Biology subjects

Patel, R.

Publications and source records attributed to Patel, R..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

High fat diet but not glucocorticoid-induced obesity results in fatty liver

Chronic stress, modeled by flattened circadian glucocorticoid (GC) oscillations, is increasingly implicated in obesity. We investigated the underlying mechanisms by disrupting GC rhythms in mice, elevating normally low GC levels during the rest period. This disruption induced substantial obesity, comparable to a 60% high-fat diet (HFD), with additive effects on fat mass, suggesting distinct mechanisms driving adiposity. Despite similar adiposity, GC-flattening and HFD produced profoundly different metabolic outcomes. HFD led to hepatic steatosis and elevated fasting glucose/fatty acid levels, reflecting typical diet-induced dysfunction. In contrast, GC-flattening maintained low fasting glucose/fatty acid levels and prevented hepatic lipid accumulation, with increased adiposity driven by a shift of glucose uptake from muscle to fat and suppression of lipolysis. This reveals a previously unrecognized mechanism of obesity development where excess fat accumulation occurs independently of the mechanisms driving metabolic dysfunction observed in diet-induced obesity. The dissociation between obesity and metabolic dysfunction in GC-flattening challenges the view that increased adiposity and persistent hyperinsulinemia inevitably leads to fatty liver disease. Understanding this pathway opens avenues for novel therapeutic interventions targeting stress-related metabolic disorders.

physiology↗

bioRxiv2025

A proteogenomic tool uncovers protein markers for human microglial states

Human microglial heterogeneity has been largely described using transcriptomic data. Here, we introduce a microglial proteomic data resource and a Cellular Indexing of Transcriptomes and Epitopes by Sequencing panel enhanced with antibodies targeting 17 microglial cell surface proteins (mCITE-Seq). We evaluated mCITE-Seq on HMC3 microglia-like cells, induced-pluripotent stem cell-derived microglia (iMG), and freshly isolated primary human microglia. We identified novel protein microglial markers such as CD51 and relate expression of 101 cell surface proteins to transcriptional programs. This results in the identification and validation of three protein marker combinations with which to purify microglia enriched with each of 23 transcriptional programs; for example, CD49D, HLA-DR and CD32 enrich for GPNMBhigh ("disease associated") microglia. Further, we identify and validate proteins - SIRPA, PDPN and CD162 - that differentiate microglia from infiltrating macrophages. The mCITE-Seq panel enables the transition from RNA-based classification and facilitates the functional characterization and harmonization of model systems.

neuroscience↗

bioRxiv2025

Ebola's Hidden Target: Virus Transmission to and Accumulation within Skin

Ebola virus (EBOV), the causative agent of Ebola virus disease (EVD), remains one of WHOs top ten threats to global health. Infectious EBOV virions can be found on the surface of skin late during systemic infection and passed from the deceased through skin-to-skin contact. Here, we assess viral load and antigen expression in the skin of EBOV-infected non-human primates (NHP) and mouse adapted-EBOV (ma-EBOV) - infected mice and use the low containment viral model, rVSV/EBOV GP, to mechanistically define skin infection in mice. Viral RNA peaked within the skin proximal to the site of injection in EBOV-infected NHPs on day 6. In contrast, mouse skin sites distal to the site of ma-EBOV injection achieved maximal viral loads by day 3. At late times of infection, viral antigen-positive cells co-localized with markers for endothelial, stromal, and immune cells in the dermis. Epidermal cells within and surrounding hair follicles also harbored viral antigen, suggesting a potential mechanism of virus trafficking to the epidermal surface. Despite robust viral infection, distal skin sites of ma-EBOV-infected mice had low expression of proinflammatory stimulated genes. A similar cellular tropism was observed in the skin of mice infected with rVSV/EBOV GP, with discrete focal areas of intense infection. When virus was applied to the surface of gently abraded skin to remove the stratum corneum, epidermal keratinocytes were robustly infected, followed by systemic viral dissemination. To define cell surface receptors critical for virus trafficking to and replication within the skin, mice lacking the phosphatidylserine receptors were infected intraperitoneally with rVSV/EBOV GP. At day 3 of infection, skin distal to the site of infection of TIM-1 knock out (KO) mice had significantly lower levels of infectious virus than the control mice, suggesting that TIM-1 is essential for efficient distribution of virus to the skin. Our findings reveal that EBOV targets specific skin cell populations at late times of viral infection and that the host receptor TIM-1 is required for optimal viral dissemination.

