Metabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in response to neural activity, ...remains largely uncharacterized. Here, we demonstrate that toxic fatty acids (FAs) produced in hyperactive neurons are transferred to astrocytic lipid droplets by ApoE-positive lipid particles. Astrocytes consume the FAs stored in lipid droplets via mitochondrial β-oxidation in response to neuronal activity and turn on a detoxification gene expression program. Our findings reveal that FA metabolism is coupled in neurons and astrocytes to protect neurons from FA toxicity during periods of enhanced activity. This coordinated mechanism for metabolizing FAs could underlie both homeostasis and a variety of disease states of the brain.
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•Hyperactive neurons release excess FAs in lipid particles associated with ApoE•Astrocytes endocytose neuron-derived lipid particles, delivering the FAs to LDs•Astrocytes with LDs upregulate metabolic and detoxification genes•Neural activity triggers astrocytic consumption of FAs by mitochondrial oxidation
Hyperactive neurons produce toxic fatty acids that are transferred via lipid particles to astrocytes where these fatty acids are detoxified as a means of protecting neurons during periods of enhanced activity.
Within cells, the spatial compartmentalization of thousands of distinct proteins serves a multitude of diverse biochemical needs. Correlative super-resolution (SR) fluorescence and electron ...microscopy (EM) can elucidate protein spatial relationships to global ultrastructure, but has suffered from tradeoffs of structure preservation, fluorescence retention, resolution, and field of view. We developed a platform for three-dimensional cryogenic SR and focused ion beam-milled block-face EM across entire vitreously frozen cells. The approach preserves ultrastructure while enabling independent SR and EM workflow optimization. We discovered unexpected protein-ultrastructure relationships in mammalian cells including intranuclear vesicles containing endoplasmic reticulum-associated proteins, web-like adhesions between cultured neurons, and chromatin domains subclassified on the basis of transcriptional activity. Our findings illustrate the value of a comprehensive multimodal view of ultrastructural variability across whole cells.
Cells display complex intracellular organization by compartmentalization of metabolic processes into organelles, yet the resolution of these structures in the native tissue context and their ...functional consequences are not well understood. Here we resolved the three-dimensional structural organization of organelles in large (more than 2.8 × 10
µm
) volumes of intact liver tissue (15 partial or full hepatocytes per condition) at high resolution (8 nm isotropic pixel size) using enhanced focused ion beam scanning electron microscopy
imaging followed by deep-learning-based automated image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese mice and found substantial alterations, particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural reorganization characterized by marked disorganization of stacks of ER sheets
and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes by monitoring the effects of experimental recovery of the subcellular organization on cellular and systemic metabolism. We conclude that the hepatic subcellular organization of the ER architecture are highly dynamic, integrated with the metabolic state and critical for adaptive homeostasis and tissue health.
Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Here, we describe a synapse between axons and primary cilia: the axo-ciliary synapse. Using enhanced ...focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered synapses between brainstem serotonergic axons and the primary cilia of hippocampal CA1 pyramidal neurons. Functionally, these cilia are enriched in a ciliary-restricted serotonin receptor, the 5-hydroxytryptamine receptor 6 (5-HTR6). Using a cilia-targeted serotonin sensor, we show that opto- and chemogenetic stimulation of serotonergic axons releases serotonin onto cilia. Ciliary 5-HTR6 stimulation activates a non-canonical G
-RhoA pathway, which modulates nuclear actin and increases histone acetylation and chromatin accessibility. Ablation of this pathway reduces chromatin accessibility in CA1 pyramidal neurons. As a signaling apparatus with proximity to the nucleus, axo-ciliary synapses short circuit neurotransmission to alter the postsynaptic neuron's epigenetic state.
