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BACKGROUND: Functional mitral regurgitation (FMR) and its severity are associated with adverse outcomes in heart failure patients. This study aims to analyze the predictors of FMR improvement after successful left bundle branch area pacing (LBBAP) in patients with LVEF < 50% and complete left bundle branch block (CLBBB). METHODS: Consecutive patients with LVEF < 50% and CLBBB who underwent successful LBBAP from July 2018 to July 2023 were retrospectively identified. Significant MR was defined as regurgitation of moderate severity or greater. Patients with significant FMR were included in the analysis. FMR improvement (FMRI) was defined as a reduction of at least one grade in regurgitation severity compared to baseline at 3 months or longer follow-up. RESULTS: Among the 81 identified patients, 42 patients with significant FMR preoperatively were included. After LBBAP, QRS duration significantly shortened from 170.6 ± 18.8 ms to 114.5 ± 20.2 ms (p < .001). Significant FMR improves in approximately 76.2%, and the patients were divided into an FMRI group (n = 32) and a non-FMRI group (n = 10). Univariate analysis showed that absence of persistent atrial fibrillation, typical CLBBB, and left atrium diameter at baseline were associated with improvement of FMR after LBBAP. Of these variables, only absence of persistent atrial fibrillation remains an independent predictor in the multivariate model (OR 12.436, p = .009). CONCLUSION: LBBAP is able to improve FMR in heart failure patients who had CLBBB with LVEF < 50%. Meanwhile, the absence of persistent atrial fibrillation is an independent predictor of FMR improvement.
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An assembly between 1,4-dicarboxylbenzene-2,3-dithiol (H2dcbdt) and different transition metal ions successfully produced 2D metal-organic frameworks (M-dcbdt, M = Ni, Co or Fe) composed of unprecedented butterfly-shaped metal-bis(dithiolene) (MS4) linkers in one-pot fashion. Such strategy provides easier access to the [MS4]-rich network and lowers the prerequisite to explore their applications.
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Diabetic cataract (DC) is a major cause of blindness in diabetic patients and it is characterized by early onset and rapid progression. MiR-204-5p was previously identified as one of the top five down-regulated miRNAs in human DC lens tissues. We aimed to determine the expression of miR-204-5p in human lens epithelial cells (HLECs) and explore its effects and mechanisms in regulating the progression of DC. The expression of miR-204-5p in the anterior capsules of DC patients and HLECs was examined by RT-qPCR. Bioinformatics tools were then used to identify the potential target of miR-204-5p. The relationship between miR-204-5p and the target gene was confirmed through a dual luciferase reporter assay. Additionally, the regulatory mechanism of oxidative stress, apoptosis, and inflammation in DC was investigated by overexpressing miR-204-5p using miR-204-5p agomir. The expression of miR-204-5p was downregulated in the anterior capsules of DC patients and HLECs. Overexpression of miR-204-5p reduced ROS levels, pro-apoptosis genes (Bid, Bax, caspase-3), and IL-1ß production in HG-treated HLECs. TXNIP was the direct target of miR-204-5p by dual luciferase reporter assay. Therefore, this study demonstrated that miR-204-5p effectively reduced oxidative damage, apoptosis, and inflammation in HLECs under HG conditions by targeting TXNIP. Targeting miR-204-5p could be a promising therapeutic strategy for the potential treatment of DC.
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Efficient thrombolysis in time is crucial for prognostic improvement of patients with acute arterial thromboembolic disease, while limitations and complications still exist in conventional thrombolytic treatment methods. Herein, our study sought to investigate a novel dual-mode strategy that integrated ultrasound (US) and near-infrared light (NIR) with establishment of hollow mesoporous silica nanoprobe (HMSN) which contains Arginine-glycine-aspartate (RGD) peptide (thrombus targeting), perfluoropentane (PFP) (thrombolysis with phase-change and stable cavitation) and indocyanine green (ICG) (thrombolysis with photothermal conversion). HMSN is used as the carrier, the surface is coupled with targeted RGD to achieve high targeting and permeability of thrombus, PFP and ICG are loaded to achieve the collaborative diagnosis and treatment of thrombus by US and NIR, so as to provide a new strategy for the integration of diagnosis and treatment of arterial thrombus. From the in vitro and in vivo evaluation, RGD/ICG/PFP@HMSN can aggregate and penetrate at the site of thrombus, and finally establish the dual-mode directional development and thrombolytic treatment under the synergistic effect of US and NIR, providing strong technical support for the accurate diagnosis and treatment of arterial thrombosis.
