Abstract Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear ...whether glymphatic transport affects the distribution of soluble Aβ in Alzheimer's disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aβ40. Interestingly, pretreatment with Aβ40 in the CSF, but not Aβ42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-β deposits, glymphatic transport was reduced, due to the accumulation of toxic Aβ species, such as soluble oligomers. CSF-derived Aβ40 co-localizes with existing endogenous vascular and parenchymal amyloid-β plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aβ accumulation. Importantly, glymphatic failure preceded significant amyloid-β deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.
Astrocytes have in recent years become the focus of intense experimental interest, yet markers for their definitive identification remain both scarce and imperfect. Astrocytes may be recognized as ...such by their expression of glial fibrillary acidic protein, glutamine synthetase, glutamate transporter 1 (GLT1), aquaporin-4, aldehyde dehydrogenase 1 family member L1, and other proteins. However, these proteins may all be regulated both developmentally and functionally, restricting their utility. To identify a nuclear marker pathognomonic of astrocytic phenotype, we assessed differential RNA expression by FACS-purified adult astrocytes and, on that basis, evaluated the expression of the transcription factor SOX9 in both mouse and human brain. We found that SOX9 is almost exclusively expressed by astrocytes in the adult brain except for ependymal cells and in the neurogenic regions, where SOX9 is also expressed by neural progenitor cells. Transcriptome comparisons of SOX9+ cells with GLT1+ cells showed that the two populations of cells exhibit largely overlapping gene expression. Expression of SOX9 did not decrease during aging and was instead upregulated by reactive astrocytes in a number of settings, including a murine model of amyotrophic lateral sclerosis (SOD1G93A), middle cerebral artery occlusion, and multiple mini-strokes. We quantified the relative number of astrocytes using the isotropic fractionator technique in combination with SOX9 immunolabeling. The analysis showed that SOX9+ astrocytes constitute ∼10-20% of the total cell number in most CNS regions, a smaller fraction of total cell number than previously estimated in the normal adult brain.
Astrocytes are traditionally identified immunohistochemically by antibodies that target cell-specific antigens in the cytosol or plasma membrane. We show here that SOX9 is an astrocyte-specific nuclear marker in all major areas of the CNS outside of the neurogenic regions. Based on SOX9 immunolabeling, we document that astrocytes constitute a smaller fraction of total cell number than previously estimated in the normal adult mouse brain.
The study of volatility rarely starts from the perspective of implied volatility, and rarely combines stochastic volatility models with option pricing, which is a major flaw in research. Based on ...this, this study combined image processing technology to construct the wave image processing model and analyze the implied volatility of stock options and combined the image processing method to construct the implicit volatility surface output model. At the same time, the implied volatility surface model is constructed by mobile phone big data, image segmentation and noise processing are performed by image processing, and the performance of the model is analyzed by regression analysis. Finally, this paper designs experiments to verify the performance of the model. The results show that the model constructed in this paper has certain effects and can provide theoretical reference for subsequent related research.
Compared with the traditional cable, the high-temperature superconducting (HTS) cable has the advantages of low loss and large capacity transmission. At present, the research on HTS cables mainly ...focuses on the calculation of AC loss, the performance under specific working conditions and cooling system design. Relatively little research has been carried out on the basic design and overall layout optimization of the cables. In this paper, an HTS cable with a rated current of 4 kA was designed. Firstly, according to the selected superconducting cable parameters, the body design of cables with different structures was carried out and the corresponding finite element models were built. Then, the performance analysis of HTS cables with different layouts was carried out based on the proposed cable performance evaluation indicators and the CORC double-layer structure was determined as the scheme of this cable. Finally, the AC loss of the cable with this topology was calculated to be 9.81 J/m under rated conditions. The cooling system can ensure the safe operation of the cable in the rated temperature range.
