JOURNAL/nrgr/04.03/01300535-202501000-00030/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery. Our previous in vitro study demonstrated that exosomes/small extracellular vesicles (sEVs) isolated from cerebral endothelial cells (CEC-sEVs) of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a (miR-27a) is an elevated miRNA in ischemic CEC-sEVs. In the present study, we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a (27a-sEVs) further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs. 27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector. Small EVs isolated from CECs transfected with a scramble vector (Scra-sEVs) were used as a control. Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs. An array of behavior assays was used to measure neurological function. Compared with treatment of ischemic stroke with Scra-sEVs, treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side, and significantly improved neurological outcomes. In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth. Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone, while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a, and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone. Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs. Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes. Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.
TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function mutations in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. Herein, we showed that gain-of-function mutation or pharmacological activation of TRPV3 resulted in PARP1/AIFM1/MIF axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging reactive oxygen species or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis (AD), while inhibiting PARP1 largely alleviated the MC903-induced dermatitis. Additionally, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of AD. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/MIF axis is a critical contributor to the pathogenesis of Olmsted syndrome and AD, suggesting that modulating the PARP1/AIFM1/MIF axis is a promising therapy for these conditions.
ETHNOPHARMACOLOGICAL RELEVANCE: China and India have unique traditional medicine systems with vast territory and rich medical resources. Traditional medicines in China include traditional Chinese medicine, Tibetan medicine, Mongolian medicine, Uyghur medicine, Dai medicine, etc. In the third national survey of Chinese medicine resources, 12694 medicinal materials were identified. Traditional medicines in India include Ayurveda, Unani, Siddha, Homoeopathy, etc. There are 7263 medicinal materials in India. AIM OF THE STUDY: To reveal the characteristics of medicinal materials between China and India respectively, and to compare the similarities and differences in terms of properties, tastes, medicinal parts and therapeutic uses and to promote the exchange of traditional medicine between China and India and the international trade of traditional medicine industry. METHODS: The information of medicinal materials between China and India was extracted from The Chinese Traditional Medicine Resource Records and Pharmacopoeia of the People's Republic of China, as well as from 71 Indian herbal monographs. The information of each medicinal material, such as types, families, genera, properties, distribution, medicinal parts, efficacy, therapeutic uses, dosage form and dosage, was recorded in Excel for statistical analysis and visual comparison. RESULTS: A total of 12694 medicinal materials in China and 5362 medicinal materials in India were identified. The medicinal materials were mostly distributed in Southwest China and northern India. Plants were the main sources of medicinal materials. The common medicinal parts in China were whole medicinal materials, roots and rhizomes, and India used more renewable fruits, seeds and leaves. They are commonly used in the treatment of digestive system diseases. There were 1048 medicinal materials used by both China and India, which were distributed in 188 families and 685 genera. The Chinese and Indian pharmacopoeias had a total of 80 species of medicinal materials used by both China and India. CONCLUSIONS: The characteristics of medicinal materials between China and India were somewhat different, which was conducive to provide a reference basis for traditional medicine in China or India to increase the medicinal parts and indications when using a certain medicinal material, as well as to expand the source of medicine and introduce new resources. However, there were certain similarities and shared medicinal materials, which can tap the potential of bilateral trade of medicinal materials between China and India, so as to promote the medical cultural exchange and economic and trade cooperation between the two countries.
The core task of neuromorphic devices is to effectively simulate the behavior of neurons and synapses. Based on the functionality of ferroelectric domains with the advantages of low power consumption and high-speed response, great progress has been made in realizing neuromimetic behaviors such as ferroelectric synaptic devices. However, the correlation between the ferroelectric domain dynamics and neuromimetic behavior remains unclear. Here, we reveal the correlation between domain/domain wall dynamics and neuromimetic behaviors from a microscopic perspective in real-time by using high temporal and spatial resolution in situ transmission electron microscopy. Furthermore, we propose utilizing ferroelectric microstructures for the simultaneous simulation of neuronal and synaptic plasticity, which is expected to improve the integration and performance of ferroelectric neuromorphic devices. We believe that this work to study neuromimetic behavior from the perspective of domain dynamics is instructive for the development of ferroelectric neuromorphic devices.
