Biology subjects

Nasser, A.

Publications and source records attributed to Nasser, A..

7 recordsLinked to original sources

bioRxiv2026

Augmenting Radiation Sensitivity by Targeting PAR-Dependent Replication Fork Vulnerability in IDH-Mutant Glioma

Mutations in isocitrate dehydrogenase 1 (IDH1) drive the early stages of gliomagenesis while simultaneously imposing replication stress that creates targetable vulnerabilities. Using both in vitro and in vivo models, we show that inhibition of poly(ADP-ribose) glycohydrolase (PARG) induces a poly(ADP-ribose) (PAR)-dependent augmentation of radiosensitivity in IDH1-mutant glioma cells. Metabolic repletion of NAD+ fails to rescue this effect, indicating that the vulnerability cannot be explained solely by NAD+ depletion. Instead, PARG inhibition profoundly alters replication fork progression and S-phase kinetics in IDH1-mutant cells. Mechanistically, ionizing radiation preferentially activates replication fork-associated damage response proteins DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and X-ray repair cross-complementing protein 1 (XRCC1) in IDH1-mutant cells, a response partially reversed by pharmacologic inhibition of mutant IDH1. Importantly, pharmacologic inhibition of DNA-PKcs with AZD7648 during irradiation disrupts fork-associated repair signaling and markedly enhances cytotoxicity in IDH1-mutant glioma models. Together, these findings identify a PAR-dependent replication fork vulnerability that can be therapeutically exploited to selectively enhance radiosensitivity in IDH1-mutant gliomas. Statement of significanceIDH-mutant gliomas harbor intrinsic replication stress yet lack targeted radiosensitization strategies. We identify a PAR-dependent replication fork vulnerability in which disruption amplifies radiation cytotoxicity by deregulating S-phase fork signaling. Pharmacologic DNA-PKcs inhibition exploits this dependency, providing a genotype-selective approach to enhance radiotherapy in IDH-mutant glioma.

cancer biology↗

bioRxiv2026

Patient-specific "Physical Twin" artery-on-chip platform reveals complex flow-dependent VWF mechanobiology and guides personalized antithrombotic therapy

Ischemic stroke triggered by carotid atherosclerosis remains unpredictable because the thrombosis embolization is governed by patient-specific vascular geometry and hemodynamics that cannot be recapitulated in conventional models. Here, we engineered "Physical Twin" artery-on-chip platforms that reproduce individualized carotid anatomy with humanized subendothelial matrix composition and arterial endothelial phenotype under physiological flow patterns. We then established thrombotic microenvironments following laser-induced injury. Computational fluid dynamics-guided experiments across distinct patient geometries reveal that local shear dictates a mechanobiological hierarchy: high-shear bifurcations ([~]3,000 s-{superscript 1}) produce von Willebrand factor (VWF) A1-dependent thrombi suppressible by conformationally sensitive inhibitors, whereas low-shear stenoses generate fragile aggregates where VWF-integrin IIb{beta} coupling governs embolization overgrowth. Pulsatile flow suppresses thrombotic growth independent of mean shear. Molecular dynamics simulations reveal why conformationally sensitive nanobodies (caplacizumab) outperform shear-independent aptamers (ARC1172) in high-shear bifurcation flow zones. This Physical Twin platform provides a mechanistic blueprint for geometry-informed, personalized antithrombotic therapy selection.

bioengineering↗

bioRxiv2026

Automated high-throughput fabrication of patient-specific vessel-on-chips enables a generative AI digital twin--Cascade Learner of Thrombosis (CLoT) for personalized thrombosis prediction

We developed an integrated platform combining high-throughput automated biofabrication, systematic patient-derived tissue experiments, and specialized artificial intelligence to enable patient-specific computational "digital twins" for thrombosis prediction. Our automated manufacturing platform fabricates 80 fully assembled, patient-specific vessel-on-chips within 10 hours from clinical imaging--a [~]100-fold improvement over manual methods--achieving sub-micron precision through novel two-stage pneumatic motion control and integrated optical feedback. Using these chips, we systematically captured thrombosis across 491 high-fidelity videos spanning 6 patient-derived vascular geometries, 5 distinct anatomical injury sites, and 14 anticoagulant/antiplatelet interventions, establishing a "physical twin" experimental corpus. We trained CLoT (Cascade Learner of Thrombosis), a conditional video diffusion model efficiently adapted via lightweight Low-Rank Adaptation (LoRA) to generate realistic thrombosis videos conditioned on patient-specific geometry, injury location, and drug treatment. Rigorous benchmarking against state-of-the-art commercial models (Sora, Wan, Kling, Seedance, Hailuo, Hunyuan) reveals CLoT achieves 7.38-fold superior temporal biological consistency and 5.3-fold higher spatial morphological fidelity. Prospective validation on unseen patients demonstrates >90% temporal accuracy. This integrated paradigm--combining automated fabrication with domain-specialized generative AI--establishes proof-of-concept for personalized medicine enabled by digital twins trained on human-derived vascular anatomy, enabling pre-treatment antithrombotic evaluation while providing a replicable template for translating tissue engineering into clinical practice.

