Biology subjects

Heidari, M.

Publications and source records attributed to Heidari, M..

8 recordsLinked to original sources

bioRxiv2026

Oligodendrocyte stress response as a driver of vascular dementia

Vascular dementia (VaD) is a prevalent and devastating neurocognitive disorder characterized by profound white matter damage, yet the precise cellular mechanisms linking cerebrovascular stress to demyelination remain poorly understood. Here, we characterize the impact of a chronic cardiometabolic stress regimen combining a high-fat diet and hypertension (HF/HBP) on central nervous system structure and function. Adult HF/HBP mice exhibit progressive oligodendroglial cell loss and myelin thinning, followed by cognitive impairments, anxiety-like behavior, and memory deficits that recapitulate clinical features of VaD. Mechanistically, we identify the integrated stress response (ISR) as a central driver of this pathology; pharmacological inhibition of the ISR restores myelination, while cell-specific genetic deletion of the ISR-activating kinase PERK from oligodendrocytes fully protects mice from HF/HBP-induced pathological and behavioral defects. Furthermore, we provide translational evidence that the ISR is activated in oligodendrocytes in human cases of cerebrovascular disease. Together, these findings reveal a critical, cell-autonomous role for oligodendroglial ISR activation during cerebrovascular stress and position this pathway as a viable therapeutic target to mitigate VaD pathogenesis.

neuroscience↗

bioRxiv2026

Evaluating Single-Cell Perturbation Response Models Is Far from Straightforward

Predicting cellular responses to genetic and chemical perturbations remains a central challenge in single-cell biology and a key step toward building in silico virtual cells. The rapid growth of perturbation datasets and advances in deep-learning models have raised expectations for accurate and generalizable prediction. We show that these expectations are overly optimistic, largely due to the failure modes of existing evaluation metrics. In this study, using cross-splitting, controlled noise experiments, and synthetic data, we systematically evaluate both prediction models and evaluation metrics. We demonstrate that widely used metrics, including correlation-based measures and common distributional distances, are strongly influenced by scale, sparsity, and dimensionality, often misrepresenting model performance. In particular, the Wasserstein distance fails in high-dimensional gene expression spaces under variance scaling, while the Energy distance can overlook disruptions in gene-gene dependencies. Our analyses further reveal that complex deep learning models often underperform simple baselines and remain far from empirical performance bounds across multiple chemical perturbation datasets. Together, our framework exposes critical pitfalls, establishes robust evaluation guidelines, and provides a foundation for trustworthy benchmarking toward reliable virtual-cell models.

bioinformatics↗

bioRxiv2025

O-GlcNAcylation and an importin-β radial gradient keep the FG barrier liquid in live-cell nuclear pores

Summary ParagraphThe nuclear pore complex (NPC) regulates the molecular traffic between nucleus and cytoplasm.1,2 Its permeability barrier is formed by intrinsically disordered proteins (IDPs) known as FG-nucleoporins (FG-NUPs), whose physical state has long been debated.3-13 Deciphering how FG-NUPs behave inside living cells is crucial for understanding how the NPC achieves selective and rapid transport. Here, by combining site-specific labelling with picosecond time-resolved fluorescence anisotropy, we reveal that FG domains exhibit nanosecond-scale, liquid-like mobility in live cells, yet undergo a liquid-to-solid transition in vitro. Experiments and coarse-grained molecular dynamics simulations further show that importin-{beta}, a major nuclear transport receptor, and O-linked {beta}-N-acetylglucosamine (O-GlcNAc), a key post-translational modification of FG-NUPs together stabilise the dynamic FG network. Finely balanced FG-FG interactions modulated by O-GlcNAcylation, along with FG-importin-{beta} interactions, maintain liquidity and enrich importin-{beta} near the NPC periphery, while extended FG domains remain in the central channel to form the transport barrier. These findings reconcile conflicting models of FG-NUP organisation4,6,8,10,14,15 and explain the recent observations in high-resolution MINFLUX studies of importin-{beta} depletion from the pore centre in mammalian cells.16 Beyond resolving debates over FG-NUP behaviour, our study underscores the importance of studying IDPs in their cellular context, with broader implications for understanding IDP-related diseases, including viral infections, cancer, and neurodegenerative disorders.

biophysics↗

bioRxiv2024

Refining Martini Force Field Interactions for Accurate Glycoprotein Modeling

Covalently attached sugar molecules play important roles as mediators of biomolecular interactions. Molecular dynamics simulations are an indispensable tool to explore these interactions at the molecular level. The large time and length scales involved frequently necessitate the use of coarse-grained representations, which heavily depend on the parameterization of sugar-protein interactions. Here, we adjust the sugar-protein interactions in the widely used Martini 2.2 force field to reproduce the experimental second virial coefficients between sugars and proteins. In simulations of two model proteins in glucose solutions with adjusted force field parameters, we observe weak protein-sugar interaction. The sugar molecules are thus acting mainly as crowding agents, in agreement with experimental measurements. The procedure to fine-tune sugar-protein interactions is generally applicable and could prove useful also for atomistic force fields.