There has been no previous study on the efficacy of the thoracic radiotherapy (TRT) in oligometastatic or polymetastatic extensive stage small-cell lung cancer (ES-SCLC) to the overall survival (OS). ...In a group of 270 ES-SCLC cases retrospective study, 78 patients (28.9%) had oligometastases and 192 (71.1%) had polymetastases, among which 51 oligometastatic patients (65.4%) and 93 polymetastatic patients (51.6%) received TRT. Propensity score matching (PSM) was utilized. The 2-year OS, progression free survival (PFS) and local control (LC) in oligometastatic and polymetastatic patients were 22.8% and 4.5% (p < 0.001), 12.0% and 3.8% (p < 0.001), and 36.7% and 6.1% (p < 0.001), respectively. The 2-year OS in oligometastatic patients with the chemotherapy + radiotherapy and chemotherapy alone were 25.2% and 12.7% (p = 0.002), in contrast to 10.0% and 6.8% (p = 0.030) in polymetastatic patients. The estimated hazard ratios for survival were 2.9 and 1.7 for both oligometastatic and polymetastatic patients with radiotherapy. The polymetastatic group has a lower LC (6.1% v.s. 36.7%, (p < 0.001)), due to polymetastases patients receiving involved-sites radiotherapy with low dose schemas. TRT improved OS of patients with oligometastases and polymetastases. Our study demonstrated that aggressive TRT might be a suitable addition of chemotherapy when treating ES-SCLC patients with oligometastases and polymetastases.
This work attempted to investigate the creep behavior of a 7075 aluminum alloy in spray formed and extruded (SFEed) and peak aged (PAed) states by equivalent stress. Arrhenius model and ...Mukherjee-Bird-Dorn (MBD) model were used to calculate creep parameters. The effects of applied stress or equivalent stress on the creep deformation of SFEed and PAed alloys were discussed and compared. The results showed that the equivalent stress could reasonably evaluate the creep resistance of 7075 Al alloys from the aspects of the steady-state creep rate, creep mechanism and dominate deformation texture, except creep rupture life. Under close equivalent stress, the PAed alloys exhibited superior steady-state creep rates and inferior creep rupture life to the SFEed alloys. The Arrhenius model and MBD model had appropriate ranges of temperature and applied stress to estimate and predict steady-state creep rates, and the accuracy of the MBD model was significantly superior. The stress exponents are computed as 7.03–7.24 for SFEed alloy and 8.11–8.62 for PAed alloy, and the tensile creep mechanism of SFEed and PAed alloys was both dislocation creep. The creep plastic deformation at 0.45–0.65Tm is processed along Cu texture orientation by dislocation climbing rather than S texture. The higher temperature and equivalent stress promote the Cu texture intensity. The applied stress or equivalent stress initiates the slipping and climbing of dislocations, and facilitates the transformation of dominant deformation texture. The main factor that affects grain boundary migration on creep deformation is grain boundary energy rather than stress or equivalent stress.
Pulsed electric current is used to inhibit the erosion of rare earth-bearing molten steel to refractory by interfering with its interface reaction. The refractory samples are eroded by molten steel ...for 5–30 min, and the average thickness of the erosion layer increases by 397% from 160 μm to 795 μm. However, the average thickness of the erosion layer only increases by 40% from 150 to 210 μm under the action of pulsed electric current. The desiliconization and oxidation of Ce/La at interface lead to a loose and porous erosion layer and the formation of initial deposits CeAlO
3
/LaAlO
3
and CeAl
11
O
18
/LaAl
11
O
18
. The adhesion of inclusions to the deposits leads to an increase in the thickness of the erosion layer. However, the pulsed electric current inhibits the desiliconization and oxidation of RE, thereby forming a Si-rich amorphous phase, which coats on refractory surface and acts as a protective film to reduce further erosion of the refractory by the molten steel. As a result, the refractory material forms a dense erosion layer and a smooth surface under the action of pulsed electric current.
Modern morphological and structural studies are coming to a new level by incorporating the latest methods of three-dimensional electron microscopy (3D-EM). One of the key problems for the wide usage ...of these methods is posed by difficulties with sample preparation, since the methods work poorly with heterogeneous (consisting of tissues different in structure and in chemical composition) samples and require expensive equipment and usually much time. We have developed a simple protocol allows preparing heterogeneous biological samples suitable for 3D-EM in a laboratory that has a standard supply of equipment and reagents for electron microscopy. This protocol, combined with focused ion-beam scanning electron microscopy, makes it possible to study 3D ultrastructure of complex biological samples, e.g., whole insect heads, over their entire volume at the cellular and subcellular levels. The protocol provides new opportunities for many areas of study, including connectomics.
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