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BACKGROUND: The diagnosis of lumbar spinal stenosis (LSS) can be challenging because radicular pain is not often present in the culprit-level localization. Accurate segmentation and quantitative analysis of the lumbar dura on radiographic images are key to the accurate differential diagnosis of LSS. The aim of this study is to develop an automatic dura-contouring tool for radiographic quantification on computed tomography myelogram (CTM) for patients with LSS. METHODS: A total of 518 CTM cases with or without lumbar stenosis were included in this study. A deep learning (DL) segmentation algorithm 3-dimensional (3D) U-Net was deployed. A total of 210 labeled cases were used to develop the dura-contouring tool, with the ratio of the training, independent testing, and external validation datasets being 150:30:30. The Dice score (DCS) was the primary measure to evaluate the segmentation performance of the 3D U-Net, which was subsequently developed as the dura-contouring tool to segment another unlabeled 308 CTM cases with LSS. Automatic masks of 446 slices on the stenotic levels were then meticulously reviewed and revised by human experts, and the cross-sectional area (CSA) of the dura was compared. RESULTS: The mean DCS of the 3D U-Net were 0.905 ± 0.080, 0.933 ± 0.018, and 0.928 ± 0.034 in the five-fold cross-validation, the independent testing, and the external validation datasets, respectively. The segmentation performance of the dura-contouring tool was also comparable to that of the second observer (the human expert). With the dura-contouring tool, only 59.0% (263/446) of the automatic masks of the stenotic slices needed to be revised. In the revised cases, there were no significant differences in the dura CSA between automatic masks and corresponding revised masks (p = 0.652). Additionally, a strong correlation of dura CSA was found between the automatic masks and corresponding revised masks (r = 0.805). CONCLUSIONS: A dura-contouring tool was developed that could automatically segment the dural sac on CTM, and it demonstrated high accuracy and generalization ability. Additionally, the dura-contouring tool has the potential to be applied in patients with LSS because it facilitates the quantification of the dural CSA on stenotic slices.
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Aprendizado Profundo , Dura-Máter , Vértebras Lombares , Mielografia , Estenose Espinal , Tomografia Computadorizada por Raios X , Humanos , Estenose Espinal/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Dura-Máter/diagnóstico por imagem , Dura-Máter/patologia , Vértebras Lombares/diagnóstico por imagem , Mielografia/métodos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Algoritmos , Processamento de Imagem Assistida por Computador/métodos , Adulto , Estudos RetrospectivosRESUMO
Peripheral nerve injuries often result in severe personal and social burden, and even with surgical treatment, patients continue to have poor clinical outcomes. Over the past two decades, electrical stimulation has been shown to promote axonal regeneration and alleviate refractory neuropathic pain. The aim of this study was to analyse this field using a bibliometric approach. Literature was searched through Web of Science Core Collection (WOSCC) for the years 2002-2023. Literature analysis included: (1) Describing publication trends in the field. (2) Exploring collaborative network relationships. (3) Finding research advances and research hotspots in the field. (4) Summarizing research trends in the field. With the number of studies in this field still increasing, a total of 693 publications were included in the analysis. This field of research is interdisciplinary in nature. Research hotspots include peripheral nerve regeneration, the treatment of neuropathic pain, materials for nerve injury repair, and the restoration of sensory function in patients with peripheral nerve injury. Correspondingly, the development of nerve conduits and systems for peripheral nerve electrical stimulation, clinical trials of peripheral nerve electrical stimulation, and tactile recovery and movement for amputees have shown significant promise as future research trends in this field.
