CX3CR1+/UCHL1+ microglial extracellular vesicles in blood: a potential biomarker for multiple sclerosis.

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.

Porous chitosan quaternary ammonium salt hydrogel embedded with Cu, Ni and Pd nanoparticles for efficient coupled adsorption-catalytic reduction of methylene blue and 4-nitrophenol.

Anthropogenic wastewater generation and water pollution can have negative impacts on public health and ecosystems. However, most materials do not have both adsorptive and catalytic properties, so the design and development of sustainable and multifunctional materials is essential for wastewater treatment. Herein, composite hydrogel (PHG) containing [2-(Methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide (SBMA) and chitosan quaternary ammonium salts (HACC) were prepared for wastewater treatment. The adsorption capacities of the PHG hydrogels for nickel (NiII), copper (CuII), and palladium (PdII) ions were 158.68, 182.99, and 229.78 mg/g, respectively. The adsorption process is consistent with the Langmuir adsorption model and quasi-secondary kinetics. For further application of adsorbed metal ions, NaBH4 was selected for in situ reduction to prepare hydrogel-based catalysts cemented with metal nanoparticles (Ni-, Cu- and Pd-NPs), respectively. The PHG-Pd catalysts demonstrated significant catalytic efficiency in reducing 4-nitrophenol and methylene blue, and Kapp were 0.307 and 0.365 min-1, respectively. Among them, the activation parameters for the reduction of 4-NP over PHG-Pd catalyst were calculated as Ea = 36.27 kJ/mol, ΔH# = 33.72 kJ/mol and ΔS# = -259.68 J/(mol·K). This study is expected to provide insights into the design of multifunctional adsorption catalysts for the removal of dyes and nitro compounds from wastewater.

CYP7B1 deficiency impairs myeloid cell activation in autoimmune disease of the central nervous system.

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.

B-cell depletion limits HTLV-1-infected T-cell expansion and ameliorate HTLV-1-associated myelopathy.

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.

Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

Enhanced Stability and Catalytic Activity of a Nanocatalyst with Reusable Ionic Liquid Hydrogels for the Reduction of Organic Pollutants.

Nitroaromatic compounds have a wide range of applications. However, they pose a significant threat to both the environment and human health. Ionic liquid hydrogels (ILs-gels) have emerged as a cost-effective and environmentally friendly option for various applications. However, conventional ILs-gels are known to possess mechanical flaws or defects. The procedure utilized a facile synthesis route that involved the polymerization of acrylamide (AM) and ionic liquids (ILs) to create a novel candidate for nanoparticle absorption. This study resolved this issue by creating toughened hydrophobic combined hydrogels synthesized through the addition of SiO2@poly(butyl acrylate) core-shell inorganic-organic hybrid latex particles (SiO2@PBA) to the AM-ILs mixture. The SiO2@PBA particles were chosen to provide the hydrogels with exceptional stretchability (up to 4050% strain) and high mechanical properties (tensile strength of 126 kPa) by acting as both a nanotoughener and a cross-linking point for hydrophobic linkage. Additionally, the P(AM/ILs)-SiO2@PBA hydrogel served as a template for the in situ and stable formation of palladium (Pd) nanoparticles. By incorporation of these Pd nanoparticles as catalysts into P(AM/ILs)-SiO2@PBA hydrogel carriers, the resulting P(AM/ILs)-SiO2@PBA/Pd hydrogels exhibited the ability to catalyze the degradation of p-nitrophenol. Remarkably, even after 15 applications, the efficiency of the degradation process remained consistently above 90%. Thus, the innovative SiO2@PBA toughened ILs-hydrogel design strategy can be utilized to develop robust and stretchable hydrogel materials for catalytic use in the sewage disposal industry.

Tailored ultra-tough, antimicrobial and recyclable hydrogels based on chitosan and ionic liquid modified montmorillonite with different chain lengths for efficient adsorption of organic dyes in wastewater.

Water pollution had exacerbated the global water crisis. Dye effluents posed a serious threat to the environment and human health, so there was an urgent need to develop sustainable methods to mitigate water pollution. In this work, sodium-based montmorillonite (MMT) was stripped using ionic liquids (ILs) with different chain lengths, and a pAAM/pAA/LMA/MMT@ILs-CS hydrogel adsorbent (MICHA) was prepared. The gel-based adsorbent was used to adsorb typical cationic (methylene blue: MB, rhodamine B: RhB) and anionic (methyl orange: MO, indigo carmine: IC) dyes from wastewater. The maximum adsorption capacities of MI16CHA for MB, MO, IC and RhB were 349.6817, 325.415, 316.0142 and 339.8154 mg/g, respectively. The adsorption kinetics and equilibrium data of MI16CHA for dyes were in accordance with the pseudo-first order and Langmuir isotherm models. The adsorption mechanism of MI16CHA on dyes were based on hydrogen bonding, electrostatic and π-π interaction. Thermodynamic studies showed that the adsorption of dyes on MI16CHA was spontaneous and heat-absorbing. The selective experiments demonstrated that MI16CHA has a promising application in real industrial conditions. Cyclic adsorption tests demonstrated the excellent recyclability of MI16CHA. In addition, MI16CHA had excellent antimicrobial and mechanical properties, which endowed the gel adsorbent with anti-pollution and durability.

