The prognosis of spinal cord injury (SCI) is closely related to secondary injury, which is dominated by neuroinflammation. There is evidence that α-synuclein aggregates after SCI and that inhibition ...of α-synuclein aggregation can improve the survival of neurons after SCI, but the mechanism is still unclear. This study was designed to investigate the effects of α-synuclein on neuroinflammation after SCI and to determine the underlying mechanisms.
A T3 spinal cord contusion model was established in adult male Sprague-Dawley rats. An SNCA-shRNA-carrying lentivirus (LV-SNCA-shRNA) was injected into the injury site to block the expression of α-synuclein (forming the SCI+KD group), and the SCI and sham groups were injected with an empty vector. Basso-Beattie-Bresnahan (BBB) behavioural scores and footprint analysis were used to detect motor function. Inflammatory infiltration and myelin loss were measured in the spinal cord tissues of each group by haematoxylin-eosin (HE) and Luxol Fast Blue (LFB) staining, respectively. Immunohistochemistry, Western blot analysis, and RT-qPCR were used to analyse protein expression and transcription levels in the tissues. Immunofluorescence was used to determine the morphology and function of glial cells and the expression of matrix metalloproteinase-9 in the central canal of the spinal cord. Finally, peripheral serum cytokine levels were determined by enzyme-linked immunosorbent assay.
Compared with the SCI group, the SCI+KD group exhibited reduced inflammatory infiltration, preserved myelin, and functional recovery. Specifically, the early arrest of α-synuclein inhibited the pro-inflammatory factors IL-1β, TNF-α, and IL-2 and increased the expression of the anti-inflammatory factors IL-10, TGF-β, and IL-4. The neuroinflammatory response was regulated by reduced proliferation of Iba1+ microglia/macrophages and promotion of the shift of M1-polarized Iba1+/iNOS+ microglia/macrophages to M2-polarized Iba1+/Arg1+ microglia/macrophages after injury. In addition, compared with the SCI group, the SCI+KD group also exhibited a smaller microglia/astrocyte (Iba1/GFAP) immunostaining area in the central canal, lower MMP-9 expression, and improved cerebrospinal barrier function.
Lentivirus-mediated downregulation of α-synuclein reduces neuroinflammation, improves blood-cerebrospinal barrier function, promotes functional recovery, reduces microglial activation, and promotes the polarization of M1 microglia/macrophages to an M2 phenotype to confer a neuroprotective immune microenvironment in rats with SCI.
Direct delivery of proteins into cells avoids many drawbacks of gene delivery, and thus has emerging applications in biotherapy. However, it remains a challenging task owing to limited charges and ...relatively large size of proteins. Here, we report an efficient protein delivery system via the co-assembly of fluoroamphiphiles and proteins into nanoparticles. Fluorous substituents on the amphiphiles play essential roles in the formation of uniform nanoparticles, avoiding protein denaturation, efficient endocytosis, and maintaining low cytotoxicity. Structure-activity relationship studies reveal that longer fluorous chain length and higher fluorination degree contribute to more efficient protein delivery, but excess fluorophilicity on the polymer leads to the pre-assembly of fluoroamphiphiles into stable vesicles, and thus failed protein encapsulation and cytosolic delivery. This study highlights the advantage of fluoroamphiphiles over other existing strategies for intracellular protein delivery.
The past decade has witnessed exponentially growing interest in the lateral habenula (LHb) owing to new discoveries relating to its critical role in regulating negatively motivated behaviour and its ...implication in major depression. The LHb, sometimes referred to as the brain's 'antireward centre', receives inputs from diverse limbic forebrain and basal ganglia structures, and targets essentially all midbrain neuromodulatory systems, including the noradrenergic, serotonergic and dopaminergic systems. Its unique anatomical position enables the LHb to act as a hub that integrates value-based, sensory and experience-dependent information to regulate various motivational, cognitive and motor processes. Dysfunction of the LHb may contribute to the pathophysiology of several psychiatric disorders, especially major depression. Recently, exciting progress has been made in identifying the molecular and cellular mechanisms in the LHb that underlie negative emotional state in animal models of drug withdrawal and major depression. A future challenge is to translate these advances into effective clinical treatments.
