Biology subjects

Gao, F.

Publications and source records attributed to Gao, F..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

AniMarkerDB: a comprehensive database for exploring cell types and marker genes in livestock and poultry at single-cell resolution

Single-cell RNA sequencing (scRNA-seq) has dramatically advanced the understanding of cellular heterogeneity. While numerous marker gene databases are available for humans and mice, a lack of systematic resources for livestock and poultry species remains, limiting progress in functional genomics, immunology, and breeding.. To address this challenge, we developed AniMarkerDB (https://animarkerdb.bio), a comprehensive and curated database dedicated to marker genes and immune-related epitopes in economically animals, including chicken, pig, and duck. AniMarkerDB integrates 7,010 marker gene across 37 tissues and 846 cell types, together with 71,442 immune epitope records from IEDB. All entries undergo rigorous literature curation, manual validation, and multi-level quality control, with standardized nomenclature and annotation to ensure data consistency and reusability. The platform supports flexible queries by species, tissue, cell type, or gene. It offers analytical tools for cross-species comparison model organisms such as human and mouse, interactive single-cell atlas visualization, and user-defined cell type annotation. Additionally, AniMarkerDB provides dynamic visualizations and export options, enabling researchers to efficiently obtain large-scale marker and epitope data for downstream applications such as infectious disease research, vaccine target design, and comparative immunology. Looking ahead, AniMarkerDB will expand species coverage and incorporate additional modalities, including single-cell atlases from healthy and disease models, establishing itself as a comprehensive and authoritative platform for animal cell biology, disease modeling, and translational research. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/682327v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@af7e7borg.highwire.dtl.DTLVardef@198d114org.highwire.dtl.DTLVardef@1c69ed2org.highwire.dtl.DTLVardef@e4fc43_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Cryoprotectants-assisted plunge freezing of thick brain tissue specimens for targeted physiologically relevant cryo-imaging in situ

In situ cryoET (cryoelectron tomography) and cryo-FIB/SEM (cryo-focused ion beam/scanning electron microscopy) volume-EM (electron microscopy) imaging provide spatiotemporal snapshots of biological systems in their near-native aqueous environment. Freezing and subsequent thinning of thick biological specimens prior to cryo-imaging is a time-consuming and challenging task that requires state-of-art methodology. As a result, cryo-imaging reports obtained from non-trivial specimens including mammalian brain tissues are scarce and their physiological relevance remains to be determined. Here, we benchmarked plunge freezing with a variety of cryoprotectants that allow for mouse brain tissue vitrification of up to about 100 microns thick and across several brain regions while keeping the tissue functional. By utilizing the knock-in (KI) mouse model with fluorescent astrocytes we have performed targeted cryo-FIB/SEM volume-EM imaging as well as targeted high-resolution cryoET imaging. Prior to cryoET, we have successfully generated lamellae in a semi-automated fashion on both LMIS (liquid metal ion source)- and plasma-based cryo-FIB/SEM instrumentation thus expanding applicability of our pipeline. We visualized the NVU (neurovascular unit) and astrocytes processes and validated the physiological relevance of our outputs based on the morphology of the corresponding cellular and subcellular features. The pipeline utilizes common vitrification setups and can be potentially extended toward alternative tissue specimens. Ultimately, we expect our approach to become an important step towards democratization of physiologically relevant in situ cryo-imaging studies.

biophysics↗

bioRxiv2025

PDLIM2 Repression: A Common Mechanism in Viral Lung Infection

BackgroundPDLIM2, a PDZ-LIM domain-containing protein expressed highest in the lung and immune cells, serves as a unique tumor suppressor and immune modulator, mainly by turning off the activation of the master transcription factors NF-{kappa}B and STAT3. While its role in cancer is established, the involvement of PDLIM2 in viral infection remains unclear. ResultsHere, we analyzed public gene expression data of blood leukocytes, bronchoalveolar lavage cells, and lung tissues from uninfected healthy humans and those infected with the respiratory virus SARS-CoV-2 or influenza. We found that PDLIM2 expression was repressed by viral infection, and notably, this repression correlated with the severity of infectious diseases. Consistently, the expression level of PDLIM2 was negatively associated with NF-{kappa}B and STAT3 activity across a diverse range of cell types, such as macrophages, monocytes, neutrophils, T cells, alveolar type 1 and 2 epithelial cells, airway epithelial cells, and fibroblasts. Accordingly, cells with low PDLIM2 expression exhibited aberrant activation of signaling pathways essential for cellular functions and immune responses. ConclusionsThese findings highlight PDLIM2 repression as a common mechanism underlying human viral infectious diseases and suggest PDLIM2 as a potential biomarker and therapeutic target for disease prognosis, prevention, and treatment.