microbiology↗

bioRxiv2025

iGABASnFR2: Improved genetically encoded protein sensors of GABA

Monitoring GABAergic inhibition in the nervous system has been enabled by development of an intensiometric molecular sensor that directly detects GABA. However, the first generation iGABASnFR exhibits low signal-to-noise and suboptimal kinetics, making in vivo experiments challenging. To improve sensor performance, we targeted several sites in the protein for near-saturation mutagenesis and evaluated the resulting sensor variants in a high throughput screening system using evoked synaptic release in primary cultured neurons. This identified a sensor variant, iGABASnFR2, with 4.1-fold improved sensitivity and 30% faster rise time, and binding affinity that remained in a range sensitive to changes in GABA concentration at synapses. We also identified sensors with an inverted response, decreasing fluorescence intensity upon GABA binding. We termed the best such negative-going sensor iGABASnFR2n, which can be used to corroborate observations with the positive-going sensor. These improvements yielded a qualitative enhancement of in vivo performance when compared directly to the original sensor. iGABASnFR2 enabled the first measurements of direction-selective GABA release in the retina. In vivo imaging in somatosensory cortex revealed that iGABASnFR2 can report volume-transmitted GABA release following whisker stimulation. Overall, the improved sensitivity and kinetics of iGABASnFR2 make it a more effective tool for imaging GABAergic transmission in intact neural circuits.

neuroscience↗

bioRxiv2025

Melatonin and GABA monotherapies are as efficacious as combination therapy in managing T1D and T2D: In-vivo studies on experimental diabetic models

BackgroundLoss of functional {beta}-cell mass is a critical factor in the ontogenesis of type 1 (T1D) and type 2 diabetes (T2D) marked by chronic hyperglycemia. Melatonin (M) and {gamma}-aminobutyric acid (GABA/G) have immunoregulatory properties and have shown potential to increase {beta}-cell mass in experimental diabetic models. Thus, we aimed to investigate the therapeutic potential of melatonin combined with GABA on {beta}-cell regeneration in streptozotocin (STZ)-induced T1D and on a high-fat diet (HFD)-induced T2D mouse models. MethodsThe BALB/c mice were injected with 50 mg/kg body weight STZ on five consecutive days to induce T1D and were subjected to six weeks of monotherapy with melatonin or GABA and combination therapy (M+G). HFD was fed to C57BL/6J mice for 30 weeks to induce insulin resistance and T2D, followed by six weeks of mono or combination therapy exposure. ResultsOur studies on monotherapies and combination therapy reduced fasting blood glucose levels, increased plasma insulin levels and glucose tolerance, and promoted {beta}-cell proliferation and transdifferentiation, with a simultaneous decrease in {beta}-cell apoptosis in T1D mice. It also improved metabolic parameters and glycolipid metabolism in the liver and adipose tissue, respectively, and increased mitochondrial function in the skeletal muscle. Moreover, it restored peripheral insulin sensitivity and {beta}-cell mass in T2D mice. ConclusionOur studies suggest that monotherapies are as effective as combination therapy since melatonin and GABA sub-additively ameliorates T1D and T2D manifestations.

biochemistry↗

bioRxiv2025

H2A.Z facilitates Sox2-nucleosome interaction by promoting DNA and histone H3 tail mobility

Epigenetic regulation of chromatin structure is strongly influenced by histone variants and post-translational modifications. The conserved histone variant H2A.Z has been functionally linked to the pioneer factors Sox2 and Oct4, which open chromatin and activate cell fate-specific transcriptional programs. However, the molecular basis of this interaction is not well understood. Here, we combine biochemistry, NMR spectroscopy, and molecular dynamics (MD) simulations to investigate how H2A.Z nucleosome dynamics influence pioneer factor binding. We find that H2A.Z enhances Sox2 and Oct4 association at distinct positions within 601 nucleosomes, correlating with increased DNA accessibility and altered H3 N-terminal tail dynamics. We show that the H3 tail competes with Sox2 for DNA binding and is more efficiently displaced with H2A.Z, while also allowing for unique Sox2-H3 tail interactions. MD simulations reveal that H2A.Z promotes DNA unwrapping, increases inter-gyre spacing, and enhances H3 tail flexibility, while simultaneously reducing contacts with DNA and with the H2A.Z C-terminal tail. This destabilizing effect is DNA-sequence dependent and prominent in the less stable Lin28B nucleosome, which Sox2 appears to substantially reshape. Together, our results suggest that H2A.Z promotes pioneer factor binding by increasing DNA accessibility and reducing histone tail competition, with broad implications for epigenetic regulation and chromatin recognition.

