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Sepsis patients are highly prone to sepsis-associated encephalopathy (SAE) complications, resulting in a high mortality rate. Recently, there has been no specific treatment for long-term improvement of cerebral function. Ginsenoside Rh2 is a form of steroidal saponins isolated from plant ginseng and has been shown to possess anti-inflammatory as well as neuroprotective characteristics; yet, the effect of ginsenoside Rh2 on SAE treatment is obscure. Accordingly, we proposed to investigate the effect of ginsenoside Rh2 in alleviating SAE damage. We established and utilized the SAE mouse model to determine the effect of Rh2 treatment on alleviating SAE. We determined the expression levels of Heme oxygenase-1(HO-1) and Nuclear factor erythroid 2-related factor 2 (Nrf2) as well as measured neural apoptosis by flow cytometry. Also, we quantified the levels of caspase-3, malondialdehyde (MDA), GSH-Px superoxide dismutase (SOD) and evaluated the animals' neural reflex function. First, used Rh2 to treat microglia BV2 and mouse neuron MN-c whether LPS exist or not, and then measured expression level of Iba-1, apoptotic rate, and ROS content applying flow cytometry. Also, we quantified the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). In comparison with the Sham group, the SAE model exhibited an elevated MDA content, caspase-3 activity, and cell apoptosis. On the other hand, the GSH-Px activity and SOD level were decreased along with a decreased neural reflex score. Our investigation concluded that Rh2 treatment significantly alleviated SAE damage and inhibited LPS-induced response via up-regulation of the Nrf2/HO-1 pathway to promote anti-oxidative stress capacity and inhibit neural cell apoptosis.
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To monitor the resistance rate and gain a deeper understanding of the resistance mechanisms, we conducted over a 2-year surveillance focusing on the Klebsiella pneumoniae associated with the clinical usage of ceftazidime-avibactam (CZA) in a teaching hospital. A total of 4,641 K. pneumoniae isolates were screened to identify the CZA resistance through antimicrobial susceptibility testing. Comprehensive analyses, including homology analysis, conjugation experiments, clone assays, and whole genome sequencing, were furtherly performed on the CZA-resistant strains. In total, four CZA-resistant K. pneumoniae (CZA-R-Kp) strains were separated from four patients, in which three of them received CZA treatment during the hospitalization, accounting for a 4% (3/75) resistance development rate of K. pneumoniae under CZA stress. All CZA-R-Kp isolates were found to possess variants of blaKPC-2. The identified mutations included blaKPC-33, blaKPC-86, and a novel variant designated as blaKPC-129, all of which were located in the Ω loop of the KPC enzyme. These mutations were found to impact the amino acid sequence and spatial structure of the enzyme's active center, consequently affecting KPC carbapenemase activity. This study underscores the importance of active surveillance to monitor the emergence of resistance to CZA, highlighting the need for ongoing research to develop effective strategies for combating antimicrobial resistance. Understanding the mechanisms behind resistance is crucial in maintaining the efficacy of CZA, a vital tool in the battle against multidrug-resistant infections.IMPORTANCEAs an effective drug for the treatment of carbapenem-resistant Klebsiella pneumoniae, ceftazidime-avibactam (CZA) began to develop resistance in recent years and showed an increasing trend. In order to effectively monitor the resistance rate of CZA and understand its resistance mechanism, we monitored K. pneumoniae for more than 2 years to find CZA-resistant strains. Through comprehensive analysis of the selected CZA-resistant strains, it was found that all the CZA-resistant strains had mutation, which could affect the activity of KPC carbapenemase. This study highlights the importance of proactive surveillance to monitor the emergence of CZA resistance, which highlights the need for ongoing research to develop effective strategies to combat antimicrobial resistance. Understanding the mechanisms behind resistance is critical to maintaining the effectiveness of CZA, an important tool in the fight against multidrug-resistant infections.
