automatic, cross-modal vessel segmentation. Here, we introduce VesSynth, a flexible vessel segmentation framework that achieves state-of-the-art accuracy across multiple modalities and spatial resolutions (MR, optical and X-ray imaging), despite being trained entirely on synthetic data. By enabling consistent vascular mapping across scales, this framework paves the way to comprehensive investigation of cerebrovascular organization and its role in health and disease.

bioengineering↗

bioRxiv2026

Cryo-electron tomography reveals paracellular claudin-15 pores at the tight junction

Tight junctions (TJs) are composed of anastomosing strands between epithelial cells. Members of the claudin family of proteins reside within TJ strands and either seal the paracellular space or assemble into charge and size-selective pathways. Functional studies suggest that claudin-mediated conductance pathways resemble traditional ion channels. However, such postulated pores have not been directly visualized. Using a model claudin deficient epithelium where exogenously introduced EGFP-CLDN15 is the only claudin family member expressed, our investigation sheds light on the arrangement and structure of the postulated claudin pores. Following correlative light and electron microscopical identification of TJs and cryo-electron tomography, we identified series of linearly distributed electron lucent features that locate between two closely apposed plasma membranes of adjacent cells. At these sites, the median spacing between adjacent features is 2.25 nm (IQR = 1.83), with a median 1.66 nm (IQR = 0.92) diameter. In contrast, such features were not observed in claudin deficient model epithelium with exogenous mCherry-ZO-1 expression. These findings agree with the postulated and extensively modeled claudin pores formed within the simple columnar epithelium. This provides the first direct evidence of paracellular pore organization and paves way for future biophysical investigation. SIGNIFICANCEBy combining correlative fluorescence imaging, FIB milling, and cryo-ET within an epithelial system restricted to a single claudin isoform, we were able to visualize repetitive, low-density pore features within CLDN15-containing tight junctions (TJs), structures not previously resolved in intact epithelia. These features were absent in claudin-negative controls and displayed placement and geometry consistent with CLDN15 X-ray crystallography and molecular dynamics models. Quantitative measurements of pore diameter, paracellular gap width, and pore spacing further support their assignment as CLDN15 pores. These findings establish a structurally validated platform for defining claudin pore ultrastructure and provide a foundation for future efforts to compare pore-forming and barrier-forming claudins, understand disease-associated junction remodeling, and guide therapeutic modulation of epithelial barrier function.

physiology↗

bioRxiv2025

Explainable machine learning identifies features and thresholds predictive of immunotherapy response

BackgroundImmunotherapy has improved patient survival for multiple cancer types, including melanoma. While a variety of molecular features have been linked to response to immune checkpoint inhibitors (ICI) treatment, clinically established biomarkers, such as tumour mutation burden (TMB) and PD-L1 expression, have shown limitations in accurately categorising responders versus non-responders. Due to the complex nature of ICI response, which includes cancer intrinsic and extrinsic features within the tumour microenvironment (TME), using a single biomarker to predict response is insufficient, necessitating the need to identify accurate clinical and multi-omic molecular predictors. MethodsWe integrate clinical, DNA and RNA sequencing data from four datasets, comprising 138 melanoma patients treated with ICI, to develop machine learning models for predicting ICI response. The performance of each model was evaluated using an independent dataset of patients with cutaneous melanoma (n=53). Interactions between trained models and features were rationalised using the explainability method SHAP. ResultsThe most optimal model was the multi-omic random forest model, with AUC-ROC of 0.78 when predicting response in the independent test dataset. Using SHAP, we predicted thresholds for mutational signatures, neoantigen load, immune cell-type abundance and immune receptor LAG3 expression. The relationship between these influential features and their SHAP scores revealed numerical thresholds constituting good and poor patient response. ConclusionsThis approach highlights patient response to ICI is influenced by both cancer intrinsic and extrinsic features, as well as identifies candidate biomarkers that could inform the use of ICI and potentially assist in the selection of combination therapy in melanoma treatment.