biophysics↗

bioRxiv2025

Structural and Thermodynamic Impact of Oncogenic Mutations on the Nucleosome Core Particle

The nucleosome core particle (NCP) is essential for chromatin structure and function, serving as the fundamental unit of eukaryotic chromatin. Oncogenic mutations in core histones disrupt chromatin dynamics, altering DNA repair and transcription processes. Here, we investigate the molecular consequences of two mutations--H2BE76K and H4R92T--using 36 {micro}s of all-atom molecular dynamics simulations and experimental biophysical assays. These mutations destabilize the H2B-H4 interface by disrupting critical salt bridges and hydrogen bonds, reducing binding free energy at this interface. Principal component analysis reveals altered helix conformations and increased interhelical distances in mutant systems. Thermal stability assays (TSA) and differential scanning calorimetry (DSC) confirm that these mutations lower the dimer dissociation temperature and reduce enthalpy compared to the wild type. Taken together, our results elucidate how these mutations compromise nucleosome stability and propose mechanisms through which they could modulate chromatin accessibility and gene dysregulation in cancer. Statement of SignificanceThe nucleosome is the essential packaging unit of DNA. Oncohistones which are histone mutations that are associated with cancer, are known to compromise the stability of the nucleosome and affect nucleosome sliding. Here we perform long-time molecular dynamics simulations of two buried histone core mutations, demonstrating that these mutations reduce the stability of the histone core at the H2B-H4 interface. Next, we demonstrate that these same mutations lower the dimer dissociation temperature and shift the nucleosome dissociation pathway.

biophysics↗

bioRxiv2025

Dopamine signaling drives skin invasion by human-infective nematodes

Skin-penetrating nematodes are one of the most prevalent causes of disease worldwide - nearly 15% of the global population is infected with at least one species of skin-penetrating nematode1,2. The World Health Organization has targeted these parasites for elimination by 20303, but the lack of preventative measures is a major obstacle to this goal. The infective larvae of skin-penetrating nematodes enter hosts through skin4, and blocking skin penetration is an as-yet unexplored approach for preventing infection. However, in order to prevent worm ingress via the skin, an understanding of the behavioral and neural mechanisms that drive skin penetration is required. Here, we describe the skin-penetration behaviors of the human-infective threadworm Strongyloides stercoralis. Using fluorescently labeled worms to enable visualization on the skin coupled with time-lapse microscopy, we show that S. stercoralis engages in repeated cycles of pushing, puncturing, and crawling on the skin surface before penetrating the skin. Pharmacological inhibition of dopamine signaling inhibits these behaviors in S. stercoralis and the human hookworm Ancylostoma ceylanicum, suggesting a critical role for dopamine signaling in driving skin penetration across distantly related nematodes. CRISPR-mediated disruption of dopamine biosynthesis and chemogenetic silencing of dopaminergic neurons also inhibit skin penetration. Finally, inactivation of the TRPN channel TRP-4, which is expressed in the dopaminergic neurons, blocks skin penetration on both rat and human skin. Our results suggest that drugs targeting TRP-4 and other nematode-specific components of the dopaminergic pathway could be developed into topical prophylactics that block skin penetration, thereby preventing infections.

neuroscience↗

bioRxiv2025

Unveiling the Conformational Dynamics of the Histone Tails Using Markov State Modeling