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Verde de Indocianina , Raios Infravermelhos , Oligopeptídeos , Terapia Trombolítica , Trombose , Animais , Terapia Trombolítica/métodos , Oligopeptídeos/química , Verde de Indocianina/química , Trombose/diagnóstico por imagem , Trombose/tratamento farmacológico , Nanopartículas/química , Fluorocarbonos/química , Dióxido de Silício/química , Humanos , Camundongos , Masculino , Coelhos , Ultrassonografia/métodos , PentanosRESUMO
BACKGROUND: Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H2) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H2 provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H2 on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice. METHODS: In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H2) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H2 under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining. RESULTS: Our results indicate that 3-4% H2 does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H2 prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H2 inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H2 plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H2 promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreover, the retinal oxygen-sensing mechanisms (HIF-1α/VEGF) are also involved in hydrogen-mediated retinal revascularization and neovascularization suppression. CONCLUSIONS: Collectively, our results indicate that H2 could be a promising therapeutic agent for POR treatment and that its beneficial effect in human ROP might involve the activation of the Nrf2-Notch axis as well as HIF-1α/VEGF pathways.
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Modelos Animais de Doenças , Hidrogênio , Neuroglia , Oxigênio , Neovascularização Retiniana , Retinopatia da Prematuridade , Animais , Hidrogênio/farmacologia , Neovascularização Retiniana/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Camundongos , Retinopatia da Prematuridade/tratamento farmacológico , Camundongos Endogâmicos C57BL , Retina/efeitos dos fármacos , Animais Recém-Nascidos , Regeneração/efeitos dos fármacos , Imuno-Histoquímica , Vasos Retinianos/efeitos dos fármacosRESUMO
BACKGROUND: Left bundle branch area pacing (LBBAP) demonstrated beneficial effects on clinical outcomes. Comparative data on the risk of atrial high-rate episodes (AHREs) between LBBAP and right ventricular pacing (RVP) are lacking. AIMS: This study aimed to investigate whether LBBAP can reduce the risk of new-onset AHREs compared with RVP in patients with atrioventricular block (AVB). METHODS: We enrolled 175 consecutive AVB patients with no history of atrial fibrillation undergoing dual-chamber pacemaker implantation (LBBAP or RVP). Propensity score matching for baseline characteristics yielded 43 matched pairs. The primary outcome was new-onset AHREs detected on a scheduled device follow-up. Changes in echocardiographic measurements were also compared between the groups. RESULTS: New-onset AHREs occurred in 42 (24.0%) of all enrolled patients (follow-up 14.1 [7.5] months) and the incidence of new-onset AHREs in the LBBAP group was lower than in the RVP group (19.8% vs. 34.7%; P = 0.04). After propensity score matching, LBBAP still resulted in a lower incidence of new-onset AHREs (11.6% vs. 32.6%; P = 0.02), and a lower hazard ratio for new-onset AHREs compared with RVP (HR, 0.274; 95% CI, 0.113-0.692). At 1 year, LBBAP achieved preserved left ventricular ejection fraction (LVEF) (63.0 [3.2]% to 63.1 [3.1]%; P = 0.56), while RVP resulted in reduced LVEF (63.4 [4.9]% to 60.5 [7.3]%; P = 0.01]). Changes in LVEF were significantly different between the 2 groups (by 2.6% [0.2 to 5.0]%; P = 0.03). CONCLUSION: LBBAP demonstrated a reduced risk of new-onset AHREs compared with RVP in patients with AVB.