bioinformatics↗

bioRxiv2024

Deficiency of mitophagy mediator Parkin in aortic smooth muscle cells exacerbates abdominal aortic aneurysm

Abdominal aortic aneurysms (AAAs) are a degenerative aortic disease and associated with hallmarks of aging, such as mitophagy. Despite this, the exact associations among mitophagy, aging, and AAA progression remain unknown. In our study, gene expression analysis of human AAA tissue revealed downregulation of mitophagy pathways, mitochondrial structure, and function-related proteins. Human proteomic analyses identified decreased levels of mitophagy mediators PINK1 and Parkin. Aged mice and, separately, a murine AAA model showed reduced mitophagy in aortic vascular smooth muscle cells (VSMCs) and PINK1 and Parkin expression. Parkin knockdown in VSMCs aggravated AAA dilation in murine models, with elevated mitochondrial ROS and impaired mitochondrial function. Importantly, inhibiting USP30, an antagonist of the PINK1/Parkin pathway, increased mitophagy in VSMCs, improved mitochondrial function, and reduced AAA incidence and growth. Our study elucidates a critical mechanism that proposes AAAs as an age-associated disease with altered mitophagy, introducing new potential therapeutic approaches.

molecular biology↗

bioRxiv2024

Development and Application of Decontamination Methods for the Re-Use of Laboratory Grade Plastic Pipette Tips

During the SARS-CoV-2 pandemic, a need for methods to decontaminate and reuse personal protective equipment (PPE) and medical plastics became a priority. In this investigation we aimed to develop a contamination evaluation protocol for laboratory pipette tips, after decontamination. Decontamination methods tested in this study included cleaning with a common laboratory detergent (2.5% Alconox(R) solution followed with steam decontamination), exposure of ozone vapor at 250 and 14400 PPM * minute, and exposure to cold atmospheric plasma (CAP). All tips (control and experimental groups) were introduced to the methods described, while tips exposed to DNA extracts of Aeromonas hydrophila (ATCC-23211) were assessed for experimental groups. Decontamination was determined by turnover ratio and log reduction in detectable genomic material on the contaminated products using real-time quantitative PCR (qPCR) assay. Our results showed, cleaning tips with lab detergents along with steam decontamination removed genetic material, resulting in the highest log reduction, compared with ozone or CAP treatments. Detergent/washing methods showed the highest turnover ratio (95.9 %) and log reduction (5.943). However, the excessive residue (post-cleaning) on the plastic, within inner filters, and tip boxes suggested that washing with lab detergents was not favorable for reuse. Ozone vapor at 14400 PPM * minutes showed the second highest turnover ratio (98.4 %) and log reduction (4.511). CAP exposure with tips inverted (the tip end exposed closer to the plasma flame) for 1 minute showed a turnover ratio of (68.3 %) and log reduction (4.002). Relatively, lower turnover ratio and log reduction of CAP could be attributed to development/optimization of treatment conditions, including increases in exposure time and relative to tip positioning.

molecular biology↗

bioRxiv2023

FOXL2 interaction with different binding partners regulates the dynamics of granulosa cell differentiation across ovarian development

The transcription factor FOXL2 is required in ovarian somatic cells for female fertility. Differential timing of Foxl2 deletion, in embryonic versus adult mouse ovary, leads to distinctive outcomes suggesting different roles across development. Here, we comprehensively investigated FOXL2s role through a multi-omics approach to characterise gene expression dynamics and chromatin accessibility changes, coupled with genome-wide identification of FOXL2 targets and on-chromatin interacting partners in granulosa cells across ovarian development. We found that FOXL2 regulates more targets postnatally, through interaction with factors regulating primordial follicle activation (PFA) and steroidogenesis. Deletion of one interactor, Ubiquitin specific protease 7 (USP7), induces PFA blockage, impaired ovary development and sterility. Our datasets constitute a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.