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Antibacterianos , Ceftazidima , Farmacorresistência Bacteriana Múltipla , Infecções por Klebsiella , Klebsiella pneumoniae , beta-Lactamases , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , beta-Lactamases/genética , beta-Lactamases/metabolismo , Ceftazidima/farmacologia , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/isolamento & purificação , Testes de Sensibilidade Microbiana , Mutação , Sequenciamento Completo do GenomaRESUMO
Introduction: The dissemination of carbapenem-resistant Enterobacteriales (CRE) in nosocomial settings is primarily associated with the horizontal transfer of plasmids. However, limited research has focused on the in-host transferability of carbapenem resistance. In this study, ten isolates were collected from gut specimens of five individuals, each hosting two different species, including Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Enterobacter cloacae, or Citrobacter koseri. Methods: Species identification and antimicrobial susceptibility were determined by MALDI-TOF MS and broth microdilution method. Carbapenemase genes were detected and localized using PCR, S1-PFGE and southern blot. The transferability of carbapenemase genes between species was investigated through filter mating experiments, and the genetic contexts of the plasmids were analyzed using whole genome sequencing. Results and discussion: Our results revealed that each of the ten isolates harbored a carbapenemase gene, including bla NDM-5, bla NDM-1, or bla KPC-2, on a plasmid. Five different plasmids were successfully transferred to recipient cells of E. coli, K. pneumoniae or A. baumannii by transconjugation. The genetic contexts of the carbapenemase gene were remarkably similar between the two CRE isolates from each individual. This study highlights the potential for interspecies plasmid transmission in human gut, emphasizing the colonization of CRE as a significant risk factor for the dissemination of carbapenemase genes within the host. These findings underscore the need for appropriate intestinal CRE screening and colonization prevention.
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It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Fragilidade , Lenalidomida , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Idoso , Estudos Prospectivos , Masculino , Feminino , Idoso de 80 Anos ou mais , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Lenalidomida/uso terapêutico , Lenalidomida/administração & dosagem , Bortezomib/uso terapêutico , Bortezomib/administração & dosagem , Medicina de Precisão/métodos , Idoso Fragilizado , Avaliação Geriátrica/métodos , Anticorpos MonoclonaisRESUMO
OBJECTIVES: To compare magnetic resonance (MR) short T1 inversion recovery (STIR) sequence with MR T2-weighted (T2W) sequence for detecting increased signal intensity (ISI) and assessing outcomes of ISI in cervical spondylotic myelopathy (CSM). METHODS: Data of patients with CSM who showed ISI on MR imaging and had undergone cervical spine surgery were retrospectively reviewed. STIR and T2W images were examined to assess signal intensity ratio (SIR), length and grading of the ISI, maximal spinal cord compression, canal narrowing ratio, and ligamentum flavum hypertrophy. The patients were divided into good and poor groups based on their outcomes. χ2 tests and variance analysis were used to assess intergroup differences. Univariate and multivariate logistic regression analyses were performed to identify risk factors for poor outcomes, and receiver operating characteristic curves were plotted to detect prognostic effects. RESULTS: SIR and ISI lengths were significantly different between the STIR and T2 images. In the univariate logistic regression analysis, age, diabetes, SIRT2, SIRSTIR, and ISISTIR grading were significant factors. Accordingly, in the multivariate logistic regression analysis, age, diabetes, SIRT2, and SIRSTIR were included in the model. Among patients with diabetes, we observed a significant difference between SIRT2 and SIRSTIR. CONCLUSIONS: The STIR sequence demonstrated superior capability to the T2W sequence in detecting ISI; however, there was no obvious difference in predicted outcomes. STIR sequence has a better prognostic value than T2W sequence in patients with diabetes who have CSM. ISI grading based on the STIR sequence may be a clinically valuable indicator.