Biomolecules predominantly exert their function through altering conformational dynamics. The nucleosome core particle (NCP) is the fundamental unit of chromatin. DNA with [~]146 base pairs wrap around the histone octamer to form a nucleosome. The histone octamer is comprised of two copies of each histone protein (H3, H4, H2A, and H2B) with a globular core and disordered N-terminal tails. Epigenetic modifications of the histone N-terminal tails play a critical role in the regulation of chromatin structure and biological processes such as transcription and DNA repair. Here, we report all-atomistic molecular dynamics (MD) simulations of the nucleosome at microsecond timescales to construct Markov state models (MSMs) to elucidate distinct conformations of the histone tails. We employ the time-lagged independent component analysis (tICA) to capture their essential slow dynamics, with k-means clustering used to discretize the conformational space. MSMs unveil distinct states and transition probabilities to characterize the dynamics and kinetics of the tails. Next, we focus on the H2B tail, one of the least studied tails. We show that acetylation increases secondary structure formation, with an increase in transition rates. These findings will aid in understanding the functional implications of tail conformations in nucleosome stability and gene regulation. Significance StatementThe nucleosome is the fundamental repeat unit of chromatin, composed of a histone octamer and DNA. Each histone has a globular core and N-terminal tail regions. N-terminal tails are major sites for post-translational modifications, chromatin structure, and gene regulation. Using all-atom molecular dynamics simulations of the nucleosome to examine the dynamics of histone tails and analyze the effects of one of the histone modifications, such as acetylation on histone tails. We explore tail dynamics and kinetics using Markov State Models (MSMs) to gain insight into histone tail structural changes. Acetylation of the H2B tail shows an increased dynamics of the tail based on transition rates. Our study characterizes transition rates of all histone tails that can influence nucleosome plasticity and gene regulation.

biophysics↗

bioRxiv2025

Simultaneous EEG-PET-MRI identifies temporally coupled, spatially structured hemodynamic and metabolic dynamics across wakefulness and NREM sleep

Sleep entails significant changes in cerebral hemodynamics and metabolism. Yet, the way these processes evolve throughout wakefulness and sleep and their spatiotemporal dependence remain largely unknown. Here, by integrating a novel functional PET technique with simultaneous EEG-fMRI, we reveal a tightly coupled temporal progression of global hemodynamics and metabolism during the descent into NREM sleep, with large hemodynamic fluctuations emerging as global glucose metabolism declines, both of which track EEG arousal dynamics. Furthermore, we identify two distinct network patterns that emerge during NREM sleep: an oscillating, high-metabolism sensorimotor network remains active and dynamic, whereas hemodynamic and metabolic activity in the default-mode network is suppressed. These results elucidate how sleep diminishes awareness while preserving sensory responses, and uncover a complex, alternating balance of neuronal, hemodynamic, and metabolic dynamics in the sleeping brain. This work also demonstrates the potential of EEG-PET-MRI to explore neuro-hemo-metabolic dynamics underlying cognition and arousal in humans.

neuroscience↗

bioRxiv2025

Evolutionary sparse learning with paired species contrast reveals the shared genetic basis of convergent traits

Cases abound in which nearly identical traits have appeared in distant species facing similar environments. These unmistakable examples of adaptive evolution offer opportunities to gain insight into their genetic origins and mechanisms through comparative analyses. Here, we present a novel comparative genomics approach to build genetic models that underlie the independent origins of convergent traits using evolutionary sparse learning. We test the hypothesis that common genes and sites are involved in the convergent evolution of two key traits: C4 photosynthesis in grasses and echolocation in mammals. Genetic models were highly predictive of independent cases of convergent evolution of C4 photosynthesis. These results support the involvement of sequence substitutions in many common genetic loci in the evolution of convergent traits studied. Genes contributing to genetic models for echolocation were highly enriched for functional categories related to hearing, sound perception, and deafness (P < 10-6); a pattern that has eluded previous efforts applying standard molecular evolutionary approaches. We conclude that phylogeny-informed machine learning naturally excludes apparent molecular convergences due to shared species history, enhances the signal-to-noise ratio for detecting molecular convergence, and empowers the discovery of common genetic bases of trait convergences.

evolutionary biology↗

bioRxiv2024

Predicting Future Development of Stress-Induced Anhedonia From Cortical Dynamics and Facial Expression