The conventional inactivated tetanus toxin plays an instrumental role in preventing tetanus. Nevertheless, the challenges associated with its production process, the potential for adverse reactions, and reduced effectiveness in vulnerable populations such as neonates and the elderly rise the need for a novel tetanus toxin vaccine. Recombinant subunit vaccine offer a viable solution, and the tetanus toxin fragment C (TTFC) is emerging as a promising candidate. In this study, through spontaneous isopeptide bond formation we conjugated the recombinant TTFC to self-assembled mi3 nanoparticle, which derived from an optimized KDPG aldolase, and generated the TTFC-mi3 protein nanoparticle vaccine. We found that TTFC-mi3 is stable, uniform spherical nanoparticles. Comparing with the free TTFC alone, TTFC-mi3 enhances the uptake and subsequent activation of dendric cells (DCs). In addition, a single dose of adjuvant-free TTFC-mi3 elicited a more rapid and potent protective immunity in mice. Moreover, TTFC-mi3 is of favorable safety in vitro and in vivo. Our findings indicate that TTFC-mi3 is a rapid-response, non-aluminum-adjuvanted vaccine against tetanus.
Considerable uncertainty remains regarding the associations of multiple factors with brain health. We aimed to conduct an exposome-wide association study on neurodegenerative disease and neuropsychiatry disorders using data of participants from the UK Biobank. Multivariable Cox regression models with the least absolute shrinkage and selection operator technique as well as principal component analyses were used to evaluate the exposures in relation to common disorders of central nervous system (CNS). Restricted cubic splines were conducted to explore potential nonlinear correlations. Then, weighted standardized scores were generated based on the coefficients to calculate the joint effects of risk factors. We also estimated the potential impact of eliminating the unfavorable profiles of risk domains on CNS disorders using population attributable fraction (PAF). Finally, sensitivity analyses were performed to reduce the risk of reverse causality. The current study discovered the significantly associated exposures fell into six primary exposome categories. The joint effects of identified risk factors demonstrated higher risks for common disorders of CNS (HR = 1.278 ~ 3.743, p < 2e-16). The PAF varied by exposome categories, with lifestyle and medical history contributing to majority of disease cases. In total, we estimated that up to 3.7 ~ 64.1% of disease cases could be prevented.This study yielded modifiable variables of different categories and assessed their joint effects on common disorders of CNS. Targeting the identified exposures might help formulate effective strategies for maintaining brain health.
Radiotherapy is a preferred treatment for brain metastases, which kills cancer cells via high doses of radiation meanwhile hardly avoiding damage to surrounding healthy cells. Therefore, the delineation of organs-at-risk (OARs) is vital in treatment planning to minimize radiation-induced toxicity. However, the following aspects make OAR delineation a challenging task: extremely imbalanced organ sizes, ambiguous boundaries, and complex anatomical structures. To alleviate these challenges, we imitate how specialized clinicians delineate OARs and present a novel cascaded multi-OAR segmentation framework, called OAR-SegNet. OAR-SegNet comprises two distinct levels of segmentation networks: an Anatomical-Prior-Guided network (APG-Net) and a Point-Cloud-Guided network (PCG-Net). Specifically, APG-Net handles segmentation for all organs, where multi-view segmentation modules and a deep prior loss are designed under the guidance of prior knowledge. After APG-Net, PCG-Net refines small organs through the mini-segmentation and the point-cloud alignment heads. The mini-segmentation head is further equipped with the deep prior feature. Extensive experiments were conducted to demonstrate the superior performance of the proposed method compared to other state-of-the-art medical segmentation methods.