developmental biology↗

bioRxiv2022

Demographic Reporting and Phenotypic Exclusion in fNIRS

1.Functional near-infrared spectroscopy (fNIRS) promises to be a leading non-invasive neuroimaging method due to its portability and low cost. However, concerns are rising over its inclusivity of all skin tones and hair types (Parker and Ricard 2022, Webb et al 2022). Functional NIRS relies on direct contact of light-emitting optodes to the scalp, which can be blocked more by longer, darker, and especially curlier hair. Additionally, NIR light can be attenuated by melanin, which is accounted for in neither fNIRS hardware nor analysis methods. Recent work has shown that overlooking these considerations in other modalities like EEG leads to the disproportionate exclusion of individuals with these phenotypes - especially Black people - in both clinical and research literature (Bradford et al 2022, Choy 2020). In this article, we sought to determine if (1) biomedical optics developers and researchers report fNIRS performance variability between skin tones and hair textures, (2a) fNIRS neuroscience practitioners report phenotypic and demographic details in their articles, and thus, (2b) is a similar pattern of participant exclusion found in EEG also present in the fNIRS literature. We present a literature review of top Biomedical Optics and Human Neuroscience journals, showing that demographic and phenotypic reporting is unpopular in both fNIRS development and neuroscience applications. We conclude with a list of recommendations to the fNIRS community including examples of Black researchers addressing these issues head-on, inclusive best practices for fNIRS researchers, and recommendations to funding and regulatory bodies to achieve an inclusive neuroscience enterprise in fNIRS and beyond.

neuroscience↗

bioRxiv2022

Daily Artificial Gravity is Associated with Greater Neural Efficiency during Sensorimotor Adaptation

Altered vestibular signaling and body unloading in microgravity results in sensory reweighting and adaptation. Microgravity effects are well-replicated in head-down tilt bed rest (HDBR). Artificial gravity (AG) is a potential countermeasure to mitigate effects of microgravity. We examined the effectiveness of daily AG for mitigating brain and/or behavioral changes in 60 days of HDBR. One group received AG for 30 minutes daily (AG; n=16) and a control group spent the same time in HDBR but received no AG (CTRL; n=8). All participants performed a sensorimotor adaptation task 5 times during fMRI scanning: twice prior to HDBR twice during HDBR, and once following HDBR. The AG group showed similar behavioral adaptation effects compared with the CTRLs. We identified decreased brain activation in the AG group from pre to late HDBR in the cerebellum for the task baseline portion and in the thalamus, calcarine, cuneus, premotor cortices, and superior frontal gyrus in the AG group during the early adaptation phase. The two groups also exhibited differential brain-behavior correlations. Together, these results suggest that AG may result in a reduced recruitment of brain activity for basic motor processes and sensorimotor adaptation. These effects may stem from somatosensory and vestibular stimulation from AG.

neuroscience↗

bioRxiv2022

Generalising uncertainty improves accuracy and safety of deep learning analytics applied to oncology

Trust and transparency are critical for deploying deep learning (DL) models into the clinic. DL application poses generalisation obstacles since training/development datasets often have different data distributions to clinical/production datasets that can lead to incorrect predictions with underestimated uncertainty. To investigate this pitfall, we benchmarked one pointwise and three approximate Bayesian DL models used to predict cancer of unknown primary with three independent RNA-seq datasets covering 10,968 samples across 57 primary cancer types. Our results highlight simple and scalable Bayesian DL significantly improves the generalisation of uncertainty estimation (e.g., p-value = 0.0013 for calibration). Moreover, we demonstrate Bayesian DL substantially improves accuracy under data distributional shifts when utilising uncertainty thresholding by designing a prototypical metric that evaluates the expected (accuracy) loss when deploying models from development to production, which we call the Area between Development and Production curve (ADP). In summary, Bayesian DL is a hopeful avenue of research for generalising uncertainty, which improves performance, transparency, and therefore safety of DL models for deployment in real-world.

bioinformatics↗

bioRxiv2022

A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance.

Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics and diagnostics. It is thereby key to develop a comprehensive genome-wide understanding of how bacteria process antibiotic stress, and how modulation of the involved processes affects their ability to overcome said stress. Here we undertake a comprehensive genetic analysis of how the major human pathogen Streptococcus pneumoniae responds to 20 antibiotics. We built a genome-wide atlas of drug susceptibility determinants and generate a genetic interaction network that connects cellular processes and genes of unknown function, which we show can be used as therapeutic targets. Pathway analysis reveals a genome-wide "tolerome", defined by cellular processes that can make a bacterium less susceptible, and often tolerant, in an antibiotic specific manner. Importantly, modulation of these processes confers fitness benefits during active infections under antibiotic selection. Moreover, screening of sequenced clinical isolates demonstrates that mutations in tolerome genes readily evolve and are frequently associated with resistant strains, indicating such mutations may be an important harbinger for the emergence of antibiotic resistance.

microbiology↗

bioRxiv2021

MRI-Visible Perivascular Space (PVS) Changes with Long-Duration Spaceflight

Humans are exposed to extreme environmental stressors during spaceflight and return with alterations in brain structure and shifts in intracranial fluids. To date, no studies have evaluated the effects of spaceflight on perivascular spaces (PVSs) within the brain, which are believed to facilitate fluid drainage and brain homeostasis. Here, we examined how the number and morphology of magnetic resonance imaging (MRI)-visible PVSs are affected by spaceflight, including prior spaceflight experience. Fifteen astronauts underwent six T1-weighted 3T MRI scans, twice prior to launch and four times following their return to Earth after [~]6-month missions to the International Space Station. White matter MRI-visible PVS number and morphology were calculated using an established automated segmentation algorithm. We found that novice astronauts showed an increase in total PVS volume from pre- to post-flight, whereas experienced crewmembers did not (adjusted for age, sex, and time between landing and first MRI scan). Moreover, experienced astronauts exhibited a significant correlation between more previous flight days and greater PVS median length at baseline, suggesting that experienced astronauts exhibit holdover effects from prior spaceflight(s). There was also a significant positive correlation between pre- to post-flight increases in PVS median length and increases in right lateral ventricular volume. The presence of spaceflight associated neuro-ocular syndrome (SANS) was not associated with PVS number or morphology. Together, these findings demonstrate that spaceflight is associated with PVS morphological changes, and specifically that spaceflight experience is an important factor in determining PVS characteristics.

neuroscience↗

bioRxiv2021

The effects of long duration spaceflight on sensorimotor control and cognition

Astronauts returning from spaceflight typically show transient declines in mobility and balance. These whole-body postural control behaviors have been investigated thoroughly, while study of the effects of spaceflight on other sensorimotor behaviors is prevalent. Here, we tested the effects of the spaceflight environment of microgravity on various sensorimotor and cognitive tasks during and after missions to the International Space Station (ISS). We obtained mobility (Functional Mobility Test), balance (Sensory Organization Test-5), bimanual coordination (bimanual Purdue Pegboard), cognitive-motor dual-tasking and various cognitive measures (Digit Symbol Substitution Test, Cube Rotation, Card Rotation, Rod and Frame Test) before, during and after 15 astronauts completed 6+ month missions aboard the ISS. We used linear mixed effect models to analyze performance changes due to entering the microgravity environment, behavioral adaptations aboard the ISS and subsequent recovery from microgravity. We identified declines in mobility and balance from pre- to post-flight, suggesting possible disruption and/or downweighting of vestibular inputs; these behaviors recovered to baseline levels within 30 days post-flight. We also identified bimanual coordination declines from pre- to post-flight and recovery to baseline levels within 30 days post-flight. There were no changes in dual-task performance during or following spaceflight. Cube rotation response time significantly improved from pre- to post-flight, suggestive of practice effects. There was a trend for better in-flight cube rotation performance on the ISS when crewmembers had their feet in foot loops on the "floor" throughout the task. This suggests that tactile inputs to the foot sole aided orientation. Overall, these results suggest that sensory reweighting due to the microgravity environment of spaceflight affected sensorimotor performance, while cognitive performance was maintained. A shift from exocentric (gravity) spatial references on Earth towards an egocentric spatial reference may also occur aboard the ISS. Upon return to Earth, microgravity adaptions become maladaptive for certain postural tasks, resulting in transient sensorimotor performance declines that recover within 30 days.