bioengineering↗

bioRxiv2025

Deciphering the Survival Strategies of the Entomopathogenic Nematode Steinernema carpocapsae Using Rapid Desiccation Assisted by Nanoparticle-Based Emulsion

Water retention is essential for survival under desiccating conditions, especially for entomopathogenic nematodes (EPNs) used as biocontrol agents. Foliar application of EPNs causes rapid desiccation (RD), severely reducing their survival and efficacy. We investigated the physiological and molecular responses of Steinernema carpocapsae to RD, delivered in a novel nanoparticle-stabilized emulsion to improve tolerance under variable humidity. We hypothesized that the formulation would enhance EPNs survival, by promoting early stress-responsive pathways and water-retention mechanisms. Formulated nematodes exhibited delayed water loss and increased survival under low humidity compared with non-formulated controls. The emulsion mitigated RD by enhanced hydration retention and reduced water loss, effects that were strongly associated with differential trehalose accumulation. In addition, maintenance of basement membrane integrity and cytoskeletal organization, emerged as a critical component of desiccation. These findings advance understanding of RD tolerance in EPNs and demonstrate how tailored formulation strategies can protect biocontrol agents under desiccation stress.

developmental biology↗

bioRxiv2022

Kinetic models for PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.

neuroscience↗

bioRxiv2022

Evaluation of the α-synuclein PET radiotracer (d3)-MODAG-001 in pigs

BackgroundA positron emission tomography (PET) radiotracer to neuroimage -synuclein aggregates would be a crucial addition for early diagnosis and treatment development in disorders such as Parkinsons disease, where elevated aggregate levels is a histopathological hallmark. The radiotracer (d3)-[11C]MODAG-001 has recently shown promise for visualization of -synuclein pre-formed fibrils (-PFF) in rodents. We here test the radiotracer in a pig model where proteins are intracerebrally injected immediately before scanning. Four pigs were injected in one hemisphere with 150 {micro}g -PFF, and in the other hemisphere, either 75 {micro}g -PFF or human brain homogenate from either dementia with Lewy bodies (DLB) or Alzheimers disease (AD) was injected. All pigs underwent one or two (d3)-[11C]MODAG-001 PET scans, quantified with the non-invasive Logan graphical analysis using the occipital cortex as a reference region. ResultsThe -PFF and AD homogenate injected brain regions had high uptake of (d3)-[11C]MODAG-001 compared to the occipital cortex or cerebellum. BPND values in 150 {micro}g -PFF injected regions was 0.78, and in the AD homogenate injected regions was 0.73. By contrast, the DLB homogenate injected region did not differ in uptake and clearance compared to the reference regions. The time-activity curves and BPND values in the 150 {micro}g and 75 {micro}g injected region of -PFFs show a dose-dependent effect, and the PET signal could be blocked by pretreatment with unlabeled MODAG-001. ConclusionWe find that both -PFF and AD brain homogenates give rise to increased binding of (d3)-[11C]MODAG-001 when injected into the pig brain. Despite its limited specificity for cerebral -synuclein pathology, (d3)-[11C]MODAG-001 shows promise as a lead tracer for future radiotracer development.

neuroscience↗

bioRxiv2022

An in vivo pig model for testing novel PET radioligands targeting cerebral protein aggregates

Positron emission tomography (PET) has become an essential clinical tool for diagnosing neurodegenerative diseases with abnormal accumulation of proteins like amyloid-{beta} or tau. Despite many attempts, it has not been possible to develop an appropriate radioligand for imaging aggregated -synuclein in the brain for diagnosing, e.g., Parkinsons Disease. Access to a large animal model with -synuclein pathology would critically enable a more translationally appropriate evaluation of novel radioligands. We here establish a pig model with cerebral injections of -synuclein preformed fibrils or brain homogenate from postmortem human brain tissue from individuals with Alzheimers disease (AD) or dementia with Lewy body (DLB) into the pigs brain, using minimally invasive surgery and validated against saline injections. In the absence of a suitable -synuclein radioligand, we validated the model with the unselective amyloid-{beta} tracer [11C]PIB, which has a high affinity for {beta}-sheet structures in aggregates. Gadolinium-enhanced MRI confirmed that the blood-brain barrier was intact. A few hours post-injection, pigs were PET scanned with [11C]PIB. Quantification was done with Logan invasive graphical analysis and simplified reference tissue model 2 using the occipital cortex as a reference region. After the scan, we retrieved the brains to confirm successful injection using autoradiography and immunohistochemistry. We found four times higher [11C]PIB uptake in AD-homogenate-injected regions and two times higher uptake in regions injected with -synuclein-preformed-fibrils compared to saline. The [11C]PIB uptake was the same in non-injected (occipital cortex, cerebellum) and injected (DLB-homogenate, saline) regions. With its large brains and ability to undergo repeated PET scans as well as neurosurgical procedures, the pig provides a robust, cost-effective, and good translational model for assessment of novel radioligands including, but not limited to, proteinopathies.

neuroscience↗