Biology subjects

Qu, J.

Publications and source records attributed to Qu, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Toward Crosstalk-free All-optical Interrogation of Neural Circuits

All-optical interrogation, based on high-resolution two-photon stimulation and imaging, has emerged as a potentially transformative approach in neuroscience, allowing for the simultaneous precise manipulation and monitoring of neuronal activity across various model organisms. However, the unintended excitation of light-gated ion channels such as channelrhodopsin (ChR) during two-photon calcium imaging with genetically encoded calcium indicators (GECIs) introduces artifactual neuronal perturbation and contaminates neural activity measurements. In this study, we propose an active pixel power control (APPC) approach, which dynamically adjusts the imaging laser power at each scanning pixel, to address the challenge. We aim to achieve simultaneous two-photon optogenetic manipulation and calcium imaging with a single femtosecond laser, while minimizing the crosstalk between manipulation and imaging. To study this technologys capabilities, we applied it to the larval zebrafish brain in vivo. Our results demonstrate that the APPC approach preserves GECI signal quality while suppressing optogenetic artifacts significantly. This enhances the accuracy of neural circuit dissection and advances the precision of all-optical interrogation, offering a robust framework for probing neural circuit dynamics and causality in vivo with high fidelity, potentially across various model organisms. Importantly, this technology can be seamlessly integrated with commonly used two-photon microscope systems in laboratories worldwide.

neuroscience↗

bioRxiv2025

β2AR Agonists Sustain Thermogenesis and Leanness via Sympathofacilitation

Human thermogenesis depends on {beta}2-adrenoceptors ({beta}2AR) expressed in thermogenic adipocytes, which are activated by norepinephrine released from sympathetic neurons. Whether {beta}2AR also modulates thermogenesis via direct presynaptic action within sympathetic neurons has remained unclear. Here, we identify Adrb2 expression in human and rodent cervical sympathetic neurons. {beta}2AR agonism exerts neurotrophic effects and facilitates cholinergic responsiveness in mouse sympathetic neurons, indicating a sympathofacilitatory role. Selective deletion of {beta}2AR in sympathetic neurons leads to impaired nerve activity in brown adipose tissue, sympathetic neuropathy, worsened fasting-induced hypothermia, and progressive obesity in chow-fed mice--without changes in food intake. These findings uncover a presynaptic role for {beta}2AR in sustaining thermogenesis and regulating adiposity, suggesting sympathofacilitation as a therapeutic avenue for obesity. HighlightsO_LIHuman and mouse cervical sympathetic neurons express adrenoceptor beta 2 (Adrb2) C_LIO_LI{beta}2-adrenoceptor ({beta}2AR) activation is neurotrophic and facilitates sympathetic neuronal excitability C_LIO_LILoss of {beta}2AR in sympathetic neurons leads to neuropathy in brown adipose tissue and reduced sympathetic activity C_LIO_LIDeletion of {beta}2AR in sympathetic neurons exacerbates fasting-induced hypothermia and promotes obesity independently of food intake C_LI

physiology↗

bioRxiv2025

An Antibody Cocktail-Based Immunoaffinity-LC-MS Method Enabled Ultra-Sensitive and Robust Quantification of Circulating Proinsulin Proteoforms and C-peptide