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Vértebras Cervicais , Imageamento por Ressonância Magnética , Espondilose , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Espondilose/cirurgia , Espondilose/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Vértebras Cervicais/cirurgia , Vértebras Cervicais/diagnóstico por imagem , Idoso , Estudos Retrospectivos , Compressão da Medula Espinal/cirurgia , Compressão da Medula Espinal/diagnóstico por imagem , Compressão da Medula Espinal/etiologia , Adulto , Doenças da Medula Espinal/cirurgia , Doenças da Medula Espinal/diagnóstico por imagemRESUMO
BACKGROUND: Autophagy is a lysosome-dependent degradation pathway that regulates macrophage activation, differentiation, and polarization. Autophagy related 5 (Atg5) is a key protein involved in phagocytic membrane elongation in autophagic vesicles that forms a complex with Atg12 and Atg16L1. Alterations in Atg5 are related to both acute and chronic kidney diseases in experimental models. However, the role of macrophage-expressed Atg5 in acute kidney injury remains unclear. METHODS: Using a myeloid cell-specific Atg5 knockout (MΦ atg5-/-) mouse, we established renal ischemia/reperfusion and unilateral ureteral obstruction models to evaluate the role of macrophage Atg5 in renal macrophage migration and fibrosis. RESULTS: Based on changes in the serum urea nitrogen and creatinine levels, Atg5 deletion had a minimal effect on renal function in the early stages after mild injury; however, MΦ atg5-/- mice had reduced renal fibrosis and reduced macrophage recruitment after 4 weeks of ischemia/reperfusion injury and 2 weeks of unilateral ureteral obstruction injury. Atg5 deficiency impaired the CCL20-CCR6 axis after severe ischemic kidneys. Chemotactic responses of bone marrow-derived monocytes (BMDMs) from MΦ atg5-/- mice to CCL20 were significantly attenuated compared with those of wild-type BMDMs, and this might be caused by the inhibition of PI3K, AKT, and ERK1/2 activation. CONCLUSIONS: Our data indicate that Atg5 deficiency decreased macrophage migration by impairing the CCL20-CCR6 axis and inhibited M2 polarization, thereby improving kidney fibrosis.
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Obstrução Ureteral , Animais , Camundongos , Proteína 5 Relacionada à Autofagia/metabolismo , Fibrose , Isquemia/metabolismo , Rim/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Receptores CCR6/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologiaRESUMO
Acinetobacter baumannii is one of the most common multidrug-resistant pathogens causing nosocomial infections. The prevalence of multidrug-resistant A. baumannii infections is increasing because of several factors, including unregulated antibiotic use. A. baumannii drug resistance rate is high; in particular, its resistance rates for tigecycline and polymyxin-the drugs of last resort for extensively drug-resistant A. baumannii-has been increasing annually. Patients with a severe infection of extensively antibiotic-resistant A. baumannii demonstrate a high mortality rate along with a poor prognosis, which makes treating them challenging. Through carbapenem enzyme production and other relevant mechanisms, A. baumannii has rapidly acquired a strong resistance to carbapenem antibiotics-once considered a class of strong antibacterials for A. baumannii infection treatment. Therefore, understanding the resistance mechanism of A. baumannii is particularly crucial. This review summarizes mechanisms underlying common antimicrobial resistance in A. baumannii, particularly those underlying tigecycline and polymyxin resistance. This review will serve as a reference for reasonable antibiotic use at clinics, as well as new antibiotic development.
