Postdoctoral Scholars Association

Acute organophosphate (OP) poisoning poses a significant public health risk through chemical warfare, accidental exposure, and suicide attempts. OPs inhibit acetylcholinesterase, triggering a cholinergic crisis marked by parasympathomimetic symptoms, respiratory distress, and seizures that may progress to status epilepticus (SE). Survivors often develop chronic neurological deficits despite treatment with atropine, an oxime, and midazolam (MDZ), which, while effective at controlling seizures, does not prevent long-term neurological damage. In a diisopropylfluorophosphate (DFP) rat model, approximately 13% of animals (low responders, LR) do not develop SE, whereas 87% (normal responders, NR) progress to SE. To elucidate seizure-independent mechanisms underlying chronic neurotoxicity, we performed RNA-sequencing on multiple brain regions—the hippocampus, piriform cortex, and cerebellum—in LRs, NRs, and MDZ-pretreated animals. Hierarchical clustering revealed distinct transcriptomic profiles, largely independent of sex. Notably, NR animals exhibited marked upregulation of TGFβ signaling (e.g., Tgfb1, Stat3, c-fos, Jak1) and neuroinflammatory genes (e.g., Cd11b, Gfap, Cd68), suggesting a maladaptive immune response likely driven by severe seizure activity. In contrast, MDZ pre-treatment attenuated these responses and reduced genes associated with protein stabilization and endoplasmic reticulum stress. These findings identify potential therapeutic targets for mitigating chronic OP-induced neuropathology and suggest seizure severity is a significant driver of neuroinflammation.

Spectrins are essential cytoskeletal proteins that maintain the structural integrity of axons and dendrites. This study investigates electroencephalographic (EEG) and behavioral phenotypes in a mouse model carrying the αII-spectrin missense mutation R1098Q-homologous to human disease-associated variants R1098C and R1098S3. R1098Q mutant mice and wild-type (WT) littermates were implanted at 3, 6 and 12 months of age. Chronic video-EEG was performed offline to assess epileptiform activity. Tails suspension test was conducted at the end of the recording, behavioral and EEG abnormalities were recorded. Results: 3 months: No significant differences in EEG spiking frequency or power spectral density between R1098Q and WT mice.

6 months: R1098Q mice exhibited increased theta relative power, elevated total power, and a higher frequency of epileptiform spikes compared to WT. 12 months: R1098Q mice showed increased delta relative power and total power relative to WT. Seizure activity: No spontaneous seizures were observed at any time point. Tail suspension test: R1098Q mice consistently displayed dystonic and dyskinetic behaviours across all ages. These findings suggest that the αII-spectrin R1098Q mutation is associated with abnormal brain activity and hyperexcitability, which become more pronounced with age.

Despite the classification of built urban environments as impervious surfaces, infiltration of precipitation occurs on paved soils and can supply water to urban trees. However, under changing climate and particularly in arid conditions, additional irrigation is necessary to sustain healthy mature urban trees that provide evaporative cooling, shade, and enhance urban wellbeing. Based on an extensive open dataset on soil moisture under 18 pavement types (Schaffitel et al. 2020), we are developing a process-based numerical model using Hydrus-1D to simulate water flows in sealed soil domains. This study examines the soil water balance under different pavement materials and atmospheric forcing conditions. We analyze irrigation scenarios under different climates to determine pavement configurations above tree root zones that require modifications to maintain ecosystem services provided by trees, while conserving water. This research aims to advance the fundamental understanding of how soil sealing impacts water availability for urban trees, which is crucial for predicting changing water demands and optimizing the use of increasingly limited water resources in urban forestry.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a complex etiology involving genetic, environment, and gene-environment interactions. We recently discovered a novel gene, NHIP (neuronal hypoxia inducible, placenta), that has decreased expression in ASD placenta and brain. Its transcript levels increase in the human neuronal cell line LUHMES following differentiation and exposure to hypoxia, suggesting that it may play a protective role during hypoxia-induced oxidative stress. Through immunoprecipitation of biotinylated NHIP peptide, we identified methyl-CPG-binding protein 2 (MeCP2) as a potential NHIP binding partner. Loss of MeCP2 leads to Rett Syndrome (RTT), and reduced expression is associated with ASD. Many RTT patients display breathing abnormalities that lead to intermittent hypoxia. We hypothesize that NHIP may interact with MeCP2 to promote proper hypoxia response. To assess the role of NHIP in hypoxia-induced oxidative stress,

we added exogenous NHIP peptide to LUHMES 24 hours prior to 1% hypoxia treatment and observed that ROS levels decreased with NHIP treatment. We also stained for NHIP and MeCP2 to observe their interaction in LUHMES under hypoxia conditions. Characterization of NHIP and its binding partners will allow for evaluation of its potential use as a neuroprotective therapeutic in neurodevelopmental disorders such as ASD.