As global climate change progresses, soil will experience prolonged periods of both drought and heavy rainfall, leading to a more frequent drought-re-wetting process that may impact the ecosystem's carbon (C) cycle. However, understanding the extent to which different water conditions and wet-dry cycles alter the process of soil organic carbon (SOC) mineralization remains limited. Therefore, our study focused on the dammed land unique to the Loess Plateau, silted by check dams constructed for erosion control. We implemented three water gradients-drought (30% WHC), water stress (100% WHC), and wet-dry cycling (30-100%)-indoors to observe the SOC mineralization process five times. We identified a transient excitation effect of the wet-dry cycles on SOC mineralization. Soil mineralization decreased gradually with the alternation of wet-dry cycles. The wet-dry cycles not only significantly impacted the contents of SOC and TN but also stimulated the activities of enzymes related to C and N cycles. As the cycle frequency increased, the utilization of C sources by soil microorganisms gradually decreased, and the dominance of carbohydrates, amines, and acids evolved into a single acid, esters, or alcohols. Phosphatase and Chloroflexi were the main factors influencing SOC mineralization under drought stress, while TN and Ascomycota were the primary factors under water stress. SOC and Gemmatimonadetes were the main limiting factors for SOC mineralization under the wet-dry cycles. Additionally, we quantified the direct and interactive contributions of each factor to SOC mineralization. The direct contributions of drought stress, water stress, and the wet-dry cycles to SOC mineralization were 0.961, 0.736, and 0.942, respectively. This study contributes to a more comprehensive understanding of the mechanisms underlying SOC mineralization in the Loess Plateau under changing conditions.
Low-light conditions pose significant challenges to vision tasks, such as salient object detection (SOD), due to insufficient photons. Light-insensitive RGB-T SOD models mitigate the above problems to some extent, but they are limited in performance as they only focus on spatial feature fusion while ignoring the frequency discrepancy. To this end, we propose an RGB-T SOD model by mining spatial-frequency cues, called SFMNet, for low-light scenes. Our SFMNet consists of spatial-frequency feature exploration (SFFE) modules and spatial-frequency feature interaction (SFFI) modules. To be specific, the SFFE module aims to separate spatial-frequency features and adaptively extract high and low-frequency features. Moreover, the SFFI module integrates cross-modality and cross-domain information to capture effective feature representations. By deploying both modules in a top-down pathway, our method generates high-quality saliency predictions. Furthermore, we construct the first low-light RGB-T SOD dataset as a benchmark for evaluating performance. Extensive experiments demonstrate that our SFMNet can achieve higher accuracy than the existing models for low-light scenes.
This study aims to investigate the role of claudin-5 (Cldn5) in cardiac structural integrity. Proteomic analysis was performed to screen the protein profiles in enlarged left atrium from atrial fibrillation (AF) patients. Cldn5 shRNA adeno-associated virus (AAV) or siRNA was injected into the mouse left ventricle or added into HL1 cells respectively to knockdown Cldn5 in cardiomyocytes to observe whether the change of Cldn5 influences cardiac morphology and function, and affects those protein expressions stem from the proteomic analysis. Mitochondrial density and membrane potential were also measured by Mitotracker staining and JC-1 staining under the confocal microscope in HL1 cells. Cldn5 was reduced in cardiomyocytes from the left atrial appendage of AF patients compared to non-AF donors. Proteomic analysis showed 83 proteins were less abundant and 102 proteins were more abundant in AF patients. KEGG pathway analysis showed less abundant CACNA2D2, CACNB2, MYL2 and MAP6 were highly associated with dilated cardiomyopathy. Cldn5 shRNA AAV injection caused severe cardiac atrophy, dilation and myocardial dysfunction in mice. The decreases in mitochondrial numbers and mitochondrial membrane potentials in HL1 cells were observed after Cldn5 knockdown. We demonstrated for the first time the mechanism of Cldn5 downregulation-induced myocyte atrophy and myocardial dysfunction might be associated with the downregulation of CACNA2D2, CACNB2, MYL2 and MAP6, and mitochondrial dysfunction in cardiomyocytes.