biophysics↗

bioRxiv2024

Passage of the HIV capsid cracks the nuclear pore

Upon infection, human immunodeficiency virus (HIV-1) releases its cone-shaped capsid into the cytoplasm of infected T-cells and macrophages. As its largest known cargo, the capsid enters the nuclear pore complex (NPC), driven by interactions with numerous FG-repeat nucleoporins (FG-Nups). Whether NPCs structurally adapt to capsid passage and whether capsids are modified during passage remains unknown, however. Here, we combined super-resolution and correlative microscopy with cryo electron tomography and molecular simulations to study nuclear entry of HIV-1 capsids in primary human macrophages. We found that cytosolically bound cyclophilin A is stripped off capsids entering the NPC, and the capsid hexagonal lattice remains largely intact inside and beyond the central channel. Strikingly, the NPC scaffold rings frequently crack during capsid passage, consistent with computer simulations indicating the need for NPC widening. The unique cone shape of the HIV-1 capsid facilitates its entry into NPCs and helps to crack their rings.

biophysics↗

bioRxiv2023

Cerebellar granule cell migration and folia development requires Mllt11/Af1q

The organization of neurons into distinct layers, known as lamination, is a common feature of the nervous system. This process, which arises from the direct coupling of neurogenesis and neuronal migration, plays a crucial role in the development of the cerebellum, a structure exhibiting a distinct folding cytoarchitecture with cells arranged in discrete layers. Disruptions to neuronal migration can lead to various neurodevelopmental disorders, highlighting the significance of understanding the molecular regulation of lamination. Here we report a role Mllt11/Af1q/Tcf7c (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q, also known as Mllt11 transcriptional cofactor 7; henceforth referred to Mllt11) in the migration of cerebellar granule cells (GCs). We now show that Mllt11 plays a role in both tangential and radial migration of GCs. Loss of Mllt11 led to an accumulation of GC precursors in the Rhombic Lip region and a reduction in the number of GCs successfully populating developing folia. Consequently, this results in smaller folia and an overall reduction in cerebellar size. Furthermore, analysis of the anchoring centers reveals disruptions in the perinatal folia cytoarchitecture, including alterations in the Bergmann glia fiber orientation and reduced infolding of the Purkinje cell plate. Lastly, we demonstrate that Mllt11 interacts with Non-muscle Myosin IIB (NMIIB) and regulates its expression. We propose the dysregulation of NMIIB underlies altered GC migratory behavior. Taken together, the findings reported herein demonstrate a role for Mllt11 in regulating neuronal migration within the developing cerebellum, which is necessary for its proper neuroanatomical organization.

developmental biology↗

bioRxiv2022

Deciphering the conformations and dynamics of FG-nucleoporins in situ

The [~]120 MDa nuclear pore complex (NPC) acts as a gatekeeper for the molecular traffic between the nucleus and the cytosol. Small cargo readily passes through the transport channel, yet large cargo requires specialized nuclear transport receptors. While the scaffold structure that anchors the NPC in the double-layered nuclear envelope has been resolved to remarkable details, the spatial organization of intrinsically disordered nucleoporins (NUPs) within the central channel remains enigmatic. These so-called FG-NUPs account for about one-third of the total mass of the NPC and form the actual transport barrier. Here we combined site-specific fluorescent labeling in non-fixed cells and fluorescent lifetime imaging microscopy (FLIM) to directly decipher the conformations of an essential constituent of the permeability barrier, NUP98, inside the functioning NPCs using Fluorescence resonance energy transfer (FRET). With detailed measurements of the distance distribution of eighteen NUP98 segments combined with coarse-grained modeling, we mapped the uncharted biochemical environment inside the nanosized transport channel. We found that good-solvent conditions for a polymer dominate the inside of the nanosized NPC, expand the FG-domain in situ and facilitate nuclear transport, in sharp contrast to the collapsed NUP98 FG-chain in aqueous solution. The combination of fluorescence microscopy, high-resolution electron tomography, and molecular simulation opens a window into the so-far unresolved organization of the FG-NUPs at the center of NPC function, allowing us to reconcile scientific models of nuclear transport.

biophysics↗

bioRxiv2022

mRNA-based vaccine candidate COReNAPCIN(R) induces robust humoral and cellular immunity in mice and non-human primates

At the forefront of biopharmaceutical industry, the messenger RNA (mRNA) technology offers a flexible and scalable platform to address the urgent need for world-wide immunization in pandemic situations. This strategic powerful platform has recently been used to immunize millions of people proving both of safety and highest level of clinical efficacy against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we provide preclinical report of COReNAPCIN(R); a vaccine candidate against SARS-CoV-2 infection. COReNAPCIN(R) is a nucleoside modified mRNA-based vaccine formulated in lipid nanoparticles (LNPs) for encoding the full-length prefusion stabilized SARS-CoV-2 spike glycoprotein on the cell surface. Vaccination of C57BL/6 and BALB/c mice and rhesus macaque with COReNAPCIN(R) induced strong humoral responses with high titers of virus-binding and neutralizing antibodies. Upon vaccination, a robust SARS-CoV-2 specific cellular immunity was also observed in both mice and non-human primate models. Additionally, vaccination protected rhesus macaques from symptomatic SARS-CoV-2 infection and pathological damage to the lung upon challenging the animals with high viral loads of up to 2x108 live viral particles. Overall, our data provide supporting evidence for COReNAPCIN(R) as a potent vaccine candidate against SARS-CoV-2 infection for clinical studies.

immunology↗