Background and purpose: The aggregation of vascular risk factors (VRFs) can aggravate cognitive impairment in stroke-free patients. Metabolites in serum and cerebrospinal fluid (CSF) may irreversibly ...reflect early functional deterioration. This study evaluated small-molecule metabolites (＜1000 Da) in the serum and CSF of patients with different degrees of cerebrovascular burden and investigated the correlation between metabolism and cognitive performance associated with VRFs. Methods: The subjects were divided into a low-risk group (10-year stroke risk ≤ 5%), a middle-risk group (10-year stroke risk＞5% and ＜15%) and a high-risk group (10 years stroke risk ≥ 15%) according to the Framingham stroke risk profile (FSRP) score, which was used to quantify VRFs. We assess the cognitive function of the participants. We semi-quantitatively quantified the small molecules using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The correlation between the small molecules and cognitive function, along with VRFs, was investigated to identify key small molecules and possible underlying metabolic pathways. Results: When the FSRP scores increased, the cognitive performances of the subjects decreased, specifically performance regarding the tasks of immediate memory, delayed recall and executive function. Seven metabolites (2-aminobutyric acid, Asp Asp Ser, Asp Thr Arg, Ile Cys Arg, 1-methyluric acid, 3-tert-butyladipic acid, and 5α-dihydrotestosterone glucuronide) in serum and 3 metabolites (Asp His, 13-HOTrE(r), and 2,5-di-tert-Butylhydroquinone) in CSF were significantly increased, and 1 metabolite (arachidonoyl PAF C-16) in serum was significantly decreased in high-risk group subjects. Among these metabolites, 1-methyluric acid, 3-tert-butyladipic acid and Ile Cys Arg in serum and 13-HOTrE(r), 2,5-di-tert-butylhydroquinone and Asp His in CSF were found to be negatively related with cognitive performance in the high-risk group. Arachidonoyl PAF C-16 in serum was found to be associated with better cognitive performance. Caffeine metabolism and the tricarboxylic acid cycle (TCA cycle) were identified as key pathways. Conclusions: 1-Methyluric acid, 3-tert-butyladipic acid, arachidonoyl PAF C-16, Ile Cys Arg in serum and 13-HOTrE(r), 2,5-di-tert-butylhydroquinone, and Asp His in CSF were identified as potential biomarkers of vascular cognitive impairment (VCI) at the early stage. Caffeine metabolism and the TCA cycle may play important roles in the pathophysiology of VRFs-associated cognitive impairment.
Vascular depression (VaD) is a depressive disorder closely associated with cerebrovascular disease and vascular risk factors. It remains underestimated owing to challenging diagnostics and limited ...information regarding the pathophysiological mechanisms of VaD. The purpose of this study was to analyze the proteomic signatures and identify the potential biomarkers with diagnostic significance in VaD.
Deep profiling of the serum proteome of 35 patients with VaD and 36 controls was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Functional enrichment analysis of the quantified proteins was based on Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Reactome databases. Machine learning algorithms were used to screen candidate proteins and develop a protein-based model to effectively distinguish patients with VaD.
There were 29 up-regulated and 31 down-regulated proteins in the VaD group compared to the controls (|log
FC| ≥ 0.26,
≤ 0.05). Enrichment pathways analyses showed that neurobiological processes related to synaptic vesicle cycle and axon guidance may be dysregulated in VaD. Extrinsic component of synaptic vesicle membrane was the most enriched term in the cellular components (CC) terms. 19 candidate proteins were filtered for further modeling. A nomogram was developed with the combination of HECT domain E3 ubiquitin protein ligase 3 (HECTD3), Nidogen-2 (NID2), FTO alpha-ketoglutarate-dependent dioxygenase (FTO), Golgi membrane protein 1 (GOLM1), and N-acetylneuraminate lyase (NPL), which could be used to predict VaD risk with favorable efficacy.
This study offers a comprehensive and integrated view of serum proteomics and contributes to a valuable proteomics-based diagnostic model for VaD.
It has been reported that the offspring of diabetic pregnant women have an increased risk for neural tube defects. Previous studies in animal models suggested that high glucose induces cell apoptosis ...and epigenetic changes in the developing neural tube. However, effects on other cellular aspects such as the cell shape changes were not fully investigated. Actin dynamics plays essential roles in cell shape change. Disruption on actin dynamics is known to cause neural tube defects. In the present study, we used a 3D neuroepithelial cyst model and a rosette model, both cultured from human embryonic stem cells, to study the cellular effects caused by high glucose. By using these models, we observed couple of new changes besides increased apoptosis. First, we observed that high glucose disturbed the distribution of pH3 positive cells in the neuroepithelial cysts. Secondly, we found that high glucose exposure caused a relatively smaller actin inner boundary enclosed area, which was unlikely due to osmolarity changes. We further investigated key glucose metabolic enzymes in our models and the results showed that the distribution of hexokinase1 (HK1) was affected by high glucose. We observed that hexokinase1 has an apical-basal polarized distribution and is highest next to actin at the boundaries. hexokinase1 was more diffused and distributed less polarized under high glucose condition. Together, our observations broadened the cellular effects that may be caused by high glucose in the developing neural tube, especially in the secondary neurulation process.