BACKGROUND: Major depressive disorder (MDD) and bipolar disorder (BD) are prevalent psychiatric conditions linked to inflammatory processes. However, it is unclear whether associations of immune cells with these disorders are likely to be causal. METHODS: We used two-sample Mendelian randomization (MR) approach to investigate the relationship between 731 immune cells and the risk of MDD and BD. Rigorous sensitivity analyses are conducted to assess the reliability, heterogeneity, and horizontal pleiotropy of the findings. RESULTS: Genetically-predicted CD27 on IgD+ CD38- unswitched memory B cell (inverse variance weighting (IVW): odds ratio (OR) [95â¯%]: 1.017 [1.007 to 1.027], pâ¯=â¯0.001), CD27 on IgD+ CD24+ B cell (IVW: OR [95â¯%]: 1.021 [1.011 to 1.031], pâ¯=â¯4.821E-05) and other 12 immune cells were associated with increased risk of MDD in MR, while HLA DR++ monocyte %leukocyte (IVW: OR [95â¯%]: 0.973 [0.948 to 0.998], pâ¯=â¯0.038), CD4 on Central Memory CD4+ T cell (IVW: OR [95â¯%]: 0.979 [0.963 to 0.995], pâ¯=â¯0.011) and other 13 immune cells were associated with decreased risk of MDD in MR. Additionally, CD33+ HLA DR+ Absolute Count (IVW: OR [95â¯%]: 1.022[1.007 to 1.036], pâ¯=â¯0.007), CD28+ CD45RA- CD8+ T cell %T cell (IVW: OR [95â¯%]: 1.024 [1.008 to 1.041], pâ¯=â¯0.004) and other 18 immune cells were associated with increased risk of BD in MR, while CD62L on CD62L+ myeloid Dendritic Cell (IVW: OR [95â¯%]: 0.926 [0.871 to 0.985], pâ¯=â¯0.014), IgD- CD27- B cell %lymphocyte (IVW: OR [95â¯%]: 0.918 [0.880 to 0.956], pâ¯=â¯4.654E-05) and other 13 immune cells were associated with decreased risk of BD in MR. CONCLUSIONS: This MR study provides robust evidence supporting a causal relationship between immune cells and the susceptibility to MDD and BD, offering valuable insights for future clinical investigations. Experimental studies are also required to further examine causality, mechanisms, and treatment potential for these immune cells for MDD and BD.
ETHNOPHARMACOLOGICAL RELEVANCE: Heart failure with preserved ejection fraction (HFpEF) has emerged as a condition with high incidence and mortality rates in recent years. Dengzhan Shengmai capsule (DZSMC) is a Chinese patent medicine based on the classic recipe "Shengmai powder". The relevant Chinese medicine ratio of Erigeron breviscapus (Vaniot) Hand.-Mazz., Panax ginseng C.A.Mey., Schisandra chinensis (Turcz.) Baill., and Ophiopogon japonicus (Thunb.) Ker Gawl. is 30 : 6 : 6 : 11 . Traditional Chinese medicine (TCM) is being increasingly explored as a safe and effective treatment modality for HFpEF. Clinical studies have shown that DZSMCs can effectively treat heart failure, however, the mechanism of action of DZSMCs in the treatment of HFpEF are still not clear. AIM OF THE STUDY: To investigate the efficacy and underlying mechanisms of Dengzhan Shengmai capsule (DZSMC), in the treatment of HFpEF by focusing on its ability to treat microvascular inflammation. MATERIALS AND METHODS: First, the efficacy of DZSMCs against HFpEF was predicted by network pharmacology. After 3 days of adaptive feeding in SPF-grade polypropylene cages, the mice in the Model group, DZSMC group, and Captopli group underwent single kidney resection, and micropumps were implanted in their backs for continuous infusion of aldosterone at a rate of 0.3 µg/h for 4 weeks. Moreover, the mice were given DZSMCs or Captopli via oral gavage for four weeks. Overall, cardiac function was evaluated in mice, and cardiac ultrasound and blood biochemical indices were evaluated in HFpEF mice. RESULTS: DZSMCs can ameliorate myocardial hypertrophy and cardiomyocyte damage caused by excessive myocardial stress, ultimately mitigating long-term cardiac impairment; it aids in the restoration of myocardial fibre proliferation and enhances mitochondrial morphology and function. In a murine model of ventricular hypertrophy and left ventricular dysfunction, which are indicative of cardiac insufficiency, the administration of DZSMCs resulted in notable improvements. Echocardiographic and overall assessments of cardiac function revealed a reduction in cardiac dysfunction and ventricular hypertrophy post-DZSMC intervention. Moreover, intervention with DZSMCs led to a reduction in the serum levels of several markers associated with chronic systemic inflammation, such as sST2, IL1RL1, CRP, and IL-6. Simultaneously, the levels of indicators of microvascular inflammation, including VCAM and E-SELECTIN, also decreased following DZSMC intervention. These findings suggest the potential multifaceted impact of DZSMCs in alleviating cardiac abnormalities, mitigating systemic inflammation, and reducing microvascular inflammatory markers, highlighting their promising therapeutic role in managing myocardial health. CONCLUSIONS: These results provide novel evidence that DZSMCs improve HFpEF by regulating microvascular inflammation.