The current state of mental health treatment for individuals diagnosed with major depressive disorder leaves billions of individuals with first-line therapies that are ineffective or burdened with undesirable side effects. One major obstacle is that distinct pathologies may currently be diagnosed as the same disease and prescribed the same treatments. The key to developing antidepressants with ubiquitous efficacy is to first identify a strategy to differentiate between heterogeneous conditions. Major depression is characterized by hallmark features such as anhedonia and a loss of motivation (1, 2), and it has been recognized that even among inbred mice raised under identical housing conditions, we observe heterogeneity in their susceptibility and resilience to stress (3). Anhedonia, a condition identified in multiple neuropsychiatric disorders, is described as the inability to experience pleasure and is linked to anomalous medial prefrontal cortex (mPFC) activity (4). The mPFC is responsible for higher order functions (5-8), such as valence encoding; however, it remains unknown how mPFC valence-specific neuronal population activity is affected during anhedonic conditions. To test this, we implemented the unpredictable chronic mild stress (CMS) protocol (9-11) in mice and examined hedonic behaviors following stress and ketamine treatment. We used unsupervised clustering to delineate individual variability in hedonic behavior in response to stress. We then performed in vivo 2-photon calcium imaging to longitudinally track mPFC valence-specific neuronal population dynamics during a Pavlovian discrimination task. Chronic mild stress mice exhibited a blunted effect in the ratio of mPFC neural population responses to rewards relative to punishments after stress that rebounds following ketamine treatment. Also, a linear classifier revealed that we can decode susceptibility to chronic mild stress based on mPFC valence-encoding properties prior to stress-exposure and behavioral expression of susceptibility. Lastly, we used a markerless pose tracking computer vision tool, SLEAP (31), to predict whether a mouse would become resilient or susceptible based on facial expressions during a Pavlovian discrimination task. These results indicate that mPFC valence encoding properties and behavior are predictive of anhedonic states. Altogether, these experiments point to the need for increased granularity in the measurement of both behavior and neural activity, as these factors can predict the predisposition to stress-induced anhedonia.

neuroscience↗

bioRxiv2024

cfos principal cells and interneurons are strongly reactivated by sharp wave ripples

Sharp wave ripples (SWRs) reactivate hippocampal activity patterns during memory consolidation, but whether they recruit cFos engram cells is unclear. We tagged CA1 neurons activated during sequential exploration of two spatial contexts and later identified them in vivo by optotagging. We found that the cfos engram population is composed of place cells, non-place principal cells and inhibitory interneurons. cFos-tagged place cells were reused across context exposures while maintaining context specific maps. During post-behavior rest, cFos-tagged place cells and interneurons showed stronger SWR recruitment than untagged cells, with cFos identity being more closely associated with SWR modulation than firing rate features. cFos-tagged interneurons were speed- and theta-modulated, preferentially coupled to cFos-tagged place cells during SWRs, and preferentially recruited from parvalbumin and somatostatin expressing classes. After exposure to contexts outside the original tagging experience, enhanced interneuron recruitment was attenuated, whereas tagged place cells retained elevated SWR coupling. Thus, SWRs engage excitatory and inhibitory components of a cFos-tagged spatial ensemble, linking cellular engram identity to hippocampal network dynamics during memory consolidation.

neuroscience↗

bioRxiv2024

Volumetric imaging and computation to explore contractile function in zebrafish hearts

Despite advancements in cardiovascular engineering, heart diseases remain a leading cause of mortality. The limited understanding of the underlying mechanisms of cardiac dysfunction at the cellular level restricts the development of effective screening and therapeutic methods. To address this, we have developed a framework that incorporates light field detection and individual cell tracking to capture real-time volumetric data in zebrafish hearts, which share structural and electrical similarities with the human heart and generate 120 to 180 beats per minute. Our results indicate that the in-house system achieves an acquisition speed of 200 volumes per second, with resolutions of up to 5.02 {+/-} 0.54 {micro}m laterally and 9.02 {+/-} 1.11 {micro}m axially across the entire depth, using the estimated-maximized-smoothed deconvolution method. The subsequent deep learning-based cell trackers enable further investigation of contractile dynamics, including cellular displacement and velocity, followed by volumetric tracking of specific cells of interest from end-systole to end-diastole in an interactive environment. Collectively, our strategy facilitates real-time volumetric imaging and assessment of contractile dynamics across the entire ventricle at the cellular resolution over multiple cycles, providing significant potential for exploring intercellular interactions in both health and disease.