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Neuralgia , Traumatismos dos Nervos Periféricos , Humanos , Traumatismos dos Nervos Periféricos/terapia , Estimulação Elétrica , Bibliometria , Movimento , Neuralgia/terapiaRESUMO
BACKGROUND: Vitamin D deficiency (VDD) is a public health problem. The variation in vitamin D status across regions and populations remains unclear, and there is a lack of consensus regarding the screening for VDD in individuals. METHODS: Children who visited the hospital from January 2019 to December 2020 were included in this study. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured using an enzyme-linked immunosorbent assay. The cutoffs for serum 25(OH)D concentrations to define deficiency, insufficiency, and sufficiency were < 20 ng/mL, 20-30 ng/mL, and ≥ 30 ng/mL, respectively. RESULTS: A total of 7285 children aged 0-11 years were assessed; the mean 25(OH)D level was 31.4 ng/mL, and the median 25(OH)D level was 30.7 (interquartile range 24.4, 37.5) ng/mL. The 25(OH)D level declined with age in clinical visiting children aged 0-11 years, but maintained a consistently high level in health examination children aged 4-11 years. The percentages of 25(OH)D < 20 ng/mL and 25(OH)D < 30 ng/mL were 10.0% and 43.8%, respectively. Higher percentages of VDD were found in clinical visiting children than in health examination children within the 6-11-year group (53.3% vs. 14.7%) and winter (44.3% vs. 15.4%). CONCLUSION: Low vitamin D status (deficiency and insufficiency) was more common in clinic-visiting children than in health examinations, especially in schoolchildren and in the winter. The study implies the positive effects of vitamin D assessments included in child health checkups to optimize vitamin D status.
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Deficiência de Vitamina D , Vitamina D , Criança , Lactente , Humanos , Estudos Transversais , China/epidemiologia , Prevalência , Vitaminas , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/epidemiologiaRESUMO
Chiral boron/nitrogen doped multiple resonance thermally activated delayed fluorescence (MR-TADF) emitters are promising for highly efficient and color-pure circularly polarized organic light-emitting diodes (CP-OLEDs). Herein, we report two pairs of MR-TADF materials (Czp-tBuCzB, Czp-POAB) based on planar chiral paracyclophane with photoluminescence quantum yields of up to 98 %. The enantiomers showed symmetric circularly polarized photoluminescence spectra with dissymmetry factors |gPL | of up to 1.6×10-3 in doped films. Meanwhile, the sky-blue CP-OLEDs with (R/S)-Czp-tBuCzB showed an external quantum efficiency of 32.1 % with the narrowest full-width at half-maximum of 24â nm among the reported CP-OLEDs, while the devices with (R/S)-Czp-POAB displayed the first nearly pure green CP electroluminescence with |gEL | factors at the 10-3 level. These results demonstrate the incorporation of planar chirality into MR-TADF emitter is a reliable strategy for constructing of efficient CP-OLEDs.
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PURPOSE: EphA2 is a key factor underlying invasive propensity of gliomas, and is associated with poor prognosis of tumors. We aimed to develop a radiomics-based imaging index for predicting EphA2 expression in diffuse gliomas, and further estimating its value for grading of tumors. METHODS: A total of 182 patients with diffuse gliomas were included. All subjects underwent pre-operative MRI and post-operative pathological diagnosis. EphA2 expression of tumors was scored on pathological sections with immunohistochemical staining using monoclonal EphA2 antibody. MRI radiomics features were extracted from three-dimensional contrast-enhanced T1-weighted imaging and diffusion kurtosis imaging. Predictive models were constructed using machine learning-based radiomics features selection and three classifiers for predicting EphA2 expression and tumor grade. Features of best EphA2 expression model were subsequently used to construct another model of tumor grading. For each model, 146 cases (80%) were randomly picked as training and the rest 36 (20%) were testing cohorts. EphA2 expression was further correlated to the radiomics features in both grade models using Spearman's correlation. RESULTS: Logistic regression model presented highest performance for predicting EphA2 expression (AUC: 0.836/0.724 in training/validation set). Tumor gradings model guided by features from EphA2 expression model demonstrated comparable performance (AUC: 0.930/0.983) to that constructed directly using imaging radiomics features (AUC: 0.960/0.977). Two radiomics features which included in both LR-grade models showed strong correlation (P < 0.05) with EphA2 expression. CONCLUSION: The expression of EphA2 in gliomas could be predicted by radiomics features extracted from diffusion kurtosis MRI, which could also be used to assist tumor grading.
