Biology subjects

Nasr, S.

Publications and source records attributed to Nasr, S..

11 recordsLinked to original sources

bioRxiv2026

Deep-learning-driven tumor microenvironment profiling improves immunotherapy response prediction

Immunotherapy has transformed the management of many cancers, such as clear cell renal cell carcinoma (ccRCC), yet durable clinical benefit is achieved in only a subset of patients. Immunotherapy outcomes are governed by the multicellular tumor microenvironment (TME), through the structured and directional interplay of regulatory programs and ligand-receptor communications. Yet most existing methods for immunotherapy response prediction rely on independent signatures or cell types and fail to model the structured and directional signaling network within the TME. To address this gap, we introduce EcoNet, a computational framework that first models ecosystems consisting of co-occurring cell states, then constructs intercellular and intracellular signaling networks based on the ecosystems, and applies a graph attention network to derive embeddings from the signaling network for immunotherapy response prediction. Pretrained on 2,532 pan-cancer immunotherapy samples across multiple cohorts, EcoNet outperformed existing prediction methods by 7.5-19.9% and marker-based signatures by 4.4-21.2% in AUC, and its high-attention genes were enriched among those required for T-cell-mediated tumor killing in an independent CRISPR screen; applied to ccRCC with disease-specific fine-tuning, it stratified an independent ccRCC cohort by clinical outcome (P=0.024). Biologically, high-attention genes capture an interferon-responsive program that enhances antigen presentation and immune infiltration. To validate these findings, we curated a ccRCC clinical cohort profiled with CosMx single-cell spatial transcriptomics (46 samples, ~450,000 cells) and found the response-associated TME configuration identified by EcoNet localized to immune-enriched niches, supporting the response stratification. These results establish EcoNet as a generalizable framework for TME-informed therapeutic response prediction, readily extensible to other cancer types and therapeutic contexts.

bioinformatics↗

bioRxiv2026

Lung surfactants as a component of lipid nanoparticles for pulmonary mRNA delivery

Pulmonary delivery of lipid nanoparticles (LNPs) remains an area of significant interest, given the broad range of genetic disorders that could be addressed through localized administration of therapeutic nucleic acids to the lung. In this study, we investigated how incorporation of the clinically used lung surfactant cocktail Poractant alfa affects the in vitro and in vivo transfection performance of mRNA-loaded LNPs. The resulting lung surfactant-enhanced LNPs (Surf-LNPs) exhibited substantial improvements in particle assembly, yielding an order of magnitude higher particle concentration at equivalent input conditions compared to conventional (Onpattro-like) LNP formulations. In vitro, Surf-LNPs demonstrated several-fold increases in mRNA transfection efficiency and protein expression while maintaining excellent cytocompatibility. These enhancements are attributed to an elevated apparent pKa and the surface-active properties of surfactant protein B (SP-B), which promote more rapid and efficient endosomal escape relative to conventional LNPs. In vivo evaluation following intranasal administration further revealed enhanced mCherry expression in the lungs of mice treated with Surf-LNPs compared to conventional LNPs. Ultimately, these findings establish lung surfactant incorporation as a simple yet powerful formulation strategy to improve pulmonary gene delivery using LNPs, with the potential to significantly advance the translation of inhaled nucleic acid therapeutics.

bioengineering↗

bioRxiv2025

Mesoscale developmental rivalry in human extrastriate visual cortex

In humans and non-human primates, the extrastriate visual cortex contains fine-scale columns selectively responsive to motion, disparity, and color. However, the developmental interplay between these functional modules remains poorly understood. Using high-resolution fMRI, we compared the mesoscale organization of extrastriate cortex in 16 individuals with normal vision and 15 participants with amblyopia (PwA) caused by strabismus (n=8) or anisometropia (n=7). In controls, the cortical territory occupied by disparity-selective columns exhibited a competitive relationship with that of motion- and color-selective columns. Consistent with this pattern, PwA showed a reduction in disparity-selective responses accompanied by enhanced motion- and color-selective activity, as well as expansion of the cortical territory allocated to them. Our results show that the mesoscale modules of the human visual system are rivals in development allowing intact functions to usurp those that are compromised.

neuroscience↗

bioRxiv2025

Unraveling the mesoscale functional connectivity of the human primary visual cortex using high-resolution functional MRI.