Accurately measuring circulating proinsulin proteoforms is crucial for clinical investigation of diabetes, but was previously not feasible owing to limited assay specificity/sensitivity. Here we devised a highly sensitive LC-MS-based strategy to quantify intact proinsulin, des-31,32 and des-64,65 proinsulin, and C-peptide in circulation. The method involves: i)quantitative, robust affinity capture using an optimized antibody cocktail, eliminating the severe quantitative bias across multiple proteomes typically introduced when using a single antibody; ii)Lys-C digestion producing unique signature peptides for each proteoform, and iii)trapping-nano-LC coupled with FAIMS/dCV-MS for an ultra-sensitive analysis. The selective trapping/delivery ensured sensitive/selective analysis of the targets while achieving excellent analytical robustness that is critical for clinical assays, and the FAIMS/dCV substantially reduces baseline noise/interferences, further enhancing S/N. The assay achieved exceptional sensitivity, with serum LOQs of 1.7, 2.3, and 3.6 pg/mL respectively for intact-proinsulin, des-31,32 and des-64,65, representing the first assay capable of sensitively quantifying these major circulating proinsulin proteoforms. We applied this assay to 78 subjects, including autoantibody positive(n=20) and new-onset type-1-diabetes(T1D, n=19) with respective age/sex/BMI-matched controls, enabling the first accurate profiling of proinsulin proteoforms in clinical groups. The assay results demonstrated a clear separation of control and new-onset T1D groups that a parallel total-proinsulin ELISA assay fails to capture. Furthermore, distinct expression patterns in relative abundance ratios among proteoforms were observed across clinical groups. This assay may provide valuable insights into the {beta}-cell functions and the onset/progression of diabetes and other associated conditions. Moreover, the strategy is broadly applicable to targeted measurement of other biomarker proteoforms.

biochemistry↗

bioRxiv2025

Leveraging Dynamic Stability to Infer Regulation in Protein-Protein Interaction Networks: A Study of Infectious Vulnerability in COPD.

The fourth leading cause of death in the US, Chronic Obstructive Pulmonary Disease (COPD) is punctuated by frequent viral and bacterial infections causing severe acute exacerbations (AECOPD) and increased mortality. In previous work we have shown that altered immune cell signaling may confer increased and persistent susceptibility to infection. Here we continue this investigation by conducting broad-spectrum proteomic profiling of circulating white blood cells to assemble an empirical protein-protein interaction network associated with frequency of infectious exacerbation. In a novel extension of conventional cross-sectional data analyses, we translate these undirected protein-protein interactions into candidate regulatory relationships with both direction and mode of action. The latter are inferred by formulating and solving a constraint satisfaction problem (SAT) whereby predicted dynamic behaviors of any valid regulatory network must support the expected persistent nature of low and high vulnerability phenotypes. Solving this SAT problem produced a set of competing candidate protein regulatory network architectures and signalling rules that unanimously highlighted several novel candidate pathway elements involved in oxidative stress response. Analysis of the overall dynamics supported by these networks, again supported the hypothesis that progression beyond an immune tipping point may confer persistent susceptibility to infection and that this may constitute a stable phenotype or regulatory trap in COPD characterized by a reactive oxygen cascade. HIGHLIGHTSO_LIInfectious vulnerability phenotypes in COPD may represent immune regulatory traps. C_LIO_LIA 15-protein oxidative stress response interactome offers a phenotypic signature. C_LIO_LIHomeostasis in cross-sectional data can support inference of co-regulatory actions. C_LIO_LI8 of 11 documented regulatory actions recovered in candidate model majority vote C_LIO_LI17 new candidate protein co-regulatory actions proposed unanimously by all models. C_LI

systems biology↗

bioRxiv2025

Rapid adaptive optics enabling near noninvasive high-resolution brain imaging in awake behaving mice

High-resolution imaging under physiological conditions is essential for studying biological mechanisms and disease processes. However, achieving this goal remains challenging due to optical aberrations and scattering from heterogeneous tissue structures, compounded by motion artifacts from awake animals. In this study, we developed a rapid and accurate adaptive optics system called multiplexing digital focus sensing and shaping (MD-FSS) for deep-tissue multiphoton microscopy. Under two-photon excitation, MD-FSS precisely measures the aberrated point spread function in approximately 0.1 s per measurement, effectively compensating for both aberrations and scattering to achieve subcellular resolution in deep tissue. Using MD-FSS integrated with two-photon microscopy, we achieved high-resolution brain imaging through thinned or optically cleared skull windows, two near noninvasive methods to access mouse brain, reaching depths up to 600 m below the pia in awake behaving mice. Our findings revealed significant differences in microglial functional states and microvascular circulation dynamics between awake and anesthetized conditions, highlighting the importance of studying brain function in awake mice through noninvasive methods. We captured functional imaging of fine neuronal structures at subcellular level in both somatosensory and visual cortices. Additionally, we demonstrated high-resolution imaging of microvascular structures and neurovascular coupling across multiple cortical regions and depths in the awake brain. Our work shows that MD-FSS robustly corrects tissue-induced aberrations and scattering through rapid PSF measurements, enabling near-noninvasive, high-resolution imaging in awake, behaving mice.