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Neoplasias Encefálicas , Carcinoma Hepatocelular , Eritropoetina , Glioma , Neoplasias Hepáticas , Encéfalo , Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Receptores da Eritropoetina , Estudos RetrospectivosRESUMO
Herein, we report the structures of chiral-at-cage carborane derivatives bearing carbazole chromophores that emit circularly polarized luminescence (CPL) and aggregation-induced electrochemiluminescence (AIECL). By adjusting the substituent positions on the carborane derivatives, two chiral luminescent molecules, Cb1 and Cb2, with different properties were obtained. The photoluminescence dissymmetry factors |gPL | of both (R/S)-Cb1 and (R/S)-Cb2 enantiomers in neat films were as high as 6.24×10-3 and 7.38×10-3 , respectively. Cb1 showed a deep blue emission peak at 434â nm in n-pentane. Interestingly, distinct fluorescence and CPL spectra were observed in solvents of different polarities due to the twisted intramolecular charge transfer effect, suggesting its potential use in solvent recognition. Meanwhile, Cb2 exhibited good AIECL property, excellent ECL stability and could be used for determining dopamine concentrations, suggesting its potential applications in biology and diagnosis.
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Luminescência , Medições Luminescentes , EstereoisomerismoRESUMO
BACKGROUND: Tumor phototherapy especially photodynamic therapy (PDT) or photothermal therapy (PTT), has been considered as an attractive strategy to elicit significant immunogenic cell death (ICD) at an optimal tumor retention of PDT/PTT agents. Heptamethine cyanine dye (IR-780), a promising PDT/PTT agent, which can be used for near-infrared (NIR) fluorescence/photoacoustic (PA) imaging guided tumor phototherapy, however, the strong hydrophobicity, short circulation time, and potential toxicity in vivo hinder its biomedical applications. To address this challenge, we developed mesoporous polydopamine nanoparticles (MPDA) with excellent biocompatibility, PTT efficacy, and PA imaging ability, facilitating an efficient loading and protection of hydrophobic IR-780. RESULTS: The IR-780 loaded MPDA (IR-780@MPDA) exhibited high loading capacity of IR-780 (49.7 wt%), good physiological solubility and stability, and reduced toxicity. In vivo NIR fluorescence and PA imaging revealed high tumor accumulation of IR-780@MPDA. Furthermore, the combined PDT/PTT of IR-780@MPDA could induce ICD, triggered immunotherapeutic response to breast tumor by the activation of cytotoxic T cells, resulting in significant suppression of tumor growth in vivo. CONCLUSION: This study demonstrated that the as-developed compact and biocompatible platform could induce combined PDT/PTT and accelerate immune activation via excellent tumor accumulation ability, offering multimodal tumor theranostics with negligible systemic toxicity.
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Antineoplásicos , Carbocianinas , Corantes Fluorescentes , Indóis/química , Nanopartículas/química , Polímeros/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Carbocianinas/química , Carbocianinas/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Neoplasias Mamárias Animais , Camundongos , Fototerapia , Nanomedicina Teranóstica , Distribuição TecidualRESUMO
The traditional simultaneous localization and mapping (SLAM) system uses static points of the environment as features for real-time localization and mapping. When there are few available point features, the system is difficult to implement. A feasible solution is to introduce line features. In complex scenarios containing rich line segments, the description of line segments is not strongly differentiated, which can lead to incorrect association of line segment data, thus introducing errors into the system and aggravating the cumulative error of the system. To address this problem, a point-line stereo visual SLAM system incorporating semantic invariants is proposed in this paper. This system improves the accuracy of line feature matching by fusing line features with image semantic invariant information. When defining the error function, the semantic invariant is fused with the reprojection error function, and the semantic constraint is applied to reduce the cumulative error of the poses in the long-term tracking process. Experiments on the Office sequence of the TartanAir dataset and the KITTI dataset show that this system improves the matching accuracy of line features and suppresses the cumulative error of the SLAM system to some extent, and the mean relative pose error (RPE) is 1.38 and 0.0593 m, respectively.