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OBJECTIVE: Computed tomography (CT) is an important tool for grading gastric cancer. Gastric cancer typically originates from epithelial cells of gastric mucosa. However, complementary markers for gastric cancer, relationship between DSCC1, GINS1 and gastric cancer remain unclear. METHODS: Gastric cancer data were obtained from gene expression omnibus (GEO). Differentially expressed genes (DEGs) were identified, weighted gene co-expression network analysis (WGCNA) was conducted. Protein-protein interaction (PPI) network was constructed and analyzed. Functional enrichment analysis, gene set enrichment analysis (GSEA), gene expression heatmaps, immune infiltration analysis were performed. The most relevant diseases related to core genes were identified using Comparative Toxicogenomics Database (CTD). TargetScan was used to screen miRNAs. Validation was carried out using Western blotting (WB) and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: 1243 DEGs were identified. Gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) analyses revealed significant enrichment in cell cycle regulation, macrophage migration control, basement membrane, extracellular regions, growth factor binding, protein complex binding, P53 signaling pathway, protein digestion and absorption, metabolic pathways. Immune infiltration analysis indicated that high expression of activated Mast cells and Neutrophils, with a strong positive correlation between them, may influence progression of gastric cancer. CTD analysis revealed associations between DSCC1, GINS1 and gastric tumors, gastrointestinal diseases, tumors, gastritis, inflammation, necrosis. WB and RT-PCR results demonstrated high expression of DSCC1 and GINS1 in gastric cancer. CONCLUSION: The expressions of DSCC1 and GINS1 are up-regulated in gastric cancer, which can be used as supplementary markers for CT diagnostic grading of gastric cancer.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/genética , Membrana Basal , Biomarcadores , Western Blotting , Perfilação da Expressão Gênica , Tomografia , Biologia Computacional , Proteínas de Ligação a DNARESUMO
STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study is to assess the potential of utilizing the MRI-based vertebral bone quality (VBQ) score as a predictive tool for pedicle screw loosening (PSL) in patients who have undergone pedicle screw fixation and to identify risk factors associated with VBQ scores. METHODS: One hundred and sixteen patients who had undergone pedicle screw fixation between December 2019 and January 2021 and had more than a year of follow-up were divided into two groups of PSL and non-PSL. The radiological and clinical parameters investigated were age, gender, body mass index, the VBQ score, length of fusion and the DXA T-score. RESULTS: Of the 116 patients included in the study, 22 patients developed pedicle screw loosening after surgery (18.97%). VBQ score of PSL group was higher than the non-PSL group (3.61 ± 0.63 vs. 2. 86 ± 0.43, p < 0.001). According to logistic regression, PSL was independently linked with a higher VBQ score (OR = 3.555, 95% confidence interval [1.620-7.802], p < 0.005). The AUC of predicting screw loosening was 0.774 (p < 0.001) for VBQ score, and the best threshold was 3.055 (sensitivity, 81.8%; specificity, 71.3%). High VBQ score was associated with age (r (114) = 0.29, p = 0.002), while it was not negatively correlated with T-scores of each part. CONCLUSION: VBQ score is an independent predictor of pedicle screw loosening, with higher scores indicating a greater risk. Our results showed that older patients and women had higher VBQ scores.
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Parafusos Pediculares , Fusão Vertebral , Humanos , Feminino , Parafusos Pediculares/efeitos adversos , Estudos Retrospectivos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Imageamento por Ressonância Magnética , Radiografia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodosRESUMO
OBJECTIVES: The diagnosis and treatment of tandem stenosis have been widely discussed. However, studies on concurrent cervical and thoracic spinal stenosis are rare in the literature. This study was aimed to investigate the risk factors for thoracic spinal stenosis (TSS) in patients with cervical spinal stenosis (CSS). METHODS: This retrospective cohort study assessed the risk factors for TSS in 162 patients who were diagnosed with CSS. Patients were divided into TSS (n = 45) and non-TSS (n = 117) groups. We retrospectively analyzed clinical characteristics and radiographic parameters including age, gender, body mass index, ossification of the cervical posterior longitudinal ligament (OPLLc), hypertrophy of cervical ligamentum flavum (HLFc), cervical stenosis segments, and cervical sagittal parameters. Cervical sagittal parameters were measured on T2-weighted magnetic resonance imaging including C2-7 Cobb angle, cervical tilt, T1 slope, thoracic inlet angle (TIA), C2-C7 sagittal vertical axis (C2-C7), and cervical curvature. RESULTS: Two groups showed significant differences in ossification of the cervical posterior longitudinal ligament, HLFc, cervical stenosis segments, and TIA. The receiver operating characteristic curves demonstrated that the optimal threshold for TIA was 68.25. In multivariate logistic regression analysis, OPLLc (odds ratio [OR] = 4.403, 95% confidence interval [CI] = 1.782-10.880, P = 0.001), HLFc (OR = 4.849, 95% CI = 1.995-11.782, P < 0.001), and TIA >68.25 degrees (OR = 2.555, 95% CI = 1.044-6.251, P = 0.040) were independent risk factors for TSS. Moreover, the multiindex receiver operating characteristic curve demonstrated that the area under the curve for predicted probability was 0.799 (P < 0.001). CONCLUSIONS: Routine thoracic magnetic resonance imaging assessment is strongly recommended in CSS patients with OPLLc, HLFc, and enlarged TIA to screen for neglected but vital thoracic disease.
