Biology subjects

Nader, N.

Publications and source records attributed to Nader, N..

4 recordsLinked to original sources

bioRxiv2026

Rapid Progesterone signaling induces meiosis through a dual coreceptor trafficking trap

Agonist-dependent signaling through plasma membrane (PM) receptors takes place through diverse modes, including post-translational modifications, second messengers, formation of signaling complexes, or ionic fluxes among others. Classical signaling downstream of steroid hormones engages nuclear/cytoplasmic receptors to induce transcription. Steroids further signal through a rapid mode within seconds to minutes independently of transcription. Despite the now well-recognized physiological roles of rapid progesterone (P4) signaling, the mechanistic steps remain poorly defined. Here we elucidate the early P4 rapid signaling steps that mediate the release of the oocyte meiotic arrest in the frog. P4 signals through two coreceptors mPR{beta}, which localizes at the PM; and ABHD2, which localizes intracellularly. Binding of P4 increases the interaction affinity between the two coreceptors leading to trapping of ABHD2 at the PM and activating signaling. Although P4 is not required for mPR{beta}-ABHD2 interaction at artificially high receptor concentration, it is essential under physiological conditions. We further show that ABHD2 is a dual pass transmembrane protein that binds P4 leading to intracellular PLA2 activity. Signaling through several receptor classes involves endocytosis, but the mPR{beta}-ABHD2 signaling modality is novel as it employs a PM trafficking trap to form the coreceptor complex and induce meiosis. Hence, our findings define a novel signaling modality for rapid steroid signaling.

cell biology↗

bioRxiv2026

Toward Large-Scale Numerical Modeling of the Cardiovascular System with up to 34 Billion Vessels

Cardiovascular diseases, such as stroke and heart attacks, are the leading cause of death worldwide. Computational models like cardiovascular digital twins (CVDTs) offer a promising path for research and intervention but are challenged by the complexity of simulating the full human vasculature. This study evaluates the feasibility of simulating blood flow through a vascular network containing 34 billion vessels (the estimated number in the human body) using first-principles physics and simplified geometry which is a first step towards CVDT. We synthesized 3D vasculature using a fractal model and computed blood flow rates via Poiseuille equation and steady-state fluid dynamics, implemented with high-performance computing. Simulations were conducted for networks ranging from 6 vessels to 34 billion vessels. The results demonstrated high accuracy (within 1% of bench-marks), reproducibility across platforms, and strong scalability. Simulating the full vasculature required 156 node-hours on the second-fastest supercomputer in the world, using 29 TB of memory and 84 TFLOPS. Maximum speedup factor was 80, with parallel efficiency no lower than 0.48. These findings show it is computationally feasible to simulate blood flow through a full-body vascular network at scale. The approach is well suited to parallel computing, suggesting that with continued development, CVDTs could enable whole-organism modeling for applications such as stroke, trauma, radiation injury, and cancer metastasis.

bioinformatics↗

bioRxiv2026

Membrane progesterone receptor signaling reverses hyperglycemia and insulin resistance in obese mice

Progesterone (P4) plays key roles in reproductive and metabolic function and signals through two receptor classes: classical nuclear receptors that regulate gene transcription and membrane progesterone receptors (mPR) that mediate rapid, non-genomic signaling. Whether mPR signaling influences systemic glucose homeostasis remains unclear. Here, we investigated whether mPR activation regulates glucose homeostasis and insulin sensitivity. Using the selective mPR agonist OD02-0, we show that mPR activation enhances glucose uptake in skeletal muscle and hepatocytes, associated with AMP-activated protein kinase (AMPK) activation. In HepG2 cells, mPR activation induces metabolic reprogramming characterized by reduced mitochondrial respiration and increased glycolytic flux. Pharmacological inhibition of AMPK suppresses this effect, indicating that these responses require AMPK activity. In diet-induced obese mice, chronic mPR activation reduces fasting glucose and insulin levels, improves glucose tolerance, and restores glucose-stimulated insulin secretion without detectable toxicity. Integrated proteomic and phosphoproteomic analyses in mouse liver reveal modulation of AMPK signaling and inhibition of mTORC1. Transcriptomic changes were limited, supporting a predominantly non-genomic mode of action. Together, these findings identify mPR signaling as a regulator of glucose homeostasis that engages central energy-sensing pathways to improve metabolic control in obesity.

physiology↗

bioRxiv2023

Progesterone induces meiosis through two obligate co-receptors with PLA2 activity

The steroid hormone progesterone (P4) regulates multiple aspects of reproductive and metabolic physiology. Classical P4 signaling operates through nuclear receptors that regulate transcription. In addition, P4 signals through membrane P4 receptors (mPRs) in a rapid nongenomic modality. Despite the established physiological importance of P4 nongenomic signaling, the details of its signal transduction cascade remain elusive. Here, using Xenopus oocyte maturation as a well- established physiological readout of nongenomic P4 signaling, we identify the lipid hydrolase ABHD2 (/{beta} hydrolase domain-containing protein 2) as an essential mPR{beta} co-receptor to trigger meiosis. We show using functional assays coupled to unbiased and targeted cell-based lipidomics that ABHD2 possesses a phospholipase A2 (PLA2) activity that requires mPR{beta}. This PLA2 activity bifurcates P4 signaling by inducing clathrin-dependent endocytosis of mPR{beta}, resulting in the production of lipid messengers that are G-protein coupled receptors agonists. Therefore, P4 drives meiosis by inducing an ABHD2 PLA2 activity that requires both mPR{beta} and ABHD2 as obligate co-receptors. Significance StatementNongenomic progesterone signaling is important for many physiological functions yet the details of its signaling remain elusive. Here we define the early signaling steps downstream of membrane progesterone receptor {beta} (mPR{beta}) during Xenopus oocyte meiosis. We show that progesterone requires two cell membrane receptors to work in unison to signal. The co-receptor complex possesses lipase activity that produces lipid messenger and induces receptor endocytosis to trigger meiosis progression. Our findings have broad physiological implications because nongenomic progesterone signaling operates in many tissues and regulates reproduction and metabolism.

cell biology↗