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BACKGROUND: Redefined hematoma expansion (rHE) including intraventricular hematoma expansion (IVHE) is a new concept in intracerebral hemorrhage (ICH), with better prognostic ability compared to the conventional hematoma expansion. Ultraearly hematoma growth (uHG) and computed tomography angiography (CTA) spot sign are both useful indictors to predict HE and poor clinical outcome. This study aims to explore the clinical characteristics of rHE in retrospective cohort and evaluate the predictive ability of uHG and spot sign in rHE. MATERIALS AND METHODS: This study included nontraumatic spontaneous ICH patients from June 1st 2013 and January 1st 2018 in West China Hospital. Multivariate logistic regression was used to determine risk factors for HE/IVHE/rHE and primary outcomes of ICH patients. Receiver operating characteristic (ROC) analysis was performed to assess the accuracy of uHG and spot sign for predicting HE/IVHE/rHE. RESULTS: This retrospective cohort included 469 consecutive patients with ICH. rHE was significantly associated with clinical variables including Glasgow coma scale (GCS), time to initial CT, presence of IVH, hematoma volume, presence of spot sign, and uHG. uHG and spot sign were independent risk factors for rHE. ROC analysis indicated that both uHG (AUC 0.726, 95%CI 0.680-0.773) and spot sign (AUC 0.735, 95%CI 0.686-0.785) possessed high predictive accuracy for rHE. HE and rHE were independent risk factors for 1-month mortality and 3-month functional outcome. CONCLUSIONS: Both uHG and the spot sign were considered to be good predictors for rHE, and the spot sign appeared to have a better predictive accuracy.
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Angiografia Cerebral , Hemorragia Cerebral/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Hematoma/diagnóstico por imagem , Idoso , Bases de Dados Factuais , Progressão da Doença , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
Click chemistry focuses on the development of highly selective reactions using simple precursors for the exquisite synthesis of molecules. Undisputedly, the CuI -catalyzed azide-alkyne cycloaddition (CuAAC) is one of the most valuable examples of click chemistry, but it suffers from some limitations as it requires additional reducing agents and ligands as well as cytotoxic copper. Here, we demonstrate a novel strategy for the azide-alkyne cycloaddition reaction that involves a photoredox electron-transfer radical mechanism instead of the traditional metal-catalyzed coordination process. This newly developed photocatalyzed azide-alkyne cycloaddition reaction can be performed under mild conditions at room temperature in the presence of air and visible light and shows good functional group tolerance, excellent atom economy, high yields of up to 99 %, and absolute regioselectivity, affording a variety of 1,4-disubstituted 1,2,3-triazole derivatives, including bioactive molecules and pharmaceuticals. The use of a recyclable photocatalyst, solar energy, and water as solvent makes this photocatalytic system sustainable and environmentally friendly. Moreover, the azide-alkyne cycloaddition reaction could be photocatalyzed in the presence of a metal-free catalyst with excellent regioselectivity, which represents an important development for click chemistry and should find versatile applications in organic synthesis, chemical biology, and materials science.
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BACKGROUND: The efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) compared with warfarin in patients with atrial fibrillation (AF) and peripheral artery disease (PAD) remain largely unknown. Therefore, we conducted a meta-analysis to explore the effects of NOACs versus warfarin in this population. METHODS: We systematically searched the PubMed and Embase databases, with no linguistic restrictions, until December 2019 for relevant randomized controlled trials (RCTs) and observational studies. A random-effects model using an inverse variance method was selected to pool the risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: A total of six studies (three post hoc analyses of RCTs and three cohort studies) were included in this meta-analysis. Among AF patients treated with NOACs and warfarin, individuals with PAD had increased rates of all-cause death (RR = 1.26, 95% CI 1.07-1.48) and cardiovascular death (RR = 1.32, 95% CI 1.06-1.64) compared with those without PAD. In AF patients with PAD, we observed a similar risk of thromboembolic events, bleeding, and death with NOACs as with warfarin. In addition, there were no interactions between PAD and non-PAD subgroups regarding any of the reported outcomes of NOACs versus warfarin in AF patients (all Pinteraction > 0.05). CONCLUSIONS: Based on current evidence, AF patients with PAD are at a higher risk of death than those without PAD. Efficacy and safety outcomes with NOACs are comparable to those with warfarin, suggesting that the use of NOACs has effects similar to warfarin in AF patients with concomitant PAD.