bioengineering↗

bioRxiv2025

Structural insights into the remodeled RNA polymerase II complex on an RNA template

DNA-dependent RNA polymerases (DdRPs) recognize not only DNA but also RNA templates. This RNA-dependent RNA polymerase (RdRP) activity is exploited by viroids in plants and human hepatitis delta virus in animals. A major knowledge gap exists regarding the molecular basis conferring this RdRP activity. Here, we provide evidence supporting the reorganization of the 12-subunit Pol II to 7-subunit in vivo for PSTVd transcription. Rpb4, Rpb5, Rpb6, Rpb7, and Rpb9 are not involved in PSTVd transcription in planta. A splicing variant of transcription factor IIIA with seven zinc finger domains (TFIIIA-7ZF) aids the remodeled Pol II in transcribing PSTVd. Using AlphaFold3, the structure of the remodeled Pol II with PSTVd RNA and TFIIIA-7ZF was generated. The predicted structure and experimental data both show that the N-terminus of TFIIIA-7ZF binds to the left terminal domain of PSTVd, while the C-terminus interacts with Rpb2. Interestingly, AlphaFold3 also predicts the bending at PSTVd loop 8 in the TFIIIA-7ZF/PSTVd complex. Replacing this loop 8 with a rigid double-stranded conformation impairs the TFIIIA-7ZF/PSTVd interaction. Altogether, our demonstrate an active form of heterogenous organization of the essential Pol II enzyme in vivo and provide structural insights into the organization of Pol II transcription complex on RNA template.

molecular biology↗

bioRxiv2025

Environmental stress sensitivity determines bacterial Mn(II) oxidation

Bacterial Mn(II) oxidation is a widespread and ecologically significant process, with Mn oxides playing essential roles in biogeochemical cycling and environmental remediation. However, the environmental cues that initiate this microbial activity remain enigmatic. In this study, a spontaneous mutant was isolated from the previously characterized Arthrobacter strain that exhibited autonomous Mn(II)-oxidizing capacity, in contrast to the parental strain, which required cocultivation with other bacteria to initiate Mn(II) oxidation1. Comparative transcriptomic analysis suggested that a gene system encoding an environmental stress-sensing receptor controlled the transcription of boxA, a Mn(II)-oxidizing gene. These findings indicate that two conditions are required for bacterial Mn(II) oxidation: the presence of a Mn(II)-oxidizing gene and an environmentally responsive regulatory system capable of activating its expression. Based on this knowledge, eight additional bacterial strains were isolated that triggered Arthrobacter Mn(II) oxidation. Transcriptomic profiling revealed a robust positive correlation between boxA expression and genes encoding two-component signal transduction systems. Given their widespread distribution (approximately 23% of environmental bacterial genomes harbor Mn(II)-oxidizing gene homologs2) and constant exposure to diverse biotic and abiotic stressors, these bacteria are likely to undergo frequent Mn(II) oxidation triggered by microbial interactions or chemical signals. This study provides critical mechanistic insight into the environmental regulation of bacterial Mn(II) oxidation, addressing a longstanding gap in understanding its natural occurrence.

microbiology↗

bioRxiv2025

Integrated Classification of Cortical Cells and Quantitative Projectomic Mapping Unveil Organizational Principles of Brain-Wide Connectomes at Single Cell Level