pathology↗

bioRxiv2025

Naltrexone has variable and schedule-dependent effects on oral squamous cell carcinoma cells

Oral squamous cell carcinoma is marked by profound differences in survival between localized and disseminated disease. While at its site of origin, oral cancer is frequently treated with surgery and/or radiation, leading to approximately 70% five-year survival. In metastatic cases, chemotherapy is preferred, but drug resistance and therapy failure is common in this setting, leading to five-year survival below 40%. New therapeutic approaches are therefore needed to supplement existing chemotherapies and improve outcomes. Naltrexone, an opioid antagonist most well-known for treatment of substance abuse, has been evaluated at low doses in other contexts, including inflammation, autoimmunity, and other forms of cancer. In this study, we sought to determine if intermittent dosing of naltrexone would impact oral cancer cell survival, either as a single agent or in combination with traditional chemotherapy. We found that its effects alone were negligible, but that combination with cytotoxic drugs may have promise as a novel treatment strategy. Further study and optimization will be needed to determine if these findings will be of clinical benefit.

pharmacology and toxicology↗

bioRxiv2025

Metabolically robust autoluminescent reporters

Self-sustained luminescence can be engineered in non-luminous organisms by integrating luciferin biosynthesis pathways with the hosts metabolism. When conditionally expressed, such pathways enable non-invasive monitoring of virtually any transcriptional event, providing a wide dynamic range and high resolution. However, because light emission depends on substrate availability within the cell, autoluminescence reporters are inherently non-quantitative: signal intensity reflects both gene expression and cellular metabolism. Here, we present an approach that disentangles the contributions of gene expression and metabolism, rendering autoluminescence signals robust against metabolic perturbations. By co-expressing an engineered reference luciferase variant that uses the same substrate but emits light at a different wavelength, and monitoring the resulting colour ratio, we dramatically reduce signal variation, enabling quantitative physiological imaging amid changing metabolic activity. Our strategy is applicable across known autoluminescence pathways from bacteria and fungi.

plant biology↗

bioRxiv2025

A step towards animal models with self-sustained fungal bioluminescence

Engineering animal models with self-sustained luminescence could enable non-invasive longitudinal monitoring of molecular events in living animals. To create animal models that report physiology with autoluminescence, both luciferin biosynthesis enzymes and the luciferase need to be optimised. Previous work on engineering the autoluminescence pathway from fungi resulted in the development of nnLuz_v3, a version of Neonothopanus nambi luciferase with enhanced thermal stability. Here, we generated an nnLuz_v3 reporter of endogenous Cyp1a1 expression as a measure of aryl hydrocarbon receptor (AHR) activation, assessing the performance of nnLuz_v3 in vivo at physiologically relevant expression levels. As AHR dynamically responds to metabolic, environmental and dietary changes it provides a validated platform to assess novel luminescence approaches. In Cyp1a1-nnLuz mice bioluminescence signal was stable, allowing the generation of well-resolved luminescence images both on standard in vivo imaging equipment and consumer-grade cameras. Using mice and nematode models, we demonstrated limited oral availability of the fungal luciferin, potentially compatible with delivering the substrate via food or the microbiome. Our results are an encouraging first step in the generation of an autoluminescent mammalian model of a molecular event and encourage optimisation of other enzymes of the fungal luciferase pathway.

genetics↗

bioRxiv2025

Population-specific brain charts reveal Chinese-Western differences in neurodevelopmental trajectories

Human brain charts provide unprecedented opportunities for decoding neurodevelopmental milestones and establishing clinical benchmarks for precision brain medicine 1-7. However, current lifespan brain charts are primarily derived from European and North American cohorts, with Asian populations severely underrepresented. Here, we present the first population-specific brain charts for China, developed through the Chinese Lifespan Brain Mapping Consortium (Phase I) using neuroimaging data from 43,037 participants (aged 0-100 years) across 384 sites nationwide. We establish the lifespan normative trajectories for 296 structural brain phenotypes, encompassing global, subcortical, and cortical measures. Cross-population comparisons with Western brain charts (based on data from 56,339 participants aged 0-100 years) reveal distinct neurodevelopmental patterns in the Chinese population, including prolonged cortical and subcortical maturation, accelerated cerebellar growth, and earlier development of sensorimotor regions relative to paralimbic regions. Crucially, these Chinese-specific charts outperform Western-derived models in predicting healthy brain phenotypes and detecting pathological deviations in Chinese clinical cohorts. These findings highlight the urgent need for diverse, population-representative brain charts to advance equitable precision neuroscience and improve clinical validity across populations.