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Bloqueio Atrioventricular , Estimulação Cardíaca Artificial , Humanos , Masculino , Feminino , Bloqueio Atrioventricular/terapia , Idoso , Estimulação Cardíaca Artificial/métodos , Pessoa de Meia-Idade , Ventrículos do Coração/fisiopatologia , Idoso de 80 Anos ou mais , Fibrilação Atrial/terapia , Resultado do TratamentoRESUMO
Conger eel (Conger myriaster) is an economically important species in China. Due to the complex life history of the conger eel, achieving artificial reproduction has remained elusive. This study aimed to explore the effect of water stimulation on hormonal regulation during the artificial reproduction of conger eel. The experiment was divided into four groups: A1 (no hormone injection, still water), A2 (no hormone injection, flowing water), B1 (hormone injection, still water), and B2 (hormone injection, flowing water). The flowing water group maintained a flow velocity of 0.4 ± 0.05 m/s for 12 h daily throughout the 60-day period. Steroid hormone levels in the serum and ovaries of conger eels were analyzed using UPLC-MS/MS and ELISA on the 30th and 60th days of the experiment. The relative expression levels of follicle-stimulating hormone (FSHß) and luteinizing hormone (LHß) in the pituitary were determined by quantitative PCR. The results showed a significantly lower gonadosomatic index (GSI) in B2 compared to B1 (p < 0.05) on the 30th day. FSH was found to act only in the early stages of ovarian development, with water stimulation significantly enhancing FSH synthesis (p < 0.05), while FSHß gene was not expressed after hormone injection. Conversely, LH was highly expressed in late ovarian development, with flowing water stimulation significantly promoting LH synthesis (p < 0.05). Serum cortisol (COR) levels were significantly higher in the flowing water group than in the still water group (p < 0.05). Furthermore, estradiol (E2) content of B2 was significantly lower than that of B1 on the 30th and 60th day. Overall, flowing water stimulation enhanced the synthesis of FSH in early ovarian development and LH in late ovarian development, while reducing E2 accumulation in the ovaries. In this study, the effect of flowing water stimulation on hormone regulation during the artificial reproduction of conger eel was initially investigated to provide a theoretical basis for optimizing artificial reproduction techniques.
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Ependymomas are neuroepithelial tumours arising from ependymal cells surrounding the cerebral ventricles that rarely metastasise to extraneural structures. This spread has been reported to occur to the lungs, lymph nodes, liver and bone. We describe the case of a patient with recurrent CNS WHO grade 3 ependymoma with extraneural metastatic disease. He was treated with multiple surgical resections, radiation therapy and salvage chemotherapy for his extraneural metastasis to the lungs, bone, pleural space and lymph nodes.
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Neoplasias Ósseas , Ependimoma , Neoplasias Pulmonares , Neoplasias Pleurais , Humanos , Masculino , Ependimoma/secundário , Ependimoma/patologia , Ependimoma/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Neoplasias Pleurais/secundário , Neoplasias Pleurais/patologia , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Ósseas/secundário , Metástase Linfática/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/diagnóstico por imagem , Linfonodos/patologia , Linfonodos/diagnóstico por imagemRESUMO
Background: The primary aim of this study was to investigate the correlation between diabetic retinopathy (DR) and the HALP score (hemoglobin, albumin, lymphocyte, and platelet) in individuals with diabetes within the United States population. Methods: This cross-sectional investigation was based on the National Health and Nutrition Examination Survey (NHANES) database from 2003-2018. The following module calculated the HALP score: HALP score = [lymphocytes (/L) × hemoglobin (g/L) × albumin (g/L)]/platelets (/L). By performing the receiver operating characteristic (ROC) analysis, the optimal cutoff value of HALP was ascertained. Restricted cubic splines (RCS), multivariable logistic regression analysis, sensitivity analysis, and subgroup analysis were conducted to evaluate the effect of the HALP score on DR patients. Finally, the decision curve analysis (DCA) and clinical impact curve (CIC) were conducted to estimate the predictive power and clinical utility of the HALP score with clinical indicators. Results: According to the cutoff value (42.9) determined by the ROC curve, the participants were stratified into a lower HALP group (HALPlow) and a higher HALP group (HALPhigh). An L-shaped relationship between HALP score and DR risk was presented in the RCS model (P for nonlinearity <0.001). The DR risk sharply decreased with the increase of HALP, and the decline reached a plateau when HALP was more than 42.9. After fully adjustment, the multivariate logistic regression analysis found that HALPlow was an independent risk factor for DR (OR = 1.363, 95% CI: 1.111-1.671, P < 0.001). Besides, sensitivity analysis showed consistent results. Furthermore, the combination of HALP score and clinical indicators demonstrated predictive power and clinical utility, as shown by the ROC curve, DCA, and CIC. Conclusion: The HALP score has an L-shaped correlation with the risk of DR, and thus, the HALP score may contribute to the timely intervention of diabetes patients.