Despite their importance for visual perception, functional connectivity between ocular dominance columns (ODCs)in the human primary visual cortex (V1) remains largely unknown. Using high- resolution functional MRI (fMRI), we localized ODCs and assessed their resting-state functional connectivity (rs-FC) in 12 human adults. Consistent with anatomical studies in animals, we found stronger rs-FC in the middle compared to deep and superficial cortical depths and selectively stronger rs- FC between ODCs with alike compared to unalike ocular polarity. Beyond what was known from animal models, and consistent with human perceptual biases, intra- and interhemispheric rs-FC was stronger in peripheral (compared to central) and in dorsal (compared to ventral) V1 subregions. Lastly, rs-FC patterns correlated with ODC maps, suggesting that ODC maps can be predicted from rs-FC patterns within V1. These results highlight the heterogeneity in rs-FC between ODCs across cortical depths and V1 subfields, underscoring their likely association with human perceptual features.

neuroscience↗

bioRxiv2024

Same-Slide Spatial Multi-Omics Integration Reveals Tumor Virus-Linked Spatial Reorganization of the Tumor Microenvironment

The advent of spatial transcriptomics and spatial proteomics have enabled profound insights into tissue organization to provide systems-level understanding of diseases. Both technologies currently remain largely independent, and emerging same slide spatial multi-omics approaches are generally limited in plex, spatial resolution, and analytical approaches. We introduce IN-situ DEtailed Phenotyping To High-resolution transcriptomics (IN-DEPTH), a streamlined and resource-effective approach compatible with various spatial platforms. This iterative approach first entails single-cell spatial proteomics and rapid analysis to guide subsequent spatial transcriptomics capture on the same slide without loss in RNA signal. To enable multi-modal insights not possible with current approaches, we introduce k-bandlimited Spectral Graph Cross-Correlation (SGCC) for integrative spatial multi-omics analysis. Application of IN-DEPTH and SGCC on lymphoid tissues demonstrated precise single-cell phenotyping and cell-type specific transcriptome capture, and accurately resolved the local and global transcriptome changes associated with the cellular organization of germinal centers. We then implemented IN-DEPTH and SGCC to dissect the tumor microenvironment (TME) of Epstein-Barr Virus (EBV)-positive and EBV-negative diffuse large B-cell lymphoma (DLBCL). Our results identified a key tumor-macrophage-CD4 T-cell immunomodulatory axis differently regulated between EBV-positive and EBV-negative DLBCL, and its central role in coordinating immune dysfunction and suppression. IN-DEPTH enables scalable, resource-efficient, and comprehensive spatial multi-omics dissection of tissues to advance clinically relevant discoveries.

systems biology↗

bioRxiv2024

Decreased scene-selective activity within the posterior intraparietal cortex in amblyopic adults

Amblyopia is a developmental disorder associated with reduced performance in visually guided tasks, including binocular navigation within natural environments. To help understand the underlying neurological disorder, we used fMRI to test the impact of amblyopia on the functional organization of scene-selective cortical areas, including the posterior intraparietal gyrus scene-selective (PIGS) area, a recently discovered region that responds selectively to ego-motion within naturalistic environments (Kennedy et al., 2024). Nineteen amblyopic adults (10 female) and thirty age-matched controls (12 female) participated in this study. Amblyopic participants spanned a wide range of amblyopia severity, based on their interocular visual acuity difference and stereoacuity. The visual function questionnaire (VFQ-39) was used to assess the participants perception of their visual capabilities. Compared to controls, we found weaker scene-selective activity within the PIGS area in amblyopic individuals. By contrast, the level of scene-selective activity across the occipital place area (OPA), parahippocampal place area (PPA), and retrosplenial cortex (RSC)) remained comparable between amblyopic and control participants. The subjects scores on "general vision" (VFQ-39 subscale) correlated with the level of scene-selective activity in PIGS. These results provide novel and direct evidence for amblyopia-related changes in scene-processing networks, thus enabling future studies to potentially link these changes across the spectrum of documented disabilities in amblyopia.

neuroscience↗

bioRxiv2024

Selective Functional Connectivity between Ocular Dominance Columns in the Primary Visual Cortex

The primary visual cortex (V1) in humans and many animals is comprised of fine-scale neuronal ensembles that respond preferentially to the stimulation of one eye over the other, also known as the ocular dominance columns (ODCs). Despite its importance in shaping our perception, to date, the nature of the functional interactions between ODCs has remained poorly understood. In this work, we aimed to improve our understanding of the interaction mechanisms between fine-scale neuronal structures distributed within V1. To that end, we applied high-resolution functional MRI to study mechanisms of functional connectivity between ODCs. Using this technique, we quantified the level of functional connectivity between ODCs as a function of the ocular preference of ODCs, showing that alike ODCs are functionally more connected compared to unalike ones. Through these experiments, we aspired to contribute to filling the gap in our knowledge of the functional connectivity of ODCs in humans as compared to animals.

neuroscience↗

bioRxiv2024

Using high-resolution functional MRI to differentiate impacts of strabismic and anisometropic amblyopia on evoked ocular dominance activity in humans

