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In neuroinflammation, distinguishing microglia from macrophages and identifying microglial-specific biomarkers in peripheral blood pose significant challenges. This study comprehensively profiled the extracellular vesicles (EVs) of microglia and macrophages, respectively, revealing co-expressed EVs with UCHL1 and CX3CR1 as EVs derived specifically from microglia in human blood. After extensive validation, using optimized nano flow cytometry, we evaluated plasma CX3CR1 + /UCHL1 + EVs across clinical cohorts [multiple sclerosis (MS), HTLV-1 associated myelopathy (HAM), Alzheimer’s disease (AD), and Parkinson’s disease (PD)], along with established neurodegenerative markers (NMDAR2A and NFL). The findings discovered a notable rise in CX3CR1 + /UCHL1 + EVs in MS, particularly heightened in HAM, in contrast to controls. Conversely, AD and PD exhibited unaltered or diminished levels of microglial EVs. An integrated model of CX3CR1 + /UCHL1 + , NMDAR2A + , and NFL + EVs demonstrated promising diagnostic potential for distinguishing MS from controls and HAM. As to the disease duration, CX3CR1 + /UCHL1 + EVs increased in the initial five years of MS, stabilizing thereafter, whereas NMDAR2A + and NFL + EVs remained stable initially but increased significantly in the subsequent five years, suggesting their correlation with disease duration. This study uncovers unique blood microglial EVs with potential as biomarkers for MS diagnosis, differentiation from HAM, and correlation with disease duration.

Neuroinflammation is a core pathological process in multiple central nervous system diseases. Although positron emission tomography (PET) targeting the translocator protein (TSPO) (e.g., ¹⁸F-DPA-714) is widely used for in vivo inflammatory imaging, the cellular heterogeneity and functional states underlying its imaging signals remain unclear, severely limiting its mechanistic research and clinical translational value. This study used the multifunctional fluorescent TSPO probe (Cy5-PEG3-DPA714) to establish a multidimensional decoding framework that enables systematic analysis of the TSPO signal in neuroinflammation across in vivo, tissue, and single-cell levels. Multiple animal models demonstrated the probe’s ability to dynamically monitor acute and chronic neuroinflammation noninvasively in vivo. Histopathology confirmed that the TSPO signal mainly comes from activated Iba1 + microglia. Using the probe’s fluorescence properties, we effectively isolated specific microglial subpopulations with distinct TSPO signaling profiles via flow cytometry. Single-cell analysis revealed that the TSPO signal is specifically enriched in a microglia subpopulation with TSPO probe high . Importantly, this subpopulation shares features with disease-associated microglia (DAM), exhibiting a robust pro-inflammatory phenotype and significant metabolic reprogramming. Furthermore, we found that TSPO probe high microglia are highly dependent on the Colony Stimulating Factor 1 Receptor (CSF1R) signal pathway, and selective elimination using the CSF1R inhibitor (PLX3397) reduces neuroinflammation. This study systematically decodes the TSPO signal in neuroinflammation through a multimodal approach, providing novel insights and tools for precision therapeutic strategies targeting specific pathological microglia subpopulations.

Objective Human T‐cell leukemia virus type 1‐associated myelopathy (HAM) is a chronic, progressive, inflammatory disease with unclear pathogenesis and no effective treatments. We aimed to investigate a novel mechanistic theory and treat HAM patients with rituximab, which can deplete CD20+ B lymphocytes in circulation. Methods Single‐cell RNA sequencing (scRNA‐seq) data was analyzed to identify HTLV‐1‐associated B cells and their effect on T cells. An observational analysis of our HAM cohort was conducted to elucidate changes in the immunological microenvironment of these patients. Peripheral blood mononuclear cells (PBMC) from HAM patients were isolated to explore the efficacy of B cell depletion in vitro. To assess the effect of B‐cell depletion on HAM patients, eligible participants in our cohort received rituximab therapy (NCT04004819). Results ScRNA‐seq results suggest a significant effect of HTLV‐1‐associated B cells on T cells. Additionally, HTLV‐1 was found to infect B cells and depletion of B cells inhibited the proliferation of T cells. Number of B cells in HAM patients had positive correlation with the proviral load and infected cell counts. Depletion of B cells led to a reduction in HTLV‐1 proviral load in vitro. Furthermore, in clinical trial, 14 HAM patients were enrolled. Three patients (21.4%) who received rituximab failed to achieve remission, compared to 24 (85.7%) patients received any other therapy that failed to achieve remission. With a low level of circulating B cells, the proportion of Ki67‐positive cells in CD4+ T cells fell. Interpretation This study provided evidence that depleting B‐lymphocytes is an innovative strategy for treating patients with HAM and broadens the understanding of the role of B cells in infectious immunity.

Abstract Dysregulation of cholesterol metabolism underlies neurodegenerative disease and is increasingly implicated in neuroinflammatory diseases, such as multiple sclerosis (MS). Cytochrome P450 family 7 subfamily B member 1 (CYP7B1) is a key enzyme in alternative cholesterol metabolism. A recessive mutation in the gene CYP7B1 is known to cause a neurodegenerative disease, hereditary spastic paraplegia type 5 and oxysterol accumulation. However, the role of CYP7B1 in neuroinflammation has been little revealed. In this study, we induced experimental autoimmune encephalomyelitis (EAE), as a murine model of MS, using CYP7B1 homozygous knockout (KO) mice. We found that CYP7B1 deficiency can significantly attenuate EAE severity. CYP7B1 deficiency is sufficient to reduce leukocyte infiltration into the central nervous system, suppress proliferation of pathogenic CD4+ T cells, and decrease myeloid cell activation during EAE. Additionally, live-animal imaging targeting translocator protein expression, an outer mitochondrial membrane protein biomarker of neuroinflammation, showed that CYP7B1 deficiency results in suppressed neuroinflammation. Using human monocyte-derived microglia-like cellular disease model and primary microglia of CYP7B1 KO mice, we also found that activation of microglia of CYP7B1 deficiency was impaired. These cumulative results suggest that CYP7B1 can regulate neuroinflammation, thus providing potential new targets for therapeutic intervention.

To constitute and adjust the injection and production pattern in fractured-vuggy reservoirs, we extracted twelve fractured-cave structures, fabricated them into physical models with acrylic plates, and performed experiments via these models. The results show that utilizing oil/water gravity segregation sufficiently and forming valid flow channels should be emphasized. Preferentially exploiting the reservoir body containing intermediate-scaled or large-scaled caves, arranging injection wells in fractures or small-scaled caves while placing production wells in large-scaled caves, and separately putting injection wells and production wells in low/high parts of an intermediate-scaled or large-scaled cave, were found to benefit oil/water gravity segregation and thus gain a better water flooding effect in these experiments. Experiments with combined models also figured out that, after adjusting the injection and production pattern, the valid flow channel newly formed must pass through caves containing enough residual oil to improve the water flooding effect and could be obtained by shutting down the old production well while adding a new production well, adding a new production well, or switching the production well into an injection well while adding a new production well. In the actual field, adjusting the well location and altering the flow channel were proposed to conduct together. This study may provide references on the production management of analogous reservoirs.