Ischemic stroke (IS) is a detrimental neurological disease with limited treatments options. It has been challenging to define the roles of brain cell subsets in IS onset and progression due to ...cellular heterogeneity in the CNS. Here, we employed single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell populations in the mouse model of MCAO (middle cerebral artery occlusion). We identified 17 principal brain clusters with cell-type specific gene expression patterns as well as specific cell subpopulations and their functions in various pathways. The CNS inflammation triggered upregulation of key cell type-specific genes unpublished before. Notably, microglia displayed a cell differentiation diversity after stroke among its five distinct subtypes. Importantly, we found the potential trajectory branches of the monocytes/macrophage’s subsets. Finally, we also identified distinct subclusters among brain vasculature cells, ependymal cells and other glia cells. Overall, scRNA-seq revealed the precise transcriptional changes during neuroinflammation at the single-cell level, opening up a new field for exploration of the disease mechanisms and drug discovery in stroke based on the cell-subtype specific molecules.
This study employed FLUENT to analyse smoke movement and temperature distribution in an evacuation corridor with varying blockage ratios, focusing on the subway tunnel section of Fuzhou Metro Line 4. ...The simulation results revealed that under natural ventilation condition, the smoke spread area in the evacuation corridor is significantly greater for the high blockage ratio tunnel than for the low blockage ratio tunnel in the tunnel’s length direction, and the entire temperature distribution in the tunnel’s height direction is also high. Following the introduction of longitudinal ventilation, smoke spread in the evacuation corridor and the tunnel ceiling upstream of the fire source are effectively controlled, with smoke suppression movement in the evacuation corridor being significantly faster than that near the tunnel ceiling. As ventilation time increases, the back-layering length of smoke in the evacuation corridor gradually shortens. Within 150 s of ventilation, the critical safety distance below the safety temperature for a low blockage ratio is shorter than that for a high blockage ratio tunnel. In conclusion, longitudinal ventilation increases the cooling rate of high-temperature smoke in a high blockage ratio tunnel, but the influence of high ventilation velocity on evacuation cannot be ignored.
Practical application
This study provides recommendations for the evacuation plan and procedures under longitudinal ventilation. It is advisable to consider lowering the height of the evacuation corridor in the tunnel from the rail surface, thereby creating a more extensive safety space for personnel evacuation. Additionally, the implementation of prominent marks and voice prompts in the upstream area of the fire outbreak is crucial. This ensures that personnel are directed to evacuate from the upstream section during emergency situations.
The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered neuroinflammation. However, ...efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains a challenge. Here we present a device for the delivery of extracellular vesicles to treat spinal cord injury. We show that the device incorporating mesenchymal stem cells and porous microneedles enables the delivery of extracellular vesicles. We demonstrate that topical application to the spinal cord lesion beneath the spinal dura, does not damage the lesion. We evaluate the efficacy of our device in a contusive spinal cord injury model and find that it reduces the cavity and scar tissue formation, promotes angiogenesis, and improves survival of nearby tissues and axons. Importantly, the sustained delivery of extracellular vesicles for at least 7 days results in significant functional recovery. Thus, our device provides an efficient and sustained extracellular vesicles delivery platform for spinal cord injury treatment.
Fibroblast growth factor 23 (FGF23), which is involved in the regulation of vitamin D, is an emerging independent risk factor for cardiovascular diseases. Previous studies have demonstrated a ...positive association between FGF23 and stroke. In this study, we aimed to assess the association of FGF23 with ischemic stroke and its subtypes by applying a Mendelian randomization (MR) framework. Five genetic variants obtained from a genome-wide association study involving 16,624 European subjects were used as valid instruments of circulating FGF23 levels. MR was applied to infer the causality of FGF23 levels and the risk of ischemic stroke using data from the MEGASTROKE consortium. Subsequently, several MR analyses, including inverse-variance weighted meta-analysis, MR-Egger, weighted median estimate (WME), MR Pleiotropy Residual Sum and Outlier were performed. The heterogeneity test analysis, including Cochran's Q,
test and leave-one-out analysis were also applied. Furthermore, potential horizontal/vertical pleiotropy was assessed. Lastly, the power of MR analysis was tested. Three validated variants were found to be associated with circulating FGF23 levels and were used for further investigation. We found that high expression level of FGF23 was not associated with any ischemic stroke. However, a causal association between genetically predicted FGF23 levels and the risk of large-artery atherosclerotic stroke (LAS) was significant, with an odds ratio of 1.74 (95% confidence interval = 1.08-2.81) per standard deviation increase in circulating FGF23 levels. Our findings provide support for the causal association between FGF23 and LAS, and therefore, offer potential therapeutic targets for LAS. The specific roles of FGF23 in LAS and associated molecules require further investigation.