We employed high-resolution functional MRI (fMRI) to distinguish the impacts of anisometropia and strabismus (the two most frequent causes of amblyopia) on the evoked ocular dominance (OD) response. Sixteen amblyopic participants (8 females), comprising 8 individuals with strabismus, 7 with anisometropia, 1 with deprivational amblyopia, along with 8 individuals with normal visual acuity (1 female), participated in this study for whom, we measured the difference between the response to stimulation of the two eyes, across early visual areas (V1-V4). In controls, as expected from the organization of OD columns, the evoked OD response formed a striped pattern that was mostly confined to V1. Compared to controls, the OD response in amblyopic participants formed larger fused patches that extended into downstream visual areas. Moreover, both anisometropic and strabismic participants showed stronger OD responses in V1, as well as in downstream visual areas V2-V4. Although this increase was most pronounced in V1, the correlation between the OD response level and the interocular visual acuity difference (measured behaviorally) was stronger in higher-level visual areas (V2-V4). Beyond these common effects, and despite similar densities of amblyopia between the anisometropic and strabismic participants, we found a greater increase in the size of V1 portion that responded preferentially to fellow eye stimulation in anisometropic compared to strabismic individuals. We also found a greater difference between the amplitudes of the response to binocular stimulation, in those regions that responded preferentially to the fellow vs. amblyopic eye, in anisometropic compared to strabismic subjects. In contrast, strabismic subjects demonstrated increased correlation between the OD responses evoked within V1 superficial and deep cortical depths, whereas anisometropic subjects did not. These results provide some of the first direct functional evidence for distinct impacts of strabismus and anisometropia on the mesoscale functional organization of the human visual system, thus extending what was inferred previously about amblyopia from animal models.

neuroscience↗

bioRxiv2023

Decoding of columnar-level organization across cortical depth using BOLD- and CBV-fMRI at 7 T

Multivariate pattern analysis (MVPA) methods are a versatile tool to retrieve information from neurophysiological data obtained with functional magnetic resonance imaging (fMRI) techniques. Since fMRI is based on measuring the hemodynamic response following neural activation, the spatial specificity of the fMRI signal is inherently limited by contributions of macrovascular compartments that drain the signal from the actual location of neural activation, making it challenging to image cortical structures at the spatial scale of cortical columns and layers. By relying on information from multiple voxels, MVPA has shown promising results in retrieving information encoded in fine-grained spatial patterns. We examined the spatial specificity of the signal exploited by MVPA. Over multiple sessions, we measured ocular dominance columns (ODCs) in human primary visual cortex (V1) with different acquisition techniques at 7 T. For measurements with blood oxygenation level dependent (BOLD) contrast, we included both gradient echo- (GE-BOLD) and spin echo-based (SE-BOLD) sequences. Furthermore, we acquired data using the vascular-space-occupancy (VASO) fMRI technique, which is sensitive to cerebral blood volume (CBV) changes. We used the data to decode eye-of-origin from signals across cortical layers. While ocularity information can be decoded with all imaging techniques, laminar profiles reveal that macrovascular contributions affect all acquisition methods, limiting their specificity across cortical depth. Therefore, although MVPA is a promising approach for investigating the mesoscopic circuitry of the human cerebral cortex, careful consideration of macrovascular contributions is needed that render the spatial specificity of the extracted signal.

neuroscience↗

bioRxiv2022

High resolution quantitative and functional MRI indicate lower myelination of thin and thick stripes in human secondary visual cortex

The characterization of cortical myelination is essential for the study of structure-function relationships in the human brain. However, knowledge about cortical myelination is largely based on post mortem histology, which generally renders direct comparison to function impossible. The repeating pattern of pale-thin-pale-thick stripes of cytochrome oxidase (CO) activity in the primate secondary visual cortex (V2) is a prominent columnar system, in which histology also indicates different myelination of thin/thick versus pale stripes. We used quantitative magnetic resonance imaging (qMRI) in conjunction with functional magnetic resonance imaging (fMRI) at ultra-high field strength (7 T) to localize and study myelination of stripes in four human participants at sub-millimeter resolution in vivo. Thin and thick stripes were functionally localized by exploiting their sensitivity to color and binocular disparity, respectively. Resulting functional activation maps showed robust stripe patterns in V2 which enabled further comparison of quantitative relaxation parameters between stripe types. Thereby, we found lower longitudinal relaxation rates (R1) of thin and thick stripes compared to surrounding gray matter in the order of 1-2%, indicating higher myelination of pale stripes. No consistent differences were found for effective transverse relaxation rates [Formula]. The study demonstrates the feasibility to investigate structure-function relationships in living humans within one cortical area at the level of columnar systems using qMRI.

neuroscience↗

bioRxiv2022

Two interdigitated fine-scale channels for encoding motion and stereopsis within the human magnocellular stream

In humans and non-human primates (NHPs), motion and stereopsis are processed within fine-scale cortical sites, including V2 thick stripes and their extensions into areas V3 and V3A that are believed to be under the influence of magnocellular stream. However, in both species, the functional organization (overlapping vs. interdigitated) of these sites remains unclear. Using high-resolution functional MRI (fMRI), we found evidence for two interdigitated channels within human extrastriate areas that contribute to processing motion and stereopsis. Across multiple experiments that included different stimuli (random dots, gratings, and natural scenes), the functional selectivity of these channels for motion vs. stereopsis remained consistent. Furthermore, an analysis of resting state functional connectivity revealed stronger functional connectivity within the two channels rather than between them. This finding provides a new perspective toward the mesoscale organization of the magnocellular stream within the human extrastriate visual cortex, beyond our previous understanding based on animal models.

neuroscience↗