neuroscience↗

bioRxiv2020

Accuracy and precision of citizen scientist animal counts from drone imagery

Repeated counts of animal abundance can reveal changes in local ecosystem health and inform conservation strategies. Unmanned aircraft systems (UAS) such as drones are commonly used to photograph animals in remote locations; however, counting animals in images is a laborious task. Crowd-sourcing can reduce the time required to conduct these censuses considerably, but must first be validated against expert counts to measure sources of error. Our objectives were to assess the accuracy and precision of citizen science counts and make recommendations for future citizen science projects. We uploaded drone imagery from Ano Nuevo Island (California, USA) to a curated Zooniverse website that instructed citizen scientists to count seals and sea lions. Across 212 days, over 1,500 volunteers counted animals in 90,000 photographs. We quantified the error associated with several descriptive statistics to extract a single citizen science count per photograph from the 15 repeat counts and then compared the resulting citizen science counts to expert counts. Although proportional error was relatively low (9% for sea lions and 5% for seals during the breeding seasons) and improved with repeat sampling, the 12+ volunteers required to reduce error was prohibitively slow, taking on average 6 weeks to estimate animals from a single drone flight covering 25 acres, despite strong public outreach efforts. The single best algorithm was Median without the lowest two values, demonstrating that citizen scientists tended to under-estimate the number of animals present. Citizen scientists accurately counted adult seals, but accuracy was lower when sea lions were present during the summer and could be confused for seals. We underscore the importance of validation efforts and careful project design for researchers hoping to combine citizen science with drone imagery.

ecology↗

bioRxiv2020

Improved 7 Tesla Transmit Field Homogeneity with Reduced Electromagnetic Power Deposition Using Coupled Tic Tac Toe Antennas

Recently cleared by the FDA, 7 Tesla (7T) MRI is a rapidly growing technology that can provide higher resolution and enhanced contrast in human MRI images. However, the increased operational frequency (~297 MHz) hinders its full potential since it causes inhomogeneities in the images and increases the power deposition in the tissues. This work describes the optimization of an innovative radiofrequency (RF) head coil coupled design, named Tic Tac Toe, currently used in large scale human MRI scanning at 7T; to date, this device was used in more than 1,300 patient/volunteer neuro 7T MRI scans. Electromagnetic simulations were performed for each of the coils antennas using the finite-difference time-domain method. Numerical optimizations were used to combine the calculated electromagnetic fields produced by these antennas, based on the superposition principle, and successfully produced homogeneous magnetic field distributions at low levels of power deposition in the tissues. The simulations were then successfully validated in-vivo using the Tic Tac Toe RF head coil system on a 7T MRI scanner.

bioengineering↗

bioRxiv2020

Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Calcific aortic valve disease (CAVD) is an increasingly prevalent condition and endothelial dysfunction is implicated in its etiology. We previously identified nitric oxide (NO) as a calcification inhibitor by its activation of NOTCH1, which is genetically linked to human CAVD. Here, we show that NO rescues calcification by a S-nitrosylation-mediated mechanism in porcine aortic valve interstitial cells (pAVICs) and single cell RNA-seq demonstrated regulation of NOTCH pathway by NO. A unbiased proteomic approach to identify S-nitrosylated proteins in valve cells found enrichment of the ubiquitin proteasome pathway and implicated S-nitrosylation of USP9X in NOTCH regulation during calcification. Furthermore, S-nitrosylated USP9X was shown to deubiquitinate and stabilize MIB1 for NOTCH1 activation. Consistent with this, genetic deletion of Usp9x in mice demonstrated aortic valve disease and human calcified aortic valves displayed reduced S-nitrosylation of USP9X. These results demonstrate a novel mechanism by which S-nitrosylation dependent regulation of ubiquitin-associated pathway prevents CAVD.

cell biology↗