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The effect of two superplasticizers (SPs) with various equivalent (eq.) alkali contents (i.e., with 0.00009% and 4.1% of Na2Oeq, respectively) on the development of an alkali-silica reaction (ASR) was investigated through the use of multilevel assessment. This testing protocol showed promising results for evaluating concrete damage due to ASRs based on mechanical and microscopical testing protocols, specifically the stiffness damage test (SDT) and the damage rating index (DRI). Concrete specimens that incorporated the aforementioned SPs and distinct reactive aggregates (coarse and fine) were manufactured and then stored in conditions that enabled ASR development and were monitored over time. Upon reaching the desired expansion levels of this study, the concrete specimens were prepared for the multilevel assessment. The results show that the SP-incorporated concrete specimens with lower and higher alkali content yielded lower and higher deterioration results, respectively. This clearly confirms that while SP-incorporated concrete that contains SPs with a higher alkali content could increase the risk of ASR deterioration, those SPs with a very low amount of alkali content could act as a mitigation strategy against ASRs. Finally, an investigation into the influence of distinct SPs on the chemical composition of an ASR gel was conducted, which confirmed that the SP with a higher alkali content had the highest potential for further deterioration.
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Spinal cord injury (SCI) can result in irreversible sensory and motor disability with no effective treatment currently. After SCI, infiltrated macrophages accumulate in epicenter through destructed blood-spinal cord barrier (BSCB). Further, great majority of macrophages are preferentially polarized to M1 phenotype, with only a few transient M2 phenotype. The purpose of this study was to explore roles of vascular endothelial cells in microglia/macrophages polarization and the underlying mechanism. Lipopolysaccharide (LPS) was used to pretreat BV2 microglia and RAW264.7 macrophages followed by administration of conditioned medium from microvascular endothelial cell line bEnd.3 cells (ECM). Analyses were then performed to determine the effects of exosomes on microglia/macrophages polarization and mitochondrial function. The findings demonstrated that administration of ECM shifted microglia/macrophages towards M2 polarization, ameliorated mitochondrial impairment, and reduced reactive oxygen species (ROS) production in vitro. Notably, administration of GW4869, an exosomal secretion inhibitor, significantly reversed these observed benefits. Further results revealed that exosomes derived from bEnd.3 cells (Exos) promote motor rehabilitation and M2 polarization of microglia/macrophages in vivo. Ubiquitin-specific protease 13 (USP13) was shown to be significantly enriched in BV2 microglia treated with Exos. USP13 binds to, deubiquitinates and stabilizes the NF-κB inhibitor alpha (IκBα), thus regulating microglia/macrophages polarization. Administration of the selective IκBα inhibitor betulinic acid (BA) inhibited the beneficial effect of Exos in vivo. These findings uncovered the potential mechanism underlying the communications between vascular endothelial cells and microglia/macrophages after SCI. In addition, this study indicates exosomes might be a promising therapeutic strategy for SCI treatment.
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The workforce has become more diverse than it used to be. Although organizations actively capitalize on workforce diversity to enhance team innovation and organizational performance, it is found that workforce diversity also has potential risks, among which interpersonal conflict is the most salient one. However, we still know relatively less about why workforce diversity may link to higher interpersonal conflict and, more importantly, how to mitigate the negative impact of workforce diversity. Based on the workplace diversity theories (e.g., the categorization-elaboration model), this study examined how workforce diversity was positively related to interpersonal conflict through impacting one's affective states, and to what extent this indirect effect can be weakened by organization-initiated practices (i.e., the inclusive human resources management (HRM) practices) and employee-initiated behaviors (i.e., employee learning-oriented behaviors). Using two-wave surveys from 203 employees from various organizations in China, we confirmed our hypotheses. Our results showed that perceived workforce diversity was positively related to interpersonal conflict through increasing negative affect (after we controlled for the objective diversity level calculated by the Blau index), and this indirect effect was weakened when the levels of inclusive HRM practices and employee learning-oriented behaviors were high. Our study suggests that it is important for organizations to be aware of the detrimental impact of workforce diversity. In addition, it is essential to use both the top-down (e.g., inclusive HRM practices) and bottom-up (e.g., employee learning-oriented behaviors) approaches to managing the challenges presented by diversity so as to unlock more potential of diversity in the workplace.