Carbon dioxide (CO2) electroreduction provides a sustainable route for realizing carbon neutrality and energy supply. Up to now, challenges remain in employing abundant and inexpensive nickel materials as candidates for CO2 reduction due to their low activity and favorable hydrogen evolution. Here, the representative iron-modified nickel nanoparticles embedded in nitrogen-doped carbon (Ni1-Fe0.125-NC) with the porous botryoid morphology were successfully developed. Hexamethylenetetramine is used as nitrogen-doped carbon source. The collaboration of internal lattice expansion with electron effect and external confinement effect with size effect endows the significant enhancement in electrocatalytic CO2 reduction. The optimized Ni1-Fe0.125-NC exhibits broad potential ranges for continuous carbon monoxide (CO) production. A superb CO Faradaic efficiency (FECO) of 85.0 % realized at -1.1 V maintains a longtime durability over 35 h, which exceeds many state-of-the-art metal catalysts. Theoretical calculations further confirm that electron redistribution promotes the desorption of CO in the process for favorable CO production. This work opens a new avenue to design efficient nickel-based materials by considering the intrinsic structure and external confinement for CO2 reduction.
In this report, non-isomerisable analogs of arginine tRNA (Arg-triazole-tRNA) have been synthesized as tools to study tRNA-dependent aminoacyl-transferases. The synthesis involves the incorporation of 1,4 substituted-1,2,3 triazole ring to mimic the ester bond that connects the amino acid to the terminal adenosine in the natural substrate. The synthetic procedure includes (i) a coupling between 2'- or 3'-azido-adenosine derivatives and a cytidine phosphoramidite to access dinucleotide molecules, (ii) Cu-catalyzed cycloaddition reactions between 2'- or 3'-azido dinucleotide in the presence of an alkyne molecule mimicking the arginine, providing the corresponding Arg-triazole-dinucleotides, (iii) enzymatic phosphorylation of the 5'-end extremity of the Arg-triazole-dinucleotides with a polynucleotide kinase, and (iv) enzymatic ligation of the 5'-phosphorylated dinucleotides with a 23-nt RNA micro helix that mimics the acceptor arm of arg-tRNA or with a full tRNAarg. Characterization of nucleoside and nucleotide compounds involved MS spectrometry, 1H, 13C and 31P NMR analysis. This strategy allows to obtain the pair of the two stable regioisomers of arg-tRNA analogs (2' and 3') which are instrumental to explore the regiospecificity of arginyl transferases enzyme. In our study, a first binding assay of the arg-tRNA micro helix with the Arginyl-tRNA-protein transferase 1 (ATE1) was performed by gel shift assays.