Molecularly defined cortical cell types have recently been linked to whole neuronal morphology (WNM), particularly those characterized by whole-brain-wide projections, such as intratelencephalic (IT), extratelencephalic (ET), and corticothalamic (CT) neurons. In contrast, classical morphological classifications (e.g., tufted TPC, small tufted SPC, and stellate SSC) are based primarily on local dendrosomatic and axonal structures, especially apical dendrites. This study bridges these perspectives by establishing a new neuronal taxonomy, analyzing the connectomes of defined cortical cell types, and comparing them with those obtained from bulk anterograde injections. Neurons were sparsely labeled via tamoxifen-inducible Cre lines with GFP reporters, and 1,419 WNM cells were comprehensively reconstructed with Vaa3D-TeraVR from [~]15 areas across six functional regions of molecularly labeled brains imaged with 2p-fMOST. These cells were newly classified by integrating current molecular-WNM and classical morphological perspectives, with sample size augmented by 1,455 publicly available WNM cells reconstructed from the Mouse-Light project and CEBSIT. This effort defined ten combined molecular-WNM-classical morphological cell types: L5ET_TPC, L6CT_NPC, L6b_HPC, and seven IT types--L2/3IT_TPC, L4IT_SSC, L4IT_UPC, L4IT_TPC, L5IT_SPC, L6IT_IPC, and L6IT_car3PC. Clustering, quantitative analyses and random Forest classifier objectively validated these types and revealed their distinct connectomes, along with convergent, topographic, and hierarchical organizations across their projection brain regions. At the single-cell level, multiple organizational principles governing cortico-cortical (C-C) and cortico-subcortical (C-subC) connectomes emerged with unprecedented detail, offering a precise GPS-like tool for in vivo recordings and robust datasets for neuronal network modeling. Comparisons with bulk anterograde injection data underscored the limitations of traditional methods in identifying projection targets. Overall, our approach provides significant insights into cortical circuitry and elucidates the complex interplay between neuronal molecular identity, whole morphology, and classical morphological classification.

neuroscience↗

bioRxiv2025

Autism-associated Scn2a haploinsufficiency disrupts in vivo dendritic signaling and impairs flexible decision-making

SCN2A is a high-confidence risk gene for autism spectrum disorder. Loss-of-function mutations in Scn2a reduce dendritic excitability in neocortical pyramidal cells. However, the impact of Scn2a haploinsufficiency on dendritic signaling in vivo, particularly during behavior, is unknown. In this study, we used two-photon microscopy to image dendritic calcium transients in deep layer pyramidal cells in the mouse medial frontal cortex. Scn2a+/- mice had diminished coupling between apical and proximal dendritic compartments. Pyramidal tract neurons had abnormal event rates, while intratelencephalic neurons had compartment-specific alterations indicative of diminished dendritic integration. In a matching pennies task, Scn2a+/- mice were inflexible in the face of changing competitive pressure. Apical dendritic tuft in IT neurons typically encoded reward and strategy, but these task-specific representations were altered in Scn2a+/- mice. Collectively, the findings demonstrate that Scn2a haploinsufficiency weakens dendritic integration in vivo and disrupts the dendritic encoding of decision variables, potentially contributing to the cognitive rigidity in autism spectrum disorder.

neuroscience↗

bioRxiv2024

A Comprehensive Assessment of Methylation-Based Age Prediction Methods

DNA methylation (DNAm) clock is widely used to measure biological age, helping to identify key biomarkers associated with aging, infer the progression of aging, and have promise for elucidating, delaying, or even reversing aging. During the past decade, a large number of epigenetic clocks have been developed. However, they are decentralized, with applicable scopes overlapping. We benchmark 15 of these methods on 142 Illumina DNAm array datasets in five criteria and analyze the biological significance of CPGs about aging and overlapping. There are many exciting commons in models performance. We found the optimal model closely related to the numbers and characteristics of the training data. We provided a comprehensive assessment process to guide DNAm clock research at (https://dnamclock.com), the corresponding data and evaluation pipeline are freely available (https://github.comyNENUBioCompute/MethylationEvaluation), this study will aid in the development of improved tools designed to analyze increasingly large DNAm datasets.