neuroscience↗

bioRxiv2025

Introducing An Argonaute-facilitated Isothermal Amplification Technology

Argonaute-facilitated targeting, which is an enzyme-mediated, high-fidelity, and highly efficient base pairing process, can be repurposed for upgrading PCR technology. An Argonaute protein derived from thermophilic Caloramator sp. (CalAgo) cleaved target dsDNA in the presence of Tte UvrD helicase at 65{degrees}C, suggesting dmCalAgo (a nuclease-inactive mutant) binding to target dsDNA in the same condition. Based on this, we designed an Argonaute-facilitated isothermal PCR platform (Isothermal Ago-PCR) through synergy of dmCalAgo, Tte UvrD helicase, and Bst DNA polymerase. Isothermal Ago-PCR realized amplification of template at 65{degrees}C. The upgrade resides in replacing primer annealing with Argonaute-facilitated targeting. Hence, Isothermal Ago-PCR not merely eliminates the reliance on complex primer design and sophisticated instruments but also achieves high-fidelity and highly efficient amplification. This platform enabled detection of low-copy templates (as few as 3 copies per reaction) within 30 minutes, achieving comparable sensitivity to qPCR while demonstrating superior amplification kinetics. This platform also demonstrated compatibility with common thermal maintenance tools. Thus, Isothermal Ago-PCR has the potential to replace qPCR with broad applicability. Details refer to our patent (China Patent CN116479095A).

biochemistry↗

bioRxiv2025

The visual system of the longest-living vertebrate, the Greenland shark

The Greenland shark (Somniosus microcephalus) is the longest-living vertebrate and inhabits the extremely dim and cold waters of the Arctic deep sea. This has led to speculations that it may have lost functional vision. Here, we present genomic, transcriptomic, histological and functional evidence that the Greenland shark retains an intact visual system well-adapted for life in dim light. Histology and in vitro opsin expression revealed visual adaptations typical of deep-sea species, including densely packed, elongated rods and a short-wavelength shift in rod visual pigment sensitivity. RNAscope confirmed the presence of essential visual cell types, such as rods, Muller glia, and bipolar, amacrine, and ganglion cells. Moreover, despite being centuries old, the examined specimens showed no signs of retinal degeneration. Using whole genome and retinal RNA-sequencing, we further show that dim-light (rod-based) vision genes are intact and robustly expressed, while many bright-light (cone-based) vision genes have become pseudogenized and/or are no longer expressed. Finally, our data suggest that efficient DNA repair mechanisms may contribute to the long-term preservation of retinal function over centuries in the Greenland shark.

evolutionary biology↗

bioRxiv2025

Altered Interpersonal Neural Synchronization during Social Interaction After Shared Excluded Experiences in Depressed Adolescents

BackgroundMajor depressive disorder (MDD) is common in adolescents, and the special development stage, during which adolescents brain and neuroendocrine system develop intensively, makes it subtly difficult to develop prevention and treatment strategies for depressed adolescents compared with depressed adults. Meanwhile, public psychosocial stressors significantly influence adolescents mental health and social interaction, rendering it essential to explore how a shared psychosocial stressor, i.e., shared excluded experiences, influences social interaction in depressed adolescents. MethodsWe designed a 4-player cyberball game to probe adolescents responses to shared excluded experiences and explore the underlying interpersonal neural synchronization (INS) with functional near-infrared spectroscopy (fNIRS). ResultsWe found that shared excluded experiences could enhance adolescents social interaction preferences but decreased INS in each pair of excluded adolescents, which indicates a reduced willingness to interact with others after the exclusion. However, no significantly different behavioral responses to the shared excluded experiences were found in depressed adolescents compared to adolescents as healthy controls (HC). Further analyses revealed that adolescents with MDD experienced more negative feelings than HC after exclusion. Of note, adolescents with MDD demonstrated stronger INS than HC, indicating the potential empathic stress in depressed adolescents. In addition, there existed altered brain-behavioral association patterns in responses to shared excluded experiences in depressed adolescents. ConclusionsIn summary, our study gives us deeper insights into how a shared psychosocial stressor impacts the INS in depressed adolescents, and it might be demonstrated that INS could be more sensitive than behavioral responses to detect social interaction deficits in depressed adolescents.