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Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Doença Arterial Periférica/terapia , Varfarina/administração & dosagem , Administração Oral , Anticoagulantes/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/mortalidade , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Estudos Observacionais como Assunto , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Vitamina K/antagonistas & inibidores , Varfarina/efeitos adversosRESUMO
Reactive Black 5 (RB5) is a typical refractory azo dye. Widespread utilization of RB5 has caused a variety of environmental and health problems. The enzymatic degradation of RB5 can be a promising solution due to its superiority as an eco-friendly and cost-competitive process. Bacterial CotA-laccase shows great application prospect to eliminate hazardous dyes from wastewater. However, efficient decolorization of RB5 CotA-laccase generally requires the participation of costly, toxic mediators. In the present study, we modified the amino acids Thr415 and Thr418 near the type 1 copper site and the amino acid Gln442 at the entrance of the substrate-binding pocket of Bacillus pumilus W3 CotA-laccase to boost its RB5 decolorization activity based on molecular docking analysis and site-saturation mutagenesis. Through the strategies, two double site mutants T415D/Q442A and T418K/Q442A obtained demonstrated 43.94 and 52.64% RB5 decolorization rates in the absence of a mediator at pH 10.0, respectively, which were about 3.70- and 4.43-fold higher compared with the wild-type CotA-laccase. Unexpectedly, the catalytic efficiency of the T418K/Q442A to ABTS was enhanced by 5.33-fold compared with the wild-type CotA-laccase. The mechanisms of conferring enhanced activity to the mutants were proposed by structural analysis. In summary, the mutants T415D/Q442A and T418K/Q442A have good application potentials for the biodegradation of RB5. KEY POINTS: ⢠Three amino acids of CotA-laccase were manipulated by site-saturation mutagenesis. ⢠Decolorization rate of two mutants to RB5 was enhanced 3.70- and 4.43-fold, respectively. ⢠The mechanisms of awarding enhanced activity to the mutants were supposed.
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Bacillus pumilus , Lacase , Bacillus pumilus/genética , Proteínas de Bactérias/genética , Corantes , Lacase/genética , Simulação de Acoplamento Molecular , Mutagênese , NaftalenossulfonatosRESUMO
In this study, mutant CotA-laccase SF was successfully expressed in Escherichia coli by co-expression with phospholipase C. The optimized extracellular expression of CotA-laccase SF was 1257.22 U/L. Extracellularly expressed CotA-laccase SF exhibits enzymatic properties similar to intracellular CotA-laccase SF. CotA-laccase SF could decolorize malachite green (MG) under neutral and alkaline conditions. The Km and kcat values of CotA-laccase SF to MG were 39.6 mM and 18.36 s-1. LC-MS analysis of degradation products showed that MG was finally transformed into 4-aminobenzophenone and 4-aminophenol by CotA-laccase. The toxicity experiment of garlic root tip cell showed that the toxicity of MG metabolites decreased. In summary, CotA-laccase SF had a good application prospect for degrading malachite green.
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Corantes/metabolismo , Lacase/metabolismo , Corantes de Rosanilina/metabolismo , Corantes/toxicidade , Escherichia coli/genética , Escherichia coli/metabolismo , Lacase/genética , Mutação , Corantes de Rosanilina/toxicidadeRESUMO
Encoding of spatial information in the superficial layers of the medial entorhinal cortex (sMEC) involves theta-modulated spiking and gamma oscillations, as well as spatially tuned grid cells and border cells. Little is known about the role of the arousal-promoting histaminergic system in the modification of information encoded in the sMEC in vivo, and how such histamine-regulated information correlates with behavioral functions. Here, we show that histamine upregulates the neural excitability of a significant proportion of neurons (16.32%, 39.18%, and 52.94% at 30 µM, 300 µM, and 3 mM, respectively) and increases local theta (4-12 Hz) and gamma power (low: 25-48 Hz; high: 60-120 Hz) in the sMEC, through activation of histamine receptor types 1 and 3. During spatial exploration, the strength of theta-modulated firing of putative principal neurons and high gamma oscillations is enhanced about 2-fold by histamine. The histamine-mediated increase of theta phase-locking of spikes and high gamma power is consistent with successful spatial recognition. These results, for the first time, reveal possible mechanisms involving the arousal-promoting histaminergic system in the modulation of spatial cognition.