bioinformatics↗

bioRxiv2024

The piRNA pathway mediates transcriptional silencing of LTR retrotransposons in the soma and germline of Aedes mosquitoes

The PIWI-interacting RNA (piRNA) pathway preserves genomic integrity by suppressing transposable elements in animal germlines. Despite its well-established function in the animal germline, piRNAs and PIWI proteins are expressed in somatic tissues across arthropod species, and their functions outside the gonads remain poorly understood. Aedes albopictus mosquitoes express four PIWI genes, Piwi4, Piwi5, Piwi6 and Ago3, in both gonadal and somatic tissues. Here, we generated Piwi6 knockout Ae. albopictus cell lines and observed a substantial upregulation of Long Terminal Repeat (LTR)-retrotransposons, including a full-length endogenous retrovirus that we named AalERV1. Nascent RNA-sequencing and CUT&Tag analyses revealed that Piwi6 silences AalERV1 transcriptionally by guiding the deposition of the repressive H3K9me3 histone mark. Consistently, Piwi6 localized to both the cytoplasm and nucleus, with sequences in the intrinsically disordered region guiding nuclear translocation. Reintroduction of full-length GFP-Piwi6, but not a mutant GFP-Piwi6 defective in nuclear localization, rescued AalERV1 derepression in Piwi6 knockout cells. Importantly, the control of AalERV1 was recapitulated in vivo as Piwi6 knockdown increased AalERV1 expression in both ovaries and somatic tissues of Ae. albopictus mosquitoes. These results establish Aedes mosquitoes as a model to study nuclear PIWI functions and suggest that somatic piRNA-mediated transposon silencing is evolutionarily conserved across arthropod species.

molecular biology↗

bioRxiv2024

A Wearable Mindfulness Brain-Computer Interface for Alleviating Car Sickness

Car sickness, an enormous vehicular travel challenge, affects a significant proportion of the population. Pharmacological interventions are limited by adverse side effects, and effective nonpharmacological alternatives remain to be identified. Here, we introduce a novel attention shifting method based on a closed-loop, artificial intelligence (AI)-driven, wearable mindfulness brain-computer interface (BCI) to alleviate car sickness. As the user performs an attentional task, i.e., focusing on breathing as in mindfulness, with a wearable headband, the BCI collects and analyses electroencephalography (EEG) data via a convolutional neural network to assess the users mindfulness state and provide real-time audiovisual feedback. This approach might sustainedly shift the users attention from physiological discomfort towards the BCI-based mindfulness practices, thereby mitigating car sickness symptoms. The efficacy of the proposed method was rigorously evaluated in two real-world experiments, namely, short and long car rides, with a large cohort of more than 100 participants susceptible to car sickness. Remarkably, over 83% of the participants rated the BCI-based attention shifting as effective, with significant reductions in car sickness severity, particularly in individuals with severe symptoms. Furthermore, EEG data analysis revealed a neurobiological signature of car sickness, which provided mechanistic insights into the efficacy of the BCI-based attention shifting for alleviating car sickness. This study proposed the first large-scale validated, nonpharmacological and wearable intervention method and system for car sickness, with the potential to transform the travel experiences of hundreds of millions of people suffering from car sickness, which also represents a new application of BCI technology.

bioengineering↗

bioRxiv2024

Chlorobaculum tepidum Outer Membrane Vesicles Are Likely a Significant Route for Biogenic Sulfur Transport.