Background:
The temporomandibular joint is often afflicted by osteoarthritis (TMJOA), causing pain and dysfunction, which is particularly prevalent in the elderly population. IL-37 is effective in ...avoiding excessive inflammatory damage to the organism. This article investigates the role and mechanism of intracellular IL-37 in TMJOA.
Methods:
Enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, Western blotting, Senescence-associated β-galactosidase staining, immunofluorescence, and lentivirus were performed to elucidate the underlying mechanism.
Results:
The results confirmed that IL-37 in synovial cells decreased with aging. Inflammatory stimulus elevated intracellular IL-37 in synoviocytes, while lentiviral knockdown of IL-37 resulted in more inflammatory factor production. Dynamic changes of IL-37 were observed in the nucleus and supernatant. In addition, Caspease-1 inhibitor hindered intracellular IL-37 maturation, and Smad3 inhibitor caused the loss of nuclear translocation of mature IL-37. Transfection of synovial cells with IL-37-expressing lentivirus resulted in relief not only of synovitis but also of the cartilage damage and inflammation caused by synovitis.
Conclusion:
This study provides new insights into the intracellular anti-inflammatory mechanism of IL-37. It also confirms that IL-37 decreases with cellular senescence and that increasing intracellular IL-37 can effectively treat synovitis and synovitis-induced inflammatory damage to cartilage.
Exosomes from tumor cells and immune cells regulate the tumor microenvironment through the biomolecules or microRNAs (miRNAs) they carry. This research aims to investigate the role of miRNA in ...exosomes derived from tumor-associated macrophages (TAMs) in the progression of oral squamous cell carcinoma (OSCC). RT-qPCR and Western blotting assays were used to determine the expression of genes and proteins in OSCC cells. CCK-8, Scratch assay and invasion-related proteins were utilized to detect the malignant progression of tumor cells. High-throughput sequencing predicted differentially expressed miRNAs in exosomes secreted by M0 and M2 macrophages. Compared with exosomes from M0 macrophages, exosomes from M2 macrophages led to enhanced proliferation and invasion of OSCC cells and inhibited their apoptosis. High-throughput sequencing results show that miR-23a-3p is differentially expressed in exosomes from M0 and M2 macrophages. MiRNA target gene database predicts that phosphatase and tensin homolog (PTEN) are target genes of miR-23a-3p. Further studies revealed that transfection of miR-23a-3p mimics inhibited PTEN expression in vivo and in vitro and promoted the malignant progression of OSCC cells, which was reversed by miR-23a-3p inhibitors. MiR-23a-3p in exosomes derived from M2 macrophages promotes malignant progression of OSCC. PTEN is a potential intracellular target of miR-23a-3p. MiR-23a-3p, an M2 macrophage-associated exosome, is a promising target for the future treatment of OSCC.
Mobile software applications (apps) have transformed how individuals oversee and maintain their own health. One way that girls can monitor their menstrual cycles is through the increasingly ...widespread use of mobile menstrual tracking apps. This study aimed to examine menstrual symptom tracking for adolescents in English and Chinese apps, exploring menstrual literacy, cross-cultural differences, and framing, or presentation, of symptoms. The mixed-methods content analysis involved 15 popular free menstrual tracking apps in English (n = 8) and Chinese (n = 7), sampled from December 2022 to January 2023. A quantitative analysis of qualitative data was conducted through manual coding of content and automatically analyzing sentiment, or emotional tone, using a computational approach. We found that (1) menstrual literacy on symptom management or treatment was generally insufficient, (2) there were more available emotional than physical symptoms in English than Chinese apps, and (3) symptoms were framed more negatively than positively somewhat more in Chinese than English apps. Our findings emphasize the urgency to provide better evidence-informed communication about symptoms, either presented more positively or neutrally, in menstrual tracking apps for adolescent users. Since adolescence is a critical developmental stage that requires ample support, we recommend that digital menstrual trackers be crucially improved and future research should investigate how they can uniquely shape attitudes and experiences, and subsequent sexual and reproductive health empowerment and bodily autonomy.
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