Carbon Nanotubes and Silica@polyaniline Core-Shell Particles Synergistically Enhance the Toughness and Electrical Conductivity in Hydrophobic Associated Hydrogels.

Soft, conductive, and stretchable sensors are highly desirable in many applications, including artificial skin, biomonitoring patches, and so on. Recently, a combination of good electrical and mechanical properties was regarded as the most important evaluation criterion for judging whether hydrogel sensors are suitable for practical applications. Herein, we demonstrate a novel carboxylated carbon nanotube (MWCNT-COOH)-embedded P(AM/LMA)/SiO2@PANI hydrogel. The hydrogel benefits from a double-network structure (hydrogen bond cross-linking and hydrophobic connectivity network) due to the role of MWCNT-COOH and SiO2@PANI as cross-linkers, thus resulting in tough composite hydrogels. The obtained P(AM/LMA)/SiO2@PANI/MWCNT-COOH hydrogels exhibited high tensile strength (1939 kPa), super stretchability (3948.37%), and excellent strain sensitivity (gauge factor = 11.566 at 100-1100% strain). Obviously, MWCNT-COOH not only improved the electrical conductivity but also enhanced the mechanical properties of the hydrogel. Therefore, the integration of MWCNT-COOH and SiO2@PANI-based hydrogel strain sensors will display broad application in sophisticated intelligence, soft robotics, bionic prosthetics, personal health care, and other fields using inexpensive, green, and easily available biomass.

USPIO-SWI Shows Fingolimod Enhanced Alteplase Action on Angiographic Reperfusion in eMCAO Rats.

BACKGROUND: Noninvasive evaluation of the status of cerebral arteriole perfusion remains a practical challenge in murine stroke models, because conventional magnetic resonance imaging (MRI) is no longer capable of capturing these very small vessels. PURPOSE: To investigate the feasibility of ultrasmall superparamagnetic iron oxide particles (USPIO)-based susceptibility weighted imaging (SWI)-MRI (USPIO-SWI) and T2* map-MRI (USPIO-T2* map) for monitoring angiographic perfusion in stroke rats. STUDY TYPE: A preclinical randomized controlled trial. ANIMAL MODEL: Normal rats (N = 9), embolic middle cerebral artery occlusion (eMCAO) rats (N = 66). FIELD STRENGTH/SEQUENCE: 7 T; T2* map (multigradient echo), SWI (3D gradient echo). ASSESSMENT: Experiment 1: To develop a method for angiographic reperfusion evaluation with USPIO-SWI. Normal rats were used to optimize the USPIO dosage (5.6, 16.8, and 56 mg/kg ferumoxytol) as well as scan time points for cerebral arterioles. Contrast-to-noise ratio (CNR) was measured. Stroke rats were further used and the number of visual cortical vessels were counted. Experiment 2: To examine whether fingolimod (lymphocytes inhibitor) enhances the action of tissue plasminogen activator (tPA) in eMCAO rats on cerebral angiographic reperfusion. STATISTICAL TESTS: Mann-Whitney test and two way-ANOVA were used. P < 0.05 was considered statistically significant. RESULTS: CNR values of cerebral cortical penetrating arteries in normal rats were significantly increased to 4.4 ± 0.5 (5.6 mg/kg), 6.1 ± 0.5 (16.8 mg/kg), and 3.4 ± 0.9 (56 mg/kg) after USPIO injection. The number of visual cortical vessels on USPIO-SWI images in ischemic regions was significantly less than in control regions (5 ± 2 vs. 56 ± 20) of eMCAO rats. Compared with eMCAO rats who received tPA only, eMCAO rats who received the combination of fingolimod and tPA exhibited significantly higher proportion of complete angiographic reperfusion (69% vs. 17%). DATA CONCLUSION: This study supports the feasibility of angiographic perfusion evaluation with USPIO-SWI in stroke rats. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Dawson's Fingers in Cerebral Small Vessel Disease.