Outer membrane-derived vesicles (OMVs) have been studied in different phyla of Gramnegative bacteria, most extensively in the Pseudomonadota, where they have been shown to participate in diverse biological and environmental processes. To date, the production of OMVs has not been reported in the Chlorobiaceae within the phylum Chlorobiota. Chlorobaculum. tepidum is the model organism for the Chlorobiaceae that synthesizes and consumes insoluble extracellular sulfur (S(0)) globules by an unknown mechanism. Here, we report evidence implicating outer membrane vesicles in biogenic S(0) globule synthesis. We demonstrate that Cba. tepidum secretes OMVs in the extracellular milieu, and that OMV concentration and size vary with growth conditions, particularly sulfide concentration. A core of 31 proteins involved in diverse biological processes such as cell wall biogenesis, inorganic ion transport and metabolism were found to be shared between OMVs, extracellular S(0) globules and Cba. tepidum intact cells. Multiple analytical methods indicated that OMVs contain S(0) and that OMVs and biogenic S(0) globules share protein and polysaccharide signatures, including lipooligosaccharides. Together these lines of evidence indicate that Cba. tepidums OMVs are one component of sulfur transport between cells and extracellular sulfur globules. IMPORTANCEAll living cells must exchange material with their environment while maintaining cellular integrity. This is a particular challenge for materials that are not water soluble, yet many bacteria utilize insoluble materials for energy conservation and as nutrients for growth. Here we show that Cba. tepidum makes outer membrane vesicles and that these vesicles are likely involved in the exchange of material with extracellular elemental sulfur globules formed and consumed by Cba. tepidum as part of its energy metabolism based on oxidizing reduced sulfur compounds like hydrogen sulfide. These data expand our basic understanding of Cba. tepidums metabolism. As elemental sulfur is an industrial by-product with a limited number of uses, the information here may help enable the use of additional sulfur compounds by Cba. tepidum to drive the synthesis of biomass and/or specialty biochemicals from waste elemental sulfur by this autotrophic bacterium.

microbiology↗

bioRxiv2024

Integration of binocular vision and motor state to promote prey pursuit

Most animals with two eyes combine the inputs to achieve binocular vision, which can serve numerous functions, and is particularly useful in hunting prey. However, the mechanisms by which visual information from the two eyes are combined remain largely unknown. Here, we designed a device to reversibly occlude the eyes of a head-fixed zebrafish larva, and used large-scale volumetric two-photon imaging to identify binocular neurons that respond to prey stimuli. We found these binocular prey-responsive neurons (bino-PRNs) were primarily located in three areas, the pretectum, thalamus, and nucleus isthmi. We then characterized the bino-PRNs functional properties, and found that their left and right eye receptive fields are offset to varying degrees, which would correspond to objects at naturalistic hunting distances for a larva with converged eyes. We also found that bino-PRNs have a significantly greater response in hunting trials, which could be the result of an eye convergence-related corollary discharge. We then optogenetically induced prey capture eye and tail movements, and found that this hunting command activates prey responsive neurons in the pretectum, thalamus, and nucleus isthmi. These findings indicate that bino-PRNs receive visual and motor input that would allow them to encode prey position in three dimensions.

neuroscience↗

bioRxiv2024

Memorize multiple phase pattern attractors in nonlinear coupled oscillators dynamic via heterogeneous connectivity strength

Whole brain neural oscillation activities exhibit multiple wave patterns and seem to be supported by the common circuit network structure. We proposed a Hebbian-like Kuramoto model based entirely on heterogeneous connectivity strength rather than phase delay, which encodes the multiple phase patterns as attractors. We systematically investigated how the model dynamic landscape influenced by attractors and their corresponding eigenvalues, as well as how to control the stability of equilibrium points and the occurrence of high dimension bifurcations. This framework enables us to reproduce the dominant wave activity components in human brain functional MRI signal, and provides a canonical model for the multi body physical system spatio-temporal pattern attractor dynamics.

neuroscience↗

bioRxiv2024

Temporal-spatially metabolic reprogramming rewires the H3K27ac landscape to enable the initiation of liver regeneration