bioengineering↗

bioRxiv2024

Unveiling Nucleosome Dynamics: A Comparative Study Using All-Atom and Coarse-Grained Simulations Enhanced by Principal Component Analysis

This study investigates nucleosome dynamics using both all-atom and coarse-grained (CG) molecular dynamics simulations, focusing on the SIRAH force field. Simulations are performed for two nucleosomal DNA sequences--ASP and Widom-601--over six microseconds at physiological salt concentrations. Comparative analysis of structural parameters, such as groove widths and base pair geometries, reveals good agreement between atomistic and CG models, though CG simulations exhibit broader conformational sampling and greater breathing motion of DNA ends. Principal component analysis (PCA) is applied to DNA structural parameters, revealing multiple free energy minima, especially in CG simulations. These findings highlight the potential of the SIRAH CG force field for studying large-scale nucleosome dynamics, offering insights into DNA repositioning and sequence-dependent behavior.

biophysics↗

bioRxiv2024

Pathophysiological Implications of Nucleotide Self-Assembly: Adenine-Derived Nucleotides Aggregation in Disease Mechanisms

Adenine nucleotides, including adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate, play pivotal roles in cellular bioenergetics, nucleic acid metabolism, and signal transduction. However, their propensity to undergo self-assembly and form supramolecular aggregates under certain conditions is not well-characterized. In this study, we examined the self-assembly, aggregation, and cytotoxicity of AMP, ADP, and ATP in both fresh and aged conditions. Utilizing advanced microscopy techniques, Thioflavin T (ThT) fluorescence assays, and cross-seeding experiments, we identified oligomer formation in freshly prepared nucleotide solutions, which progressed to larger, more stable aggregates over time. The cytotoxic potential of these nucleotide aggregates was assessed using in vitro models, including human retinal pigment epithelial (RPE-1) and colorectal carcinoma (HCT-116) cell lines. Our findings demonstrate that nucleotide aggregation induces significant cytotoxic effects, particularly in aged conditions. Further investigations into bacterial toxicity models revealed similar deleterious impacts, indicating a broad-spectrum biological stress response to nucleotide aggregates. These results suggest that nucleotide self-assembly and aggregation may contribute to cellular dysfunction, offering new insights into their non-canonical roles in disease pathophysiology, potentially analogous to protein misfolding disorders.

bioengineering↗

bioRxiv2024

TRIM24 directs replicative stress responses to maintain ALT telomeres via chromatin signaling

An inability to replicate the genome can cause replication stress and genome instability. Here, we develop BLOCK-ID, a proteomic method to identify and visualize proteins at stressed replication forks. This approach successfully identified novel mediators of the replication stress response, including the chromatin acetylation reader protein TRIM24. In validating TRIM24 function, we uncovered its crucial role in coordinating Alternative Lengthening of Telomeres (ALT), a cancer-specific telomere extension pathway involving replication stress. Our data reveal that TRIM24 is directed to telomeres via a p300/CBP-dependent acetylation chromatin signaling cascade, where it organizes ALT-associated PML bodies (APBs) to promote telomere DNA synthesis. Strikingly, we demonstrate that when artificially tethered at telomeres, TRIM24 can stimulate new telomere DNA synthesis in a SUMO-dependent manner, independently of p300/CBP or PML-dependent APBs. Thus, this study identifies a TRIM24 chromatin signaling pathway required for ALT telomere maintenance.

cell biology↗

bioRxiv2024

HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signatures in vitro

Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes1. Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans2-6; however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate7,8. Here, we present a pharmacological approach to mimic human DAM in vitro by exposing different human microglia models to selected histone deacetylase (HDAC) inhibitors. We also provide an initial functional characterization of our model system, showing a specific increase of amyloid beta phagocytosis along with a reduction of MCP-1 secretion. Additionally, we report an increase in MITF expression, a transcription factor previously described to drive expression towards the DAM phenotype. We further identify CADM1, LIPA and SCIN as DAM- marker genes shared across various proposed DAM signatures and in our model systems. Overall, our strategy for targeted microglial polarization bears great potential to further explore human DAM function and biology.

neuroscience↗