To explore Dawson's fingers in cerebral small vessel disease (CSVD) and factors related to the development of Dawson's finger, we collected and analyzed clinical data of 65 patients with CSVD. We found a venous abnormality feature called Dawson's fingers around the ventricles in magnetic resonance images (MRIs) of 20 out of 65 patients with CSVD (30. 8%). A significant association between Dawson's fingers and diabetes mellitus (DM) was also detected (30 vs. 8.9%, P < 0.05). CSVD patients with Dawson's fingers had significantly increased cerebral microbleeds (CMB) (44.2 vs. 75.0%, p < 0.05), lacunae (66.7 vs. 95.0%, p < 0.05), and white matter hyperintensity (WMH) (p < 0.05) damage, and these patients exhibited significant cognitive domain impairment as assessed via Montreal Cognitive Assessment (MoCA) (18.9 ± 1.8 vs. 24.0 ± 0.8, p < 0.05) and Mini-Mental State Examination (MMSE) (24.5 ± 1.1 vs. 26.6 ± 0.6, p < 0.05). Our results show a distinctly high incidence of Dawson's fingers in CSVD patients and identify a significant association with DM, thus yielding insights about the appropriate use of Dawson's fingers, a venous imaging marker, to explore the basic pathophysiology of CSVD.

Tanshinone IIA alleviates brain damage in a mouse model of neuromyelitis optica spectrum disorder by inducing neutrophil apoptosis.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune astrocytopathic disease associated with the anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions primarily located on the optic nerves and spinal cord. Tanshinone IIA (TSA), an active natural compound extracted from Salvia miltiorrhiza Bunge, has profound immunosuppressive effects on neutrophils. OBJECTIVE: The present study aimed to evaluate the effect of TSA on NMOSD mice and explore the underlying mechanisms. Mice were initially administered TSA (pre-TSA group, n = 20) or vehicle (vehicle group, n = 20) every 8 h for 3 days, and then NMOSD model was induced by intracerebral injection of NMOSD-immunoglobulin G (NMO-IgG) and human complement (hC). In addition, post-TSA mice (n = 10) were administered equal dose of TSA at 8 h and 16 h after model induction. At 24 h after intracerebral injection, histological analysis was performed to assess the inhibitory effects of TSA on astrocyte damage, demyelination, and neuroinflammation in NMOSD mice, and western blotting was conducted to clarify the effect of TSA on the NF-κB and MAPK signaling pathways. Furthermore, flow cytometry and western blotting were conducted to verify the proapoptotic effects of TSA on neutrophils in vitro. RESULTS: There was a profound reduction in astrocyte damage and demyelination in the pre-TSA group and post-TSA group. However, prophylactic administration of TSA induced a better effect than therapeutic treatment. The number of infiltrated neutrophils was also decreased in the lesions of NMOSD mice that were pretreated with TSA. We confirmed that prophylactic administration of TSA significantly promoted neutrophil apoptosis in NMOSD lesions in vivo, and this proapoptotic effect was mediated by modulating the caspase pathway in the presence of inflammatory stimuli in vitro. In addition, TSA restricted activation of the NF-κB signaling pathway in vivo. CONCLUSION: Our data provide evidence that TSA can act as a prophylactic agent that reduces NMO-IgG-induced damage in the mouse brain by enhancing the resolution of inflammation by inducing neutrophil apoptosis, and TSA may serve as a promising therapeutic agent for neutrophil-associated inflammatory disorders, such as NMOSD.

Neural Stem Cells Transfected with Leukemia Inhibitory Factor Promote Neuroprotection in a Rat Model of Cerebral Ischemia.

Leukemia inhibitory factor (LIF) contributes to the neuroprotection by neural stem cells (NSCs) after ischemic stroke. Our aim was to explore whether LIF-transfected NSCs (LIF-NSCs) can ameliorate brain injury and promote neuroprotection in a rat model of cerebral ischemia. To accomplish this goal, we transfected NSCs with a lentivirus carrying the LIF gene to stably overexpress LIF. The LIF-NSCs reduced caspase 3 activation under conditions of oxygen-glucose deprivation in vitro. Transient cerebral ischemia was induced in rats by 2 h of middle cerebral artery occlusion (MCAo), and LIF-NSCs were intravenously injected at 6 h post-ischemia. LIF-NSC treatment reduced the infarction volume and improved neurological recovery. Moreover, LIF-NSCs improved glial cell regeneration and ameliorated white matter injury in the MCAo rats. The NSCs acted as carriers and increased the expression of LIF in the lesions to protect against cerebral infarction, suggesting that LIF-NSCs could be a potential treatment for cerebral infarction.