neuroscience↗

bioRxiv2025

Integrative Analysis of Single-cell and Bulk RNA Sequencing Reveals Macrophage Heterogeneity in Lyme Arthritis

IntroductionLyme arthritis (LA) is a common late-stage manifestation of Lyme disease caused by Borrelia burgdorferi (Bb) infection. Macrophages play a crucial role in LA pathogenesis, yet their heterogeneity and functional states within the arthritic microenvironment remain poorly understood. MethodsWe integrated single-cell RNA sequencing data from ankle joint tissues of Bb-infected C57BL/6 mice with bulk RNA sequencing data from both infected ankle joints and bone marrow-derived macrophages. We developed a LA mouse model and validated key findings through histopathological examination and RT-qPCR analysis. ResultsWe identified nine distinct cell types in the joint microenvironment with significant compositional shifts during disease progression. Analysis of 16,617 Macrophages/Monocytes revealed seven functionally distinct subpopulations with differential responses to infection. Pseudo-time trajectory analysis demonstrated three principal differentiation pathways from monocyte-derived macrophages toward anti-inflammatory, TNF+, and IL1b+ inflammatory phenotypes. Cell-cell communication analysis revealed significantly altered TGF-{beta} signaling networks in LA, with the Tgfb1-(Tglbr1+TgIbr2) axis playing a critical role. GSVA and pathway analyses showed metabolic reprogramming from oxidative phosphorylation toward glycolysis in macrophages during infection. Through integrated analysis and LASSO regression, we identified four characteristic genes (SIRPB1C, FABP5, MMP14, and EGR1) as potential LA biomarkers and developed a diagnostic nomogram with high predictive accuracy. ConclusionOur integrative analysis provides comprehensive insights into macrophage heterogeneity and functional plasticity in LA, identifying characteristic biomarkers and potential therapeutic targets. The metabolic reprogramming and altered TGF-{beta} signaling networks we identified may contribute to disease pathogenesis and offer new avenues for intervention strategies.

genomics↗

bioRxiv2025

Subunit specialisation in AAA+ proteins and substrate unfolding during transcription complex remodelling

Bacterial RNA polymerase (RNAP) is a multi-subunit enzyme that copies DNA into RNA in a process known as transcription. Bacteria use {sigma} factors to recruit RNAP to promoter regions of genes that need to be transcribed, with 60% bacteria containing at least one specialized {sigma} factor {sigma}54. {sigma}54 recruits RNAP to promoters of genes associated with stress responses and forms a stable closed complex that does not spontaneously isomerize to the open state where promoter DNA is melted out and competent for transcription. The {sigma}54-mediated open complex formation requires specific AAA+ proteins (ATPases Associated with diverse cellular Activities) known as bacterial enhancer-binding proteins (bEBPs). We have now obtained structures of new intermediate states of bEBP-bound complexes during transcription initiation, which elucidate the mechanism of DNA melting driven by ATPase activity of bEBPs and suggest a mechanistic model that couples the ATP hydrolysis cycle within the bEBP hexamer with {sigma}54 unfolding. Our data reveal that bEBP forms a non-planar hexamer with the hydrolysis-ready subunit located at the furthest/highest point of the spiral hexamer relative to the RNAP. ATP hydrolysis induces conformational changes in bEBP that drives a vectoral transiting of the regulatory N-terminus of {sigma}54 into the bEBP hexamer central pore causing the partial unfolding of {sigma}54, while forming specific bEBP contacts with promoter DNA. Furthermore, our data suggest a mechanism of AAA+ protein that is distinct from the hand-over-hand mechanism proposed for many AAA+ proteins, highlighting the versatile mechanisms utilized by the large protein family.