In conjunction with the classical functions of regulating intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization of vitamin D, the population-based association ...between low vitamin D status and increased cancer risk is now generally accepted. Inflammation is causally related to oncogenesis. It is widely thought that vitamin D plays an important role in the modulation of the inflammation system by regulating the production of inflammatory cytokines and immune cells, which are crucial for the pathogenesis of many immune-related diseases. Mechanistic studies have shown that vitamin D influences inflammatory processes involved in cancer progression, including cytokines, prostaglandins, MAP kinase phosphatase 5 (MKP5), the nuclear factor kappa B (NF-κB) pathway, and immune cells. Multiple studies have shown that vitamin D has the potential to inhibit tumor development by interfering with the inflammation system. The present review summarizes recent studies of the mechanisms of vitamin D on regulating the inflammation system, which contributes to its potential for cancer prevention and therapy. This review helps answer whether inflammation mediates a causal relationship between vitamin D and tumorigenesis.
Owing to the sustainability, environmental friendliness, and structural diversity of biomass‐derived materials, extensive efforts have been devoted to use them as energy storage materials in ...high‐energy rechargeable batteries. A timely and comprehensive review from the structures to mechanisms will significantly widen this research field. Here, it starts with the operation mechanism of batteries, and it aims to summarize the latest advances for biomass‐derived carbon to achieve high‐energy battery materials, including activation carbon methods and the structural classification of biomass‐derived carbon materials from zero dimension, one dimension, two dimension, and three dimension. Each strategy starts with carefully selected examples and then moves to illustrate the underlying transport mechanism of electrons in the structure. In the end, challenges, strategies, and outlooks are pointed out for the future development of biomass‐derived carbon materials. Overall, this review will help researchers choose appropriate strategies to design biomass‐derived carbon materials, thereby promoting the application of biomass materials in battery design.
This review comprehensively summarizes the internal structure of biomass‐derived carbon materials, which aims to provide suitable environment‐friendly and low consumption green materials for high‐performance batteries design.
Designing high-performance and cost-effective electrocatalysts toward oxygen evolution and hydrogen evolution reactions in water-alkali electrolyzers is pivotal for large-scale and sustainable ...hydrogen production. Earth-abundant transition metal oxide-based catalysts are particularly active for oxygen evolution reaction; however, they are generally considered inactive toward hydrogen evolution reaction. Here, we show that strain engineering of the outermost surface of cobalt(II) oxide nanorods can turn them into efficient electrocatalysts for the hydrogen evolution reaction. They are competitive with the best electrocatalysts for this reaction in alkaline media so far. Our theoretical and experimental results demonstrate that the tensile strain strongly couples the atomic, electronic structure properties and the activity of the cobalt(II) oxide surface, which results in the creation of a large quantity of oxygen vacancies that facilitate water dissociation, and fine tunes the electronic structure to weaken hydrogen adsorption toward the optimum region.
The role of N6‐methyladenosine (m6A) demethylase fat mass and obesity‐associated protein (FTO) in the regulation of chemo‐radiotherapy resistance remains largely unknown. Here, we show that the mRNA ...level of FTO is elevated in cervical squamous cell carcinoma (CSCC) tissues when compared with respective adjacent normal tissues. FTO enhances the chemo‐radiotherapy resistance both in vitro and in vivo through regulating expression of β‐catenin by reducing m6A levels in its mRNA transcripts and in turn increases excision repair cross‐complementation group 1 (ERCC1) activity. Clinically, the prognostic value of FTO for overall survival is found to be dependent on β‐catenin expression in human CSCC samples. Taken together, these findings uncover a critical function for FTO and its substrate m6A in the regulation of chemo‐radiotherapy resistance, which may bear potential clinical implications for CSCC treatment.