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RNA N6-methyladenosine (m6A) modification is involved in diverse biological processes. However, its role in spinal cord injury (SCI) is poorly understood. The m6A level increases in injured spinal cord, and METTL3, which is the core subunit of methyltransferase complex, is upregulated in reactive astrocytes and further stabilized by the USP1/UAF1 complex after SCI. The USP1/UAF1 complex specifically binds to and subsequently removes K48-linked ubiquitination of the METTL3 protein to maintain its stability after SCI. Moreover, conditional knockout of astrocytic METTL3 in both sexes of mice significantly suppressed reactive astrogliosis after SCI, thus resulting in widespread infiltration of inflammatory cells, aggravated neuronal loss, hampered axonal regeneration, and impaired functional recovery. Mechanistically, the YAP1 transcript was identified as a potential target of METTL3 in astrocytes. METTL3 could selectively methylate the 3'-UTR region of the YAP1 transcript, which subsequently maintains its stability in an IGF2BP2-dependent manner. In vivo, YAP1 overexpression by adeno-associated virus injection remarkably contributed to reactive astrogliosis and partly reversed the detrimental effects of METTL3 knockout on functional recovery after SCI. Furthermore, we found that the methyltransferase activity of METTL3 plays an essential role in reactive astrogliosis and motor repair, whereas METTL3 mutant without methyltransferase function failed to promote functional recovery after SCI. Our study reveals the previously unreported role of METTL3-mediated m6A modification in SCI and might provide a potential therapy for SCI.SIGNIFICANCE STATEMENT Spinal cord injury is a devastating trauma of the CNS involving motor and sensory impairments. However, epigenetic modification in spinal cord injury is still unclear. Here, we propose an m6A regulation effect of astrocytic METTL3 following spinal cord injury, and we further characterize its underlying mechanism, which might provide promising strategies for spinal cord injury treatment.
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Gliose , Traumatismos da Medula Espinal , Animais , Feminino , Masculino , Camundongos , Astrócitos/metabolismo , Gliose/metabolismo , Inflamação/metabolismo , Metiltransferases/metabolismo , Metiltransferases/farmacologia , RNA Mensageiro/metabolismo , Medula Espinal/metabolismoRESUMO
The rational design of ingenious strategies to boost the intrinsic activity and stability of ruthenium (Ru) is of great importance for the substantial progression of water electrolysis technology. Based on Mott-Schottky effect, electronic regulation within a metal/semiconductor hybrid electrocatalyst represents a versatile strategy to boost the electrochemical performance. Herein, a typical Mott-Schottky hydrogen evolution reaction (HER) electrocatalyst composed of uniform ultrafine Ru nanoclusters in situ anchored on N-doped carbon nanofibers (abbreviated as Ru@N-CNFs hereafter) through a feasible and scalable "phenolic resin-bridged" strategy is reported. Both spectroscopy analyses and density functional theory calculations manifest that such rectifying contact can induce the spontaneous electron transfer from Ru to N-doped carbon nanofibers to generate a built-in electric field, thus enormously promoting the charge transfer efficiency and HER intrinsic activity. Moreover, the seamless immobilization of Ru nanoclusters on the substrate can prevent the active sites from unfavorable migration, coarsening, and detachment, rendering the excellent structural stability. Consequently, the well-designed Ru@N-CNFs afford prominent pH-universal HER performances with small overpotentials of 16 and 17 mV at 10 mA cm-2 and low Tafel slopes of 31.8 and 28.5 mV dec-1 in acidic and alkaline electrolytes, respectively, which are superior to the state-of-the-art commercial Pt/C and Ru/C benchmarks.
