Biology subjects

Jamali, A.

Publications and source records attributed to Jamali, A..

5 recordsLinked to original sources

bioRxiv2026

Finite afterload during asymmetrically cycled preload promotes fetal ventricular growth, maturation, and contractile function while suppressing fibrotic remodeling

Myocardial development requires precise modulation of its growth and maturation by the mechanical loads within cardiac cycle, including preload and afterload. However, the mechanisms by which these natural cardiac loads interact to simultaneously govern growth and maturation of the developing myocardium in both cellular and mesoscale levels remain poorly understood. Here, we developed a naturally engineered fetal ventricular tissue (NFVT) platform that enables the application of afterload under dynamic preload using cyclic stretching with an asymmetrical duty cycle (asymmetrically cycled preload) to better replicate the natural cardiac loading in chick NFVT. Our results showed that low afterload (LA) enhanced NFVT contractile function with sustained tissue growth and improved cardiomyocyte maturation while suppressing fibrosis phenotypes. These effects were associated with reduced YAP1 and NOTCH activation in cardiomyocytes and enhanced tissue architecture. In contrast, high afterload (HA) induced contractile impairment with fibrotic remodeling through activation of cardiomyocyte PIEZO1/YAP1 signaling and sustained fibroblast entanglement. TeaserLow afterload under asymmetrically cycled preload promotes NFVTs contractile function with sustained tissue growth and cardiomyocyte maturation while suppressing fibrosis phenotypes through regulation of cellular mechanotransduction, including minimal PIEZO1 expression and inhibited YAP1 and NOTCH activation in cardiomyocytes, and improvement of collective cellular organization.

Cell Biology↗

bioRxiv2024

Cilia-mediated cerebrospinal fluid flow modulates neuronal and astroglial activity in the zebrafish larval brain.

The brain uses a specialized system to transport cerebrospinal fluid (CSF). This system consists of interconnected ventricles lined by ependymal cells, which generate a directional flow upon beating of their motile cilia. Motile cilia act jointly with other physiological factors, including active CSF secretion and cardiac pressure gradients, to regulate CSF dynamics. The content and movement of CSF are thought to be important for brain physiology. Yet, the link between cilia-mediated CSF flow and brain function is poorly understood. In this study, we addressed the role of motile cilia-mediated CSF flow on brain development and physiology using zebrafish larvae as a model system. By analyzing mutant animals with paralyzed cilia, we identified that loss of ciliary motility did not alter progenitor proliferation, overall brain morphology, or spontaneous neural activity. Instead, we identified that cilia paralysis led to randomization of brain asymmetry. We also observed altered neuronal responses to photic stimulation, especially in the optic tectum and hindbrain. Since astroglia contact CSF at the ventricular walls and are essential for regulating neuronal activity, we next investigated astroglial activity in motile cilia mutants. Our analyses revealed a striking reduction in astroglial calcium signals both during spontaneous and light-evoked activity. Altogether, our findings highlight a novel role of motile cilia-mediated flow in regulating brain physiology through modulation of neural and astroglial networks.

neuroscience↗

bioRxiv2022

Early induction of severe cytokine release syndrome by rapidly generated CAR T cells in a preclinical mouse model

Chimeric antigen receptor (CAR) T cells have emerged as effective strategy against B cell malignancies. Since the long manufacturing process limits patient accessability, short-term (st) CAR T cells are under investigation. Here, we evaluated CD19-CAR T cells 24 hours after exposure to lentiviral vectors. In co-culture with tumor cells and monocytes, stCAR T cells exhibited anti-tumoral activity and strong release of CRS-relevant cytokines (IL-6, IFN-{gamma}, TNF-, GM-CSF, IL-2, IL-10). When administered into tumor engrafted NSG-SGM3 mice, severe acute adverse events encompassing high body scoring, temperature and weight drop arised rapidly within 24 hours. Human (IFN-Y, TNF-, IL-2, IL-10) and murine (MCP-1, IL-6, G-CSF) cytokines typical for severe cytokine release syndrome (CRS) were systemically elevated. Our data highlight potential safety risks of CAR T cells manufactured within short time and suggest simple models for their preclinical safety evaluation.

pharmacology and toxicology↗

bioRxiv2022

Elevated photic response is followed by a rapid decay and depressed state in ictogenic networks

The switch between non-seizure and seizure states involves profound alterations in network excitability and synchrony. Both increased and decreased excitability may underlie the state transitions, as shown in epilepsy patients and animal models. Inspired by video-electroencephalography recordings in patients, we developed a framework to study spontaneous and photic-evoked neural and locomotor activity in zebrafish larvae. We combined high-throughput behavioral tracking and whole-brain in vivo two-photon calcium imaging to perform side-by-side comparison of multiple zebrafish seizure and epilepsy models. Our setup allowed us to dissect behavioral and physiological features that are divergent or convergent across multiple models. We observed that locomotor and neural activity during interictal and spontaneous ictal periods exhibit great diversity across models. Yet, during photic stimulation, hyperexcitability and rapid response dynamics was well conserved across multiple models, highlighting the reliability of photic-evoked seizure activity for high-throughput assays. Intriguingly, in several models, we observed that the initial elevated photic response is often followed by fast decay of neural activity and a prominent depressed state. We argue that such depressed states are likely due to homeostatic mechanisms triggered by excessive neural activity. An improved understanding of the interplay between elevated and depressed excitability states might suggest tailored epilepsy therapies. KEY POINTSO_LIFeatures of spontaneous locomotor and neural activity varies across zebrafish epilepsy and seizure models. C_LIO_LIWe propose photic stimulation as a reliable tool to investigate behavioral and physiological phenotypes in zebrafish epilepsy and seizure models. C_LIO_LIWe observed elevated activity with faster dynamics in response to photic stimulation in all tested zebrafish models. C_LIO_LIPhotic-evoked neural responses were often followed by depressed state in seizure-prone networks C_LI

neuroscience↗

bioRxiv2021

Loss of the glial glutamate transporter eaat2a leads to a combined developmental and epileptic encephalopathy in zebrafish

Astroglial excitatory amino acid transporter 2 (EAAT2, GLT-1, SLC1A2) regulates the duration and extent of neuronal excitation by removing glutamate from the synaptic cleft. Hence, an impairment in EAAT2 function could lead to an imbalanced neural network excitability. Here, we investigated the functional alterations of neuronal and astroglial networks associated with the loss of function in the astroglia predominant eaat2a gene in zebrafish. We observed that eaat2a-/- mutant zebrafish larvae display recurrent spontaneous and light-induced seizures in neurons and astroglia, which coincide with an abrupt increase in extracellular glutamate levels. In stark contrast to this hyperexcitability, basal neuronal and astroglial activity was surprisingly reduced in eaat2a-/- mutant animals, which manifested in decreased overall locomotion. Our results reveal an essential and mechanistic contribution of EAAT2a in balancing brain excitability, and its direct link to epileptic seizures.

neuroscience↗