Despite considerable unmet medical needs, effective pharmacological treatments that promote functional recovery after spinal cord injury remain limited. Although multiple pathological events are ...implicated in spinal cord injuries, the development of a microinvasive pharmacological approach that simultaneously targets the different mechanisms involved in spinal cord injury remains a formidable challenge. Here we report the development of a microinvasive nanodrug delivery system that consists of amphiphilic copolymers responsive to reactive oxygen species and an encapsulated neurotransmitter-conjugated KCC2 agonist. Upon intravenous administration, the nanodrugs enter the injured spinal cord due to a disruption in the blood-spinal cord barrier and disassembly due to damage-triggered reactive oxygen species. The nanodrugs exhibit dual functions in the injured spinal cord: scavenging accumulated reactive oxygen species in the lesion, thereby protecting spared tissues, and facilitating the integration of spared circuits into the host spinal cord through targeted modulation of inhibitory neurons. This microinvasive treatment leads to notable functional recovery in rats with contusive spinal cord injury.
•RF rapidly scavenges ROS, protecting MS and spinal cord from peroxidative damage.•3D MSs exhibit enhanced paracrine effects compared with 2D MSCs.•RF-pGel-MS poses dual-phase treatment, which ...promotes function recovery in SCI rats.
Implanting mesenchymal stem cells (MSCs) has offered a great promise in spinal cord injury (SCI) repair. However, the harsh environment accompanied with excessive ROS following SCI seriously threatens MSC survival and compromises its efficacy. Additionally, the intricate pathology distinguished as the acute phase and chronic phase makes MSC therapeutics alone difficult to alleviate severe inflammation and promote functional recovery simultaneously. Despite scaffold systems for local stem cell delivery being extensively explored, dual-phase management for SCI using one protective scaffold system has rarely been reported. Herein, a composite scaffold system (RF-pGel-MS), which consisted of an outer ROS filter (RF) and an inner porous GelMA hydrogel (pGel) harbored with MSC spheroids (MSs), was designed for SCI repair. Specifically, RF rapidly scavenged ROS, protecting the MS from peroxidation damage in the acute phase. MS constructed via 3D culture of MSCs presented enhanced paracrine effects, which remarkably facilitated neuron repair and functional recovery in the chronic phase. The dual-phase therapeutic efficacy of RF-pGel-MS led to significant locomotor and electrophysiology recovery in the SCI rats. Hence, the currently proposed strategy using RF-pGel-MS is efficient for ROS scavenging and boosting the stem cell therapeutics, which is insightful for the SCI treatment.
Mitochondria, key organelles which keep in tune with energy demands for eukaryotic cells, are firmly associated with neurological conditions and post-traumatic rehabilitation.
fluorescence imaging of ...mitochondria, especially with deep tissue penetration, would open a window to investigate the actual context of the brain. However, the depth of traditional two-photon mitochondrial fluorescence imaging is still limited due to the poor biological compatibility or low two-photon absorption cross-sections. A biocompatible mitochondria-targeted two-photon fluorescent dye (FO2) with an excellent two-photon absorption cross-section (the maximum of 1184 GM at 790 nm) and low cellular toxicity was designed and synthesized to overcome this problem. With this dye, we reached an imaging depth of
640 μm during mitochondrial imaging of cortical cells in live animals. FO2 could be an excellent mitochondrial probe for live animal neural imaging to investigate the function and dysfunction of mitochondria in the brain.
Using the alloxan-induced hyperglycemic mice, the hypoglycemic activity of ZYZH proliposome was evaluated from body weight and fasting blood glucose level. 2Materials and methods 2.1 Materials and ...Instruments Methanol (chromatographically pure, Chengdu Kelong Chemical Reagent Factory) ; ZYZH API (Content & 80% , Institute of Ethnic Minoéty Medicine of Southwest Minzu University); rutin standard (Content & 98% , China National Institute for the Control of Pharmaceutical and Biological Products) ; ZYZH proliposome (laboratory-made) ; sephadex G-50 (100 - 200 $m, Taizhou Luqiao Sijia Biochemical Plastic Factory); sorbitol; potassium dihydrogen phosphate (Chengdu Kelong Chemical Reagent Factory) ; cholesterol; lecithin; vitamin E ( Beijing Dingguo Biotechnology Co. , Ltd. ) ; alloxan (Sigma Corporation) ; Kunming mice ( SPF grade, body weight of 25 - 28 g, male, Chengdu Dashuo Expeémental Animal Research Center). MS-2000 laser particle size analyzer ( Malvern, UK) ; JEM- 1200EX transmission electron microscope (JEOL Etd. $ ; AE104 electronic analytical balance; Mettler-Toledo; UV-2450 ultraviolet spectrophotometer ( Shimadzu Corporation, Japan $ ; Waters 2695 high performance litļuid chromatograph (Waters, USA$; SHB-3 circulating water multi-purpose vacuum pump ( Zhengzhou Du Fu Instrument Factory $ ; SENCO-R rotary evaporator ( Shanghai Shenshen Technology Co. , Ltd. $ ; FD-1 freeze d^er ( Beijing Boyikang Experimental Instrument Co. , Ltd. $ ; TGL-16B desktop centrifuge ( Shanghai Anting Scientific Instrument Factory $ ; automatic blood glucose meter ( Roche, Germany $ ; blood glucose test strip ( Roche, Germany $ . According to the standard curve, the drug concentration was calculated. The prescribed amounts of soy lecithin and cholesterol and a little amount of vitamin E were disolved sonically in an appropriate amount of organic solvent ( chloroform % methanol $ , then added with the organic mixture of phospholipids in portions at a rate of 1.0 mL/min, and finally vacuum-evaporated on a rotary evaporator.
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