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Córtex Entorrinal/efeitos dos fármacos , Ritmo Gama/efeitos dos fármacos , Histamina/farmacologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Ritmo Teta/efeitos dos fármacos , Animais , Biofísica , Relação Dose-Resposta a Droga , Estimulação Elétrica , Córtex Entorrinal/citologia , Córtex Entorrinal/fisiologia , Histamínicos/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Estimulação Luminosa , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Potenciais Sinápticos/efeitos dos fármacos , Vigília , Ácido gama-Aminobutírico/metabolismoRESUMO
Childhood obesity is a predictor of adult obesity and has its roots in the pre-pregnancy or pregnancy period. This review presents an overview of the prenatal risk factors for childhood obesity, which were categorized into 2 groups: biological risk factors (maternal pre-pregnancy body mass index, gestational weight gain, diabetes in pregnancy, and caesarean section), and environmental and behavioural risk factors (maternal smoking and exposure to obesogens, maternal dietary patterns, maternal intestinal microbiome and antibiotics exposure, and maternal psychosocial stress). Identifying modifiable predisposing prenatal factors for obesity will inform further development of inventions to prevent obesity over the life course, and future directions for research and intervention are discussed.
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Obesidade Infantil/etiologia , Animais , Feminino , Humanos , Gravidez , Complicações na Gravidez/etiologia , Fatores de RiscoRESUMO
Multicopper oxidases (MCOs) are a pervasive family of enzymes that oxidize a wide range of phenolic and nonphenolic aromatic substrates, concomitantly with the reduction of dioxygen to water. MCOs are usually divided into two functional classes: metalloxidases and laccases. Given their broad substrate specificity and eco-friendliness (molecular oxygen from air as is used as the final electron acceptor and they only release water as byproduct), laccases are regarded as promising biological green tools for an array of applications. Among these laccases, those of bacterial origin have attracted research attention because of their notable advantages, including broad substrate spectrum, wide pH range, high thermostability, and tolerance to alkaline environments. This review aims to summarize the significant research efforts on the properties, mechanisms and structures, laccase-mediator systems, genetic engineering, immobilization, and biotechnological applications of the bacteria-source laccases and laccase-like enzymes, which principally include Bacillus laccases, actinomycetic laccases and some other species of bacterial laccases. In addition, these enzymes may offer tremendous potential for environmental and industrial applications.
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Bactérias/enzimologia , Bioengenharia/tendências , Química Verde/tendências , Indústrias/tendências , Lacase/fisiologia , Animais , Bactérias/genética , Bioengenharia/métodos , Microbiologia Ambiental , Química Verde/métodos , Humanos , Indústrias/métodos , Invenções/tendências , Lacase/genéticaRESUMO
BACKGROUND: Interleukin-33 (IL-33) is increasingly being recognized as a key immunomodulatory cytokine in many neurological diseases. METHODS: In the present study, wild-type (WT) and IL-33-/- mice received intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS) to induce neuroinflammation. Intravital microscopy was employed to examine leukocyte-endothelial interactions in the brain vasculature. The degree of neutrophil infiltration was determined by myeloperoxidase (MPO) staining. Real-time PCR and western blotting were used to detect endothelial activation. Enzyme-linked immunosorbent assay and quantitative PCR were conducted to detect pro-inflammatory cytokine levels in the brain. RESULTS: In IL-33-/- mice, neutrophil infiltration in the brain cortex and leukocyte-endothelial cell interactions in the cerebral microvessels were significantly decreased as compared to WT mice after LPS injection. In addition, IL-33-/- mice showed reduced activation of microglia and cerebral endothelial cells. In vitro results indicated that IL-33 directly activated cerebral endothelial cells and promoted pro-inflammatory cytokine production in LPS-stimulated microglia. CONCLUSIONS: Our study indicated that IL-33/ST2 signaling plays an important role in the activation of microglia and cerebral endothelial cells and, therefore, is essential in leukocyte recruitment in brain inflammation. The role of IL-33/ST2 in LPS induced neuroinflammation.