Background: Virtual non-calcium (VNCa) imaging based on dual-energy computed tomography (CT) plays an increasingly important role in diagnosing spinal diseases. However, the utility of VNCa technology in the measurement of vertebral bone mineral density (BMD) is limited, especially the VNCa CT value at multiple calcium suppression levels and the slope of VNCa curve. This retrospective cross-sectional study aimed to explore the correlation between vertebral BMD and new VNCa parameters from dual-layer spectral detector CT. Methods: The dual-layer spectral detector CT and quantitative CT (QCT) data of 4 hydroxyapatite (HAP) inserts and 667 vertebrae of 234 patients (132 male and 102 female) who visited a university teaching hospital between April and May 2023 were retrospectively analyzed. The BMD values of 3 vertebrae (T12, L1, and L2) and inserts were measured using QCT, defined as QCT-BMD. The VNCa CT values and the slope λ of the VNCa attenuation curve of vertebrae and inserts were recorded. The correlations between VNCa parameters (VNCa CT value, slope λ) and QCT-BMD were analyzed. Results: For the vertebrae, the correlation coefficient ranged from -0.904 to 0.712 (all P<0.05). As the calcium suppression index (CaSI) increased, the correlation degree exhibited a decrease first and then increased, with the best correlation (r=-0.904, P<0.001) observed at the index of 25%. In contrast, the correlation coefficient for the inserts remained relatively stable (r=-0.899 to -1, all P<0.05). For the vertebrae, the values of 3 slopes λ (λ1, λ2, and λ3) derived from the VNCa attenuation curve were 6.50±1.99, 3.75±1.15, and 2.04±0.62, respectively. Regarding the inserts, the λ1, λ2, and λ3 values were 11.56 [interquartile range (IQR): 2.40-22.62], 6.68 (IQR: 1.39-13.49), and 3.63 (IQR: 0.75-7.8), respectively. For the vertebrae, all 3 correlation coefficients between 3 slopes λ and QCT-BMD were 0.956 (all P<0.05). For the inserts, the 3 correlation coefficients were 0.996, 0.998, and 1 (all P<0.05), respectively. Conclusions: A promising correlation was detected between VNCa CT parameters and QCT-BMD in vertebrae, warranting further investigation to explore the possibility of VNCa imaging to assess BMD.
Preventing the occurrence of secondary caries serves as one of the significant issues in dental clinic, thus make it indispensable to improving the properties of conventional composite resin (CR) by developing a novel CR. In present study, two groups of experimental CRs loaded with different contents of fluoride-doped nano-zirconia fillers (25 wt% and 50 wt%) were fabricated. The surface topography, mechanical performance, fluoride release, antibacterial effect, aging property and cytotoxicity of the experimental CRs were evaluated subsequently. A uniform distribution of the F-zirconia fillers over the whole surface of resin matrix could be observed. The experimental CRs showed continuous fluoride release within 28 days, which was positively correlated with the content of F-zirconia fillers. Moreover, the amount of fluoride release increased in the acidic buffer. Addition of F-zirconia fillers could improve the color stability, wear resistance and microhardness of the experimental CRs, without reducing the flexure strength. Furtherly, the fluoride ions released continuously from the experimental CRs resulted in effective contact and antibacterial properties, while they showed no cytotoxicity. As a consequence, considerations can be made to employ this new kind of composite resin loaded with fluoride-doped nano-zirconia fillers to meet clinical requirements when the antimicrobial benefits are desired.
OBJECTIVE: We performed a post hoc exploratory analysis of Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke (RICAMIS) to determine whether hypertension history and baseline systolic blood pressure (SBP) affect the efficacy of remote ischemic conditioning (RIC). METHODS: Based on the full analysis set of RICAMIS, patients were divided into hypertension versus non-hypertension group, or <140 mmHg versus ≥140 mmHg group. Each group was further subdivided into RIC and control subgroups. The primary outcome was modified Rankin Scale (mRS) 0-1 at 90 days. Efficacy of RIC was compared among patients with hypertension versus nonhypertension history and SBP of <140 mmHg versus ≥140 mmHg. Furthermore, the interaction effect of treatment with hypertension and SBP was assessed. RESULTS: Compared with control group, RIC produced a significantly higher proportion of patients with excellent functional outcome in the nonhypertension group (RIC vs. control: 65.7% vs. 57.0%, OR 1.45, 95% CI 1.06-1.98; p = 0.02), but no significant difference was observed in the hypertension group (RIC vs. control: 69.1% vs. 65.2%, p = 0.17). Similar results were observed in SBP ≥140 mmHg group (RIC vs. control: 68.0% vs. 61.2%, p = 0.009) and SBP <140 mmHg group (RIC vs. control: 65.6% vs. 64.7%, p = 0.77). No interaction effect of RIC on primary outcome was identified. INTERPRETATION: Hypertension and baseline SBP did not affect the neuroprotective effect of RIC, but they were associated with higher probability of excellent functional outcome in patients with acute moderate ischemic stroke who received RIC treatment.