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Spinal cord injury (SCI) is a severe disease of the nervous system that causes irreparable damage and loss of function, for which no effective treatments are available to date. Engineered extracellular vesicles (EVs) carrying therapeutic molecules hold promise as an alternative SCI therapy depending on the specific functionalized EVs and the appropriate engineering strategy. In this study, we demonstrated the design of a drug delivery system of peptide CAQK-modified, siRNA-loaded EVs (C-EVs-siRNA) for SCI-targeted therapy. The peptide CAQK was anchored through a chemical modification to the membranes of EVs isolated from induced neural stem cells (iNSCs). CCL2-siRNA was then loaded into the EVs through electroporation. The modified EVs still maintained the basic properties of EVs and showed favorable targeting and therapeutic effects in vitro and in vivo. C-EVs-siRNA specifically delivered siRNA to the SCI region and was taken up by target cells. C-EVs-siRNA used the inherent anti-inflammatory and neuroreparative functions of iNSCs-derived EVs in synergy with the loaded siRNA, thus enhancing the therapeutic effect against SCI. The combination of targeted modified EVs and siRNA effectively regulated the microenvironmental disturbance after SCI, promoted the transformation of microglia/macrophages from M1 to M2 and limited the negative effects of the inflammatory response and neuronal injury on functional recovery in mice after SCI. Thus, engineered EVs are a potentially feasible and efficacious treatment for SCI, and may also be used to develop targeted treatments for other diseases.
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Post-traumatic epilepsy (PTE) is an important cause of poor prognosis in patients with cerebral contusions. The primary purpose of this study is to evaluate the high-risk factors of PTE by summarizing and analyzing the baseline data, laboratory examination, and imaging features of patients with a cerebral contusion, and then developing a Nomogram prediction model and validating it. This study included 457 patients diagnosed with cerebral contusion who met the inclusion criteria from November 2016 to November 2019 at the Qinghai Provincial People's Hospital. All patients were assessed for seizure activity seven days after injury. Univariate analysis was used to determine the risk factors for PTE. Significant risk factors in univariate analysis were selected for binary logistic regression analysis. P < 0.05 was statistically significant. Based on the binary logistic regression analysis results, the prediction scoring system of PTE is established by Nomogram, and the line chart model is drawn. Finally, external validation was performed on 457 participants to assess its performance. Univariate and binary logistic regression analyses were performed using SPSS software, and the independent predictors significantly associated with PTE were screened as Contusion site, Chronic alcohol use, Contusion volume, Skull fracture, Subdural hematoma (SDH), Glasgow coma scale (GCS) score, and Non late post-traumatic seizure (Non-LPTS). Based on this, a Nomogram model was developed. The prediction accuracy of our scoring system was C-index = 98.29%. The confidence interval of the C-index was 97.28% ~ 99.30%. Internal validation showed that the calibration plot of this model was close to the ideal line. This study developed and verified a highly accurate Nomogram model, which can be used to individualize PTE prediction in patients with a cerebral contusion. It can identify individuals at high risk of PTE and help us pay attention to prevention in advance. The model has a low cost and is easy to be popularized in the clinic. This model still has some limitations and deficiencies, which need to be verified and improved by future large-sample and multicenter prospective studies.