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Encefalite/metabolismo , Células Endoteliais/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/biossíntese , Interleucina-33/biossíntese , Microglia/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Encefalite/induzido quimicamente , Encefalite/imunologia , Células Endoteliais/imunologia , Imunidade Inata/fisiologia , Injeções Intraventriculares , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/imunologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Infiltração de Neutrófilos/fisiologiaRESUMO
The ability of the brain to predict future events based on the pattern of recent sensory experience is critical for guiding animal's behavior. Neocortical circuits for ongoing processing of sensory stimuli are extensively studied, but their contributions to the anticipation of upcoming sensory stimuli remain less understood. We, therefore, used in vivo cellular imaging and fiber photometry to record mouse primary auditory cortex to elucidate its role in processing anticipated stimulation. We found neuronal ensembles in layers 2/3, 4, and 5 which were activated in relationship to anticipated sound events following rhythmic stimulation. These neuronal activities correlated with the occurrence of anticipatory motor responses in an auditory learning task. Optogenetic manipulation experiments revealed an essential role of such neuronal activities in producing the anticipatory behavior. These results strongly suggest that the neural circuits of primary sensory cortex are critical for coding predictive information and transforming it into anticipatory motor behavior.
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Córtex Auditivo/fisiologia , Percepção Auditiva/fisiologia , Motivação/fisiologia , Atividade Motora/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Potenciais de Ação/fisiologia , Animais , Córtex Auditivo/citologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Condicionamento Clássico , Comportamento de Ingestão de Líquido , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parvalbuminas/genética , Parvalbuminas/metabolismo , Transdução Genética , VigíliaRESUMO
Shenxiong glucose injection, a pharmaceutical preparation containing a water extract of the roots of Salvia miltiorrhizae and ligustrazine hydrochloride, is widely used in clinical to treat cardiovascular diseases in China. The chemical components of the water extract have been reported and the cardioprotective effects of the injection have been evaluated. However, the chemical constituents of the injection and their correlations with its pharmacological effects have not been established. In this study, 13 chemical constituents of the injection have been identified or characterized by ultra-high performance liquid chromatography with diode array detection and electrospray ionization quadrupole time-of-flight tandem mass spectrometry. Besides, the potentially active compounds of this preparation that directly act on cardiac cells have been screened by cell extraction and ultra high performance liquid chromatography targeted multiple reaction monitoring. As a result, eight potentially active compounds, danshensu (1), ligustrazine hydrochloride (4), salvianolic acid I/H (7), lithospermic acid (8), salvianolic acid D (9), rosmarinic acid (10), salvianolic acid B (12), and salvianolic acid C (13), were obtained and structurally characterized from the 11 target compounds used for screening. The liquid chromatography with quadrupole time-of-flight mass spectrometry and liquid chromatography with multiple reaction monitoring tandem mass spectrometry combination method has demonstrated its potency for the screening, detection, and structural identification of bioactive compounds in a complex matrix.
Assuntos
Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/análise , Espectrometria de Massas em Tandem , Animais , Linhagem Celular , Concentração de Íons de Hidrogênio , Luz , Raízes de Plantas/química , Pirazinas/química , Ratos , Salvia miltiorrhiza/química , Espectrometria de Massas por Ionização por Electrospray , Água/químicaRESUMO
Acetaminophen (APAP, paracetamol) overdose has been the most frequent cause of drug-induced liver failure. APAP-induced liver toxicity can be fatal in many cases even with treatment of the clinically used N-acetylcysteine (NAC), and the need for novel therapeutic agents is apparent. Through evaluating the hepatoprotective effects of the co-occurring substances present in oleanolic acid tablets which have been used in China for decades as an adjuvant therapy for acute and chronic hepatitis, auriculatone was found to protect HL-7702 cells from APAP-induced liver injury comparable to NAC at the concentration of 10µM. Structure activity relationship on auriculatone and its analogs showed that absence of the C17 carboxyl group of auriculatone was essential to achieve good hepatoprotective activity, and that the C3-OH, C16 carbonyl and C12-C13 olefinic group were critical for retaining the exceptional activity of auriculatone. Any modifications in the current investigation were all detrimental to the hepatoprotective activity. Docking and drug-metabolizing activity studies demonstrated that CYP3A4 was likely the main target of auriculatone, and that auriculatone elicited the hepatoprotective effect possibly through inhibiting CYP3A4's metabolism of APAP to the toxic metabolite NAPQI. The work may pave the way for the use of auriculatone in the treatment of APAP-induced liver injury.