The pathogenesis of ferroptosis in traumatic brain injury (TBI) is unclear; therefore, we aimed to identify key molecules associated with ferroptosis in TBI using bioinformatics analysis to determine its underlying mechanisms. GSE128543 dataset was downloaded from the Gene Expression Omnibus (GEO) database, and TBI-associated modules were obtained by weighted gene co-expression network analysis (WGCNA). We identified 60 differentially expressed genes (DEGs) by intersecting the modules with ferroptosis and glycolysis/gluconeogenesis gene libraries. The hypoxia-inducible factor-1 (HIF-1) signaling pathway was identified to be critical for ferroptosis post-TBI, and protein-protein interaction (PPI) network identified 20 hub genes, including phosphoglycerate kinase 1 (PGK1), ribosomal protein (RP) family, pyruvate kinase M1/2 (PKM), hypoxia-inducible factor 1α subunit (HIF-1α), and MYC genes. In this study, we further explored the role of PGK1, a gene involved in HIF-1 signaling pathway; however, its role and mechanism in TBI are still unclear. Moreover, we constructed a TBI mouse model and examined PGK1 and HIF-1α expression levels, and the results revealed their expressions increased after cortical injury in mice and they co-localized in the same cells. Furthermore, we examined the expressions of PGK1 in the cerebrospinal fluid of 20 clinical patients with different degrees of brain injuries within 48 h of surgery and examined the cognitive function of patients according to the Glasgow Coma Scale (GCS). The results revealed that PGK1 expression level was negatively correlated with the severity of the brain injury. These findings suggest that PGK1 may become a potential hub gene for ferroptosis via the HIF-1 signaling pathway, second to neurological injury after TBI, thereby affecting patient prognosis.
BACKGROUND: Compared with the time-consuming and labor-intensive for biological validation in vitro or in vivo, the computational models can provide high-quality and purposeful candidates in an instant. Existing computational models face limitations in effectively utilizing sparse local structural information for accurate predictions in circRNA-disease associations. This study addresses this challenge with a proposed method, CDA-DGRL (Prediction of CircRNA-Disease Association based on Double-line Graph Representation Learning), which employs a deep learning framework leveraging graph networks and a dual-line representation model integrating graph node features. METHOD: CDA-DGRL comprises several key steps: initially, the integration of diverse biological information to compute integrated similarities among circRNAs and diseases, leading to the construction of a heterogeneous network specific to circRNA-disease associations. Subsequently, circRNA and disease node features are derived using sparse autoencoders. Thirdly, a graph convolutional neural network is employed to capture the local graph network structure by inputting the circRNA-disease heterogeneous network alongside node features. Fourthly, the utilization of node2vec facilitates depth-first sampling of the circRNA-disease heterogeneous network to grasp the global graph network structure, addressing issues associated with sparse raw data. Finally, the fusion of local and global graph network structures is inputted into an extra trees classifier to identify potential circRNA-disease associations. RESULTS: The results, obtained through a rigorous five-fold cross-validation on the circR2Disease dataset, demonstrate the superiority of CDA-DGRL with an AUC value of 0.9866 and an AUPR value of 0.9897 compared to existing state-of-the-art models. Notably, the hyper-random tree classifier employed in this model outperforms other machine learning classifiers. CONCLUSION: Thus, CDA-DGRL stands as a promising methodology for reliably identifying circRNA-disease associations, offering potential avenues to alleviate the necessity for extensive traditional biological experiments. The source code and data for this study are available at https://github.com/zywait/CDA-DGRL .
Biomarkers, Tumor , Neoplasms , RNA, Circular , Humans , RNA, Circular/genetics , Neoplasms/genetics , Biomarkers, Tumor/genetics , Deep Learning , Computational Biology/methods , Neural Networks, Computer