Digital subtraction angiography (DSA) is an interventional radiology used for visualization of blood vessels for disease diagnosis and prognosis. DSA has been the gold standard for the identification of vascular abnormalities in patients. The blood vessels are extracted by subtracting the angiographic images (obtained after contrast injection) with the mask (prior to contrast injection). The interpretation of angiography is challenging due to motion artifacts, imaging noise, and vessel overlapping in the DSA images. Anatomic localization is a vital step in interpretation in DSA sequences to minimize misdiagnosis. Deep learning has been used for segmentation, registration, and labelling of blood vessels but limited works have been proposed for localization of vascular anatomies in DSA images. In this study, we propose a deep learning model for the classification of anatomical localization in both first and second vascular structures in DSA sequences obtained during routine clinical practice. The model’s performance on unseen data will be assessed both qualitatively and quantitatively. Hence, by using the proposed methodology, automatic and accurate interpretation of angiography is feasible leading to faster diagnosis, decision-making, and further reduce the amount of time and effort required for report generation in clinical practice.

Last year, summer drought cost the state over a billion dollars in crop losses. Understanding how plant can cope with this stress is a challenge, but various species in nature are already adapted and have their own mechanisms for combating drought. Native to the American west coast, Mimulus guttatus can survive in Mexican desert, on serpentine rocks, or snow-covered peaks. This suggests that different populations have evolved various resistance mechanisms. Using 29 different populations harvested across California and Oregon, we plan to carry out a genome-wide association study. We want to compare the SNPs present in these populations with their root system architecture phenotype, an analyze of differentially expressed genes and a histological analysis focusing on cell wall compounds such as lignin and suberin. We hope to find new QTLs involved in drought resistance and even shed light new defense mechanisms that could be exported to crops in the future.

Lung cancer is currently the most common type of cancer and contributes to the highest mortality rate worldwide. Non-small cell lung cancer (NSCLC) comprises ~75% of all lung cancer and has a broad spectrum of histopathologic, molecular, genomic, and immunological heterogeneity that affect the prognosis and treatment selection. Despite recent advances in screening, diagnosis and treatment, patients with recurrent or metastatic NSCLC inevitably develop resistance to treatment and succumb to metastatic disease. The discrepancy of treatment response between clinical trials and real-world clinical practice clearly indicates the need to generate patient-derived preclinical models that can stimulate the morphologic and genomic features of patient’s tumor for selecting personalized targeted and immunotherapy. In our laboratory, we have successfully established patient-derived organoids (PDO) and focus on characterizing these lung cancer PDOs and assessing their translational potential for novel targeted therapies and cancer immunotherapies.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer characterized by N-Myc (MYCN) amplification. Due to N-Myc’s disordered domains and lack of druggable sites, targeting its proteostasis offers a novel therapeutic angle. Here, we investigated the molecular chaperones involved in regulating N-Myc protein turnover. Mass spectrometry analysis following N-Myc pulldown identified several HSP70 family proteins as prominent interactors. Functional assays revealed that HSP70 interacts with N-Myc and recruits the E3 ligase STUB1 to facilitate ubiquitination at lysines 416 and 419, targeting N-Myc for K11-linked polyubiquitin-mediated proteasomal degradation. This interaction was dependent on a conserved degron motif, SELILKR, within the N-Myc protein. siRNA-mediated knockdown of N-Myc significantly reduced cell proliferation in NEPC models, underscoring its oncogenic importance. Our findings reveal a novel HSP70-STUB1-N-Myc regulatory axis and suggest a potential vulnerability in NEPC that could be exploited therapeutically through proteostasis-targeting strategies.

Optoretinography has potential to measure photoreceptor function objectively and noninvasively. Its sensitivity to disease-related dysfunction depends essentially on the amount of variation in the responses among cones, individuals, and measurements. Our study uses AO-SS-OCT with 3D cellular resolution to measure phase changes in response to stimulus flashes in the human retina. We aim to quantify these sources of response variation, to establish a reliable baseline for assessing visual dysfunction in clinical populations. Preliminary results are presented here.