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With the ever-growing development of multifunctional and miniature electronics, the exploring of high-power microwatt-milliwatt self-charging technology is highly essential. Flexible ...thermoelectric materials and devices, utilizing small temperature difference to generate electricity, exhibit great potentials to provide the continuous power supply for wearable and implantable electronics. In this review, we summarize the recent progress of flexible thermoelectric materials, including conducting polymers, organic/inorganic hybrid composites, and fully inorganic materials. The strategies and approaches for enhancing the thermoelectric properties of different flexible materials are detailed overviewed. Besides, we highlight the advanced strategies for the design of mechanical robust flexible thermoelectric devices. In the end, we point out the challenges and outlook for the future development of flexible thermoelectric materials and devices.
This paper studies clustering of multi-view data, known as multi-view clustering. Among existing multi-view clustering methods, one representative category of methods is the graph-based approach. ...Despite its elegant and simple formulation, the graph-based approach has not been studied in terms of (a) the generalization of the approach or (b) the impact of different graph metrics on the clustering results. This paper extends this important approach by first proposing a general Graph-Based System (GBS) for multi-view clustering, and then discussing and evaluating the impact of different graph metrics on the multi-view clustering performance within the proposed framework. GBS works by extracting data feature matrix of each view, constructing graph matrices of all views, and fusing the constructed graph matrices to generate a unified graph matrix, which gives the final clusters. A novel multi-view clustering method that works in the GBS framework is also proposed, which can (1) construct data graph matrices effectively, (2) weight each graph matrix automatically, and (3) produce clustering results directly. Experimental results on benchmark datasets show that the proposed method outperforms state-of-the-art baselines significantly.
What is known and objective
Propofol and esketamine are routine anaesthetics used in sedation or general anaesthesia for paediatric procedures. Coadministration could reduce the dose of either ...propofol or esketamine required and lower the incidence of drug‐related adverse events. We designed a four‐arm randomized controlled trial in children undergoing diagnostic upper gastrointestinal endoscopy to investigate the dose of propofol with different doses of esketamine inducing appropriate depth of anaesthesia in 50% patients (median effective dose, ED50).
Methods
After getting the approval of the research ethics committee and informed consent, 92 paediatric patients planning for upper gastrointestinal endoscopy were divided into four groups randomly: esketamine 0, 0.25, 0.5 and 1 mg/kg groups (n = 23/group). Propofol doses followed the Dixon and Massey up‐and‐down method with different starting and interval doses between groups. During the first attempt of endoscope insertion, if patients' reactions prevented the insertion, it would be considered as a failure. The awakening time, total propofol doses, as well as the perioperative and post‐procedure adverse events were evaluated and recorded for each patient.
Results and discussion
The ED50 (median, 95% confidence interval) of propofol was significantly greater in esketamine 0 and 0.25 mg/kg groups in comparison with the esketamine 0.5 and 1 mg/kg groups (4.1 3.3–4.9; 3.1 2.5–3.8 mg/kg vs. 1.8 1.1–2.4; 0.8 0.2–1.3 mg/kg, respectively, p < .05). The total doses of propofol in esketamine 0.5 and 1 mg/kg groups were statistically lower than these in esketamine 0 and 0.25 mg/kg group (p < .01). The mean blood pressure was lower in the esketamine 0 mg/kg group than that in 1 mg/kg group after administration and during the procedure (p < .01). The esketamine 1 mg/kg group showed a higher incidence of vomiting and visual disturbances than the other three groups (p < .001).
What is new and conclusion
In children who accomplished diagnostic paediatric upper gastrointestinal endoscopy under deep sedation/anaesthesia, the total dosage of propofol needed was reduced significantly in esketamine 0.5 and 1 mg/kg groups with a corresponding reduce in propofol‐related hemodynamic changes. However, a higher incidence of esketamine‐related adverse effects was found in esketamine 1 mg/kg group.
This trial aimed to investigate the median effective dose of propofol with different doses of esketamine in children undergoing diagnostic upper gastrointestinal endoscopy. The total dosage of propofol was reduced in esketamine 0.5 and 1 mg/kg groups with a corresponding reduce in propofol‐related hemodynamic changes, while a higher incidence of esketamine‐related adverse effects was found in esketamine 1 mg/kg group.
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