The liver possesses extensive regenerative capacity. Nevertheless, the most proximal events driving the transition from quiescent to proliferative hepatocytes remain largely elusive. Using the combination of spatiotemporal metabolomics and transcriptomics, our study mapped out the temporal-spatial landscape of metabolic reprogramming, epigenetic remodeling, and transcriptomic rewiring from 3 to 12 hours post-partial hepatectomy. Specifically, we identified a profound metabolic shift towards hyperactive fatty acid oxidation (FAO) and suppressed phospholipid biosynthesis during the preparation phase of liver regeneration, which were surprisingly reversed afterwards. FAO-dependent accumulation of Acetyl-CoA particularly remodeled H3K27ac landscape. These metabolic reprograming and epigenetic regulation were spatially specific, aligning with the zonation of hepatocyte proliferation. Blocking FAO in etomoxir-treated or hepatocyte-specific Cpt1a knockout mice, suppressing Acetyl-CoA biosynthesis, and inhibiting histone acetyltransferase all resulted in lethal liver regeneration deficiency. CUT&Tag analysis further revealed that the reshaping of H3K27ac profiles favored the transcription of genes associated with cell cycle transition and mitosis, and rewired the metabolic gene network. Collectively, we highlight a previously underappreciated role of FAO in epigenetic remodeling that is essential for the initiation of liver regeneration, offering exciting opportunity for the rescue of regeneration-deficient livers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC="FIGDIR/small/602368v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@8dd836org.highwire.dtl.DTLVardef@6ddb27org.highwire.dtl.DTLVardef@4f1e49org.highwire.dtl.DTLVardef@4d7afe_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Inhibition of serine racemase prevents diabetic retinopathy

Retinal diabetic neuropathy (RDN) precedes retinal microvascular pathology in diabetic retinopathy (DR), but the therapy by antagonizing RDN to stall DR is rare. Emerging evidence including ours suggest that serine racemase (SRR) drives DR at least by promoting RDN. Thus, we explore the therapy by antagonizing SRR to stall and treat DR. We herein indicate that inhibition of SRR by oral gavage of l-aspartic acid {beta}-hydroxymate (L-ABH), a competitive inhibitor of SRR, mitigated photoreceptor dysfunction, loss of retinal ganglion cells (RGC) and retinal endothelial cell and pericyte in db/db mice, a type II diabetes model. To dissect the mechanism, intravitreal injection of L-ABH mitigates glutamate-induced neurotoxicity in the retina. In the whole body, gastrointestinal-based delivery of L-ABH maintained euglycemia and improved glucose tolerance either in db/db mice or in diet-induced obesity mice. In conclusion, inhibition of SRR prevented retinal neurovascular abnormalities in diabetic animals through executing neuroprotection in the retina and maintaining glucose homeostasis in the system. Our study reveals a novel strategy to prevent DR.

biochemistry↗

bioRxiv2024

Microglial-Mediated Prevention of Axonal Degeneration in the Injured Spinal Cord: Insights from an In Vivo Imaging Study

Microglia, the primary immune cells in the central nervous system, play a critical role in regulating neuronal function and fate through their interaction with neurons. Despite extensive research, the specific functions and mechanisms of microglia-neuron interactions remain incompletely understood. In this study, we demonstrate that microglia establish direct contact with myelinated axons at Nodes of Ranvier in the spinal cord of mice. Under normal physiological conditions, microglia-node contact occurs in a random scanning pattern and is associated with neuronal activity. However, in response to axonal injury, microglia rapidly transform their contact into a robust wrapping form, preventing acute axonal degeneration from extending beyond the nodes. This neuroprotective wrapping behavior of microglia is dependent on the function of their P2Y12 receptors, which may be activated by ATP released through axonal volume-activated anion channels at the nodes. Additionally, voltage-gated sodium channels (NaV) contribute to the interaction between nodes and glial cells following injury, and inhibition of NaV delays axonal degeneration. Through in vivo imaging, our findings reveal a neuroprotective role of microglia during the acute phase of spinal cord injury, achieved through a novel form of neuron-glia interaction.

neuroscience↗