biochemistry↗

bioRxiv2024

Spatially Resolved in vivo CRISPR Screen Sequencing via Perturb-DBiT

Perturb-seq enabled the profiling of transcriptional effects of genetic perturbations in single cells but lacks the ability to examine the impact on tissue environments. We present Perturb-DBiT for simultaneous co- sequencing of spatial transcriptome and guide RNAs (gRNAs) on the same tissue section for in vivo CRISPR screen with genome-scale gRNA libraries, offering a comprehensive understanding of how genetic modifications affect cellular behavior and tissue architecture. This platform supports a variety of delivery vectors, gRNA library sizes, and tissue preparations, along with two distinct gRNA capture methods, making it adaptable to a wide range of experimental setups. In applying Perturb-DBiT, we conducted un-biased knockouts of tens of genes or at genome-wide scale across three cancer models. We mapped all gRNAs in individual colonies and corresponding transcriptomes in a human cancer metastatic colonization model, revealing clonal dynamics and cooperation. We also examined the effect of genetic perturbation on the tumor immune microenvironment in an immune-competent syngeneic model, uncovering differential and synergistic perturbations in promoting immune infiltration or suppression in tumors. Perturb-DBiT allows for simultaneously evaluating the impact of each knockout on tumor initiation, development, metastasis, histopathology, and immune landscape. Ultimately, it not only broadens the scope of genetic inquiry, but also lays the groundwork for developing targeted therapeutic strategies.

genomics↗

bioRxiv2024

Neutralization of recent SARS-CoV-2 variants by genetically and structurally related mAbs of the pemivibart lineage

Pemivibart is a monoclonal antibody therapy currently under Emergency Use Authorization for the for the pre-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents over 12 years of age with certain immunocompromised conditions. As a part of the overall monitoring strategy for the activity of pemivibart, the antibody is regularly evaluated against emerging variants of SARS-CoV-2 using pseudovirus neutralization assays. Recent clinical data from Invivyd demonstrates that the PhenoSense pseudovirus assays carried out at Monogram Biosciences have been a reliable and consistent predictor of continued pemivibart clinical activity against SARS-COV-2 variants that have predominated across the timespan that includes the CANOPY clinical trial and the post-EUA authorization period. Additionally, new potential antibodies based upon the structural framework of pemivibart are continuously under evaluation. Fifteen of these yeast-produced "pemivibart-like" antibodies were tested for neutralization activity against recent variants KP.3 and KP.3.1.1. Like pemivibart, all 15 maintained activity against KP.3.1.1, with the change in IC50 averaging 2.51-fold +/-0.7 compared to KP.3. Four pemivibart-like antibodies were also tested against the XEC variant, with the change in IC50 averaging 3.01-fold compared to KP.3. These data suggest continued activity for pemivibart and pemivibart-like antibodies against KP.3.1.1 and XEC, recent variants containing N-terminal domain modifications.

microbiology↗

bioRxiv2024

Embryonic Mast Cells Arise from Cpa3-expressing Precursors Independent of Granulocyte-Monocyte Progenitors

Most of the mast cells (MCs) in connective tissues, such as skin, are long-lived embryonic-derived immune cells that play important roles in host defense and various immunological diseases, including allergies. Their embryonic origin and ontogeny remain to be fully studied since several overlapping waves of embryonic hematopoiesis have been shown to give rise to these cells. Here, combining single-cell RNA sequencing and new genetic fate mapping models, we identified a Cpa3-expressing population sequentially appearing in the yolk sac, fetal liver, and peripheral tissues which gives rise to dermal MCs during embryonic days 11.5 to 14.5. Using in vitro differentiation and in vivo transplant methods, we identified a Ter119-F4/80- CD45+CD117+CD16/32+CD135-CD115-Ly6C-CD34lo population as potential fetal liver MC precursors. Fate mapping with Cpa3CreERT2and Zbtb16CreERT2 models, as well as the granulocyte-monocyte progenitor (GMP) models Ms4a3Cre and ElaneCre, demonstrated that MCs arise from Cpa3+ progenitors rather than Ms4a3+ or Elane+ GMPs. A corresponding population with a similar developmental trajectory was also identified in human early yolk sac and fetal liver, suggesting a conserved MC developmental program across species. These findings delineate the detailed developmental path of MCs in embryos, permitting future functional studies in immunity and development. HighlightsO_LICpa3-expressing cells in the yolk sac and fetal liver contain mast cell precursors C_LIO_LICpa3CreERT2 labels embryonic mast cells and their precursors C_LIO_LIEmbryonic mast cells arise through Cpa3+ mast cell precursors, but not Elane+/Ms4a3+ GMPs C_LIO_LIThe seeding of MCPs to embryonic skin slows down after E14.5 C_LI

immunology↗

bioRxiv2024

An all-in-one AAV vector for cardiac-specific gene silencing by an adenine base editor