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Contusão Encefálica , Contusões , Epilepsia Pós-Traumática , Humanos , Estudos Prospectivos , ConvulsõesRESUMO
Alzheimer's disease (AD), a common neurodegenerative disease, is characterised by the deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles. An increasing number of studies have demonstrated that Aß causes neuronal damage and mitochondrial dysfunction. Herein, we evaluated the neuroprotective effect of sodium butyrate (NaB) against Aß induced neurotoxicity in PC12 cells. The results revealed that 3 mM of NaB promoted the expression of angiotensin-converting enzyme and brain-derived neurotrophic factor, which exert a neuroprotective effect by activating G protein-coupled receptors. Moreover, NaB could significantly improve mitochondrial dysfunction caused by Aß. In conclusion, NaB protected PC12 cells from Aß-induced cell damage, highlighting the potential of NaB in AD treatment.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Animais , Ratos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/toxicidade , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/metabolismo , Apoptose , Ácido Butírico/farmacologia , Sobrevivência Celular , Potencial da Membrana Mitocondrial , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Fragmentos de Peptídeos/toxicidade , Fragmentos de Peptídeos/metabolismoRESUMO
Problems such as low light, similar background colors, and noisy image acquisition often occur when collecting images of lunar surface obstacles. Given these problems, this study focuses on the AD-Census algorithm. In the original Census algorithm, in the bit string calculated with the central pixel point, the bit string will be affected by the noise that the central point is subjected to. The effect of noise results in errors and mismatching. We introduce an improved algorithm to calculate the average window pixel for solving the problem of being susceptible to the central pixel value and improve the accuracy of the algorithm. Experiments have proven that the object contour in the grayscale map of disparity obtained by the improved algorithm is more apparent, and the edge part of the image is significantly improved, which is more in line with the real scene. In addition, because the traditional Census algorithm matches the window size in a fixed rectangle, it is difficult to obtain a suitable window in the image range of different textures, affecting the timeliness of the algorithm. An improvement idea of area growth adaptive window matching is proposed. The improved Census algorithm is applied to the AD-Census algorithm. The results show that the improved AD-Census algorithm has been shown to have an average run time of 5.3% and better matching compared to the traditional AD-Census algorithm for all tested image sets. Finally, the improved algorithm is applied to the simulation environment, and the experimental results show that the obstacles in the image can be effectively detected. The improved algorithm has important practical application value and is important to improve the feasibility and reliability of obstacle detection in lunar exploration projects.
RESUMO
OBJECTIVE: To develop a new classification of acromion based on the subacromial impingement theory and the Rockwood tilt view. And explore the application value of the new classification in the diagnosis and treatment of rotator cuff tear. METHODS: The clinical data of 101 patients underwent shoulder arthroscopic surgery for impingement syndrome or rotator cuff tear from January to December 2017 were retrospectively analyzed. There were 34 males and 67 females, aged from 34 to 76 years with an average of (56.31±9.63) years old, course of disease from 2 to 12 months with average of 6 months. Preoperative radiographs of the routine anteroposterior view, Rockwood tilt view and the supraspinatus outlet view were obtained. Based on the subacromial impingement theory and Rockwood radiographs, the morphology of the acromion can be divided into three types:typeâ (flat type), typeâ ¡(bump type), and type â ¢ (impingement type). Two observers classified 101 shoulder Rockwood radiographs according to the new classification method and the supraspinatus Outlet radiographs according to the traditional acromial morphological classification method. Supraspinatus tendon injuries were classified into no tear, partial-thickness tear, and full-thickness tear according to the arthroscopic findings. Concordance test (Kappa value) between the inter-observer and intra-observer was carried out for the new classification method and the traditional classification method respectively. The rank sum test was used to compare the mean acromiohumeral distance(AHD) of the three acromion forms in the new acromion classification method. Spearman rank correlation test and Gamma method were used to analyze the correlation between the new acromion classification method and the degree of supraspinatus tendon tear. RESULTS: The inter-observer consistency analysis of the new classification system was significantly better than that of the traditional classification (0.827 vs 0.278), the intra-observer consistency analysis of the new classification system were also significantly better than that of the traditional classification (0.921 vs 0.448, 0.890 vs 0.539). There was no statistical significance in the AHD among three types of the new classification(H=2.186, P>0.05). In all 101 patients, the highest proportion of impingement type acromion was 45.5% (46 cases), followed by bump type acromion was 36.6% (37 cases), and flat type acromion was 17.8% (18 cases). The incidence of supraspinatus tendon tear in the patients with impingement type acromion was significantly higher than that of the other two types of acromion, there was a spearman rank correlation between the new acromion type and the degree of the supraspinatus tendon tear(rs=0.719, P<0.001). CONCLUSION: Rockwood radiographs of the shoulder can well display the anterolateral osteophytes of the acromion. The new acromion classification method based on Rockwood radiographs has high reliability and good reproducibility, in which impingement type of acromion is closely related to supraspinatus tendon tear. Compared with the traditional classification and AHD, the new classification method has more diagnostic value than for rotator cuff injury.