ABE editing outcomes are highly variable and unpredictable, depending on various factors. Therefore, the success rate of creating targeted A*T-to-G*C conversions using ABE is not high. But utilizing ABE to target RNA splicing sites for gene silencing has a higher success rate. Another challenge for base editing in the heart is that traditional ABE is too large in size, necessitating dual AAV delivery. Whether single AAV delivery can be achieved remains to be explored. In this study, we demonstrated how the diversity of Cas9 homologs and screening of sgRNAs can facilitate cardiac base editing. Single-AAV base editing outperformed dual-AAV systems in the heart, potentially benefiting from chromatin accessibility-guided sgRNA selection. These findings have important implications for the development of more effective and predictable base editing tools for cardiac gene therapy.

molecular biology↗

bioRxiv2024

Systemic deficits in lipid homeostasis promote aging-associated impairments in B cell progenitor development

Organismal aging has been associated with diverse metabolic and functional changes across tissues. Within the immune system, key features of physiological hematopoietic cell aging include increased fat deposition in the bone marrow, impaired hematopoietic stem and progenitor cell (HSPC) function, and a propensity towards myeloid differentiation. This shift in lineage bias can lead to pre-malignant bone marrow conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), frequently setting the stage for subsequent development of age-related cancers in myeloid or lymphoid lineages. At the systemic as well as sub-cellular level, human aging has also been associated with diverse lipid alterations, such as decreased phospholipid membrane fluidity that arises as a result of increased saturated fatty acid (FA) accumulation and a decay in n-3 polyunsaturated fatty acid (PUFA) species by the age of 80 years, however the extent to which impaired FA metabolism contributes to hematopoietic aging is less clear. Here, we performed comprehensive multi-omics analyses and uncovered a role for a key PUFA biosynthesis gene, ELOVL2, in mouse and human immune cell aging. Whole transcriptome RNA-sequencing studies of bone marrow from aged Elovl2 mutant (enzyme-deficient) mice compared with age-matched controls revealed global down-regulation in lymphoid cell markers and expression of genes involved specifically in B cell development. Flow cytometric analyses of immune cell markers confirmed an aging-associated loss of B cell markers that was exacerbated in the bone marrow of Elovl2 mutant mice and unveiled CD79B, a vital molecular regulator of lymphoid progenitor development from the pro-B to pre-B cell stage, as a putative surface biomarker of accelerated immune aging. Complementary lipidomic studies extended these findings to reveal select alterations in lipid species in aged and Elovl2 mutant mouse bone marrow samples, suggesting significant changes in the biophysical properties of cellular membranes. Furthermore, single cell RNA-seq analysis of human HSPCs across the spectrum of human development and aging uncovered a rare subpopulation (<7%) of CD34+ HSPCs that expresses ELOVL2 in healthy adult bone marrow. This HSPC subset, along with CD79B-expressing lymphoid-committed cells, were almost completely absent in CD34+ cells isolated from elderly (>60 years old) bone marrow samples. Together, these findings uncover new roles for lipid metabolism enzymes in the molecular regulation of cellular aging and immune cell function in mouse and human hematopoiesis. In addition, because systemic loss of ELOVL2 enzymatic activity resulted in down-regulation of B cell genes that are also associated with lymphoproliferative neoplasms, this study sheds light on an intriguing metabolic pathway that could be leveraged in future studies as a novel therapeutic modality to target blood cancers or other age-related conditions involving the B cell lineage.

cell biology↗

bioRxiv2024

Overabundant endocannabinoids in neurons are detrimental to cognitive function

2-Arachidonoylglycerol (2-AG) is the most prevalent endocannabinoid involved in maintaining brain homeostasis. Previous studies have demonstrated that inactivating monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading 2-AG in the brain, alleviates neuropathology and prevents synaptic and cognitive decline in animal models of neurodegenerative diseases. However, we show that selectively inhibiting 2-AG metabolism in neurons impairs cognitive function in mice. This cognitive impairment appears to result from decreased expression of synaptic proteins and synapse numbers, impaired long-term synaptic plasticity and cortical circuit functional connectivity, and diminished neurogenesis. Interestingly, the synaptic and cognitive deficits induced by neuronal MAGL inactivation can be counterbalanced by inhibiting astrocytic 2-AG metabolism. Transcriptomic analyses reveal that inhibiting neuronal 2-AG degradation leads to widespread changes in expression of genes associated with synaptic function. These findings suggest that crosstalk in 2-AG signaling between astrocytes and neurons is crucial for maintaining synaptic and cognitive functions and that excessive 2-AG in neurons alone is detrimental to cognitive function.

neuroscience↗