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Plaquetas , Retinopatia Diabética , Hemoglobinas , Linfócitos , Inquéritos Nutricionais , Humanos , Retinopatia Diabética/sangue , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Estados Unidos/epidemiologia , Hemoglobinas/análise , Hemoglobinas/metabolismo , Plaquetas/patologia , Adulto , Fatores de Risco , Idoso , Albumina Sérica/análise , Albumina Sérica/metabolismo , Curva ROC , Biomarcadores/sangueRESUMO
Cardiovascular thrombotic events have long been a perplexing factor in clinical settings, influencing patient prognoses significantly. Ultrasound-mediated acoustic therapy, an innovative thrombolytic treatment method known for its high efficiency, non-invasiveness, safety, and convenience, has demonstrated promising potential for clinical applications and has gradually become a focal point in cardiovascular thrombotic disease research. The current challenge lies in the technical complexities of preparing ultrasound-responsive carriers with thrombus-targeting capabilities and high thrombolytic efficiency. Additionally, optimizing the corresponding acoustic treatment mode is crucial to markedly enhance the thrombolytic effectiveness of ultrasound-mediated acoustic therapy. In light of the current status, this article provides a comprehensive review of the research progress in innovative ultrasound-mediated acoustic therapy for cardiovascular thrombotic diseases. It explores the impact of technical methods, therapeutic mechanisms, and influencing factors on the thrombolytic efficiency and clinical potential of ultrasound-mediated acoustic therapy. The review places particular emphasis on identifying solutions and key considerations in addressing the challenges associated with this cutting-edge therapeutic approach.
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Trombose , Terapia por Ultrassom , Humanos , Trombose/diagnóstico por imagem , Trombose/terapia , Terapia por Ultrassom/métodos , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/diagnóstico por imagem , Terapia Trombolítica/métodosRESUMO
Lead (Pb) poisoning and CO2-induced global warming represent two exemplary environmental and energy issues threatening humanity. Various biomass-derived materials are reported to take up Pb and convert CO2 electrochemically into low-valent carbon species, but these works address the problems separately rather than settle the issues simultaneously. In this work, cheap, natural ellagic acid (EA) extracted from common plants is adopted to assemble a stable metal-organic framework (MOF), EA-Pb, by effective capture of Pb2+ ions in an aqueous medium (removal rate close to 99%). EA-Pb represents the first structurally well-defined Pb-based MOF showing selective electrocatalytic CO2-to-HCOO- conversion with Faradaic efficiency (FE) of 95.37% at -1.08 V versus RHE. The catalytic mechanism is studied by 13CO2 labeling, in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), and theoretical calculation. The use of EA-Pb as an electrocatalyst for CO2 reduction represents a 2-in-1 solution of converting detrimental wastes (Pb2+) as well as natural resources (EA) into wealth (electrocatalytic EA-Pb) for addressing the global warming issue.
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BACKGROUND: Usual measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time. We aimed to demonstrate the effect of a novel time-weighted BP on cardiovascular outcomes using a post hoc analysis of two published randomized trials. HYPOTHESIS: Time-weighted blood pressure is associated with cardiovascular risk among patients with or without diabetes. METHODS: The limited-access ACCORD and SPRINT data sets were used for the current study. Time-weighted BP is obtained by dividing cumulative BP by the total follow-up time. Time-weighted BP burden above a threshold is also determined after deriving the time-weighted BP by re-zeroing the interpolated pressure values at two different hypertension thresholds (>140/90 and >130/80 mmHg). RESULTS: Eighteen thousand five hundred forty-one patients from the two clinical trials were enrolled in this study. A J-curve relation was observed between time-weighted BP and major cardiovascular events (MACE). The systolic blood pressure (SBP) burden independently predicted MACE across the two trials at different thresholds (ACCORD: SBP > 130 mmHg, HR = 1.05 [1.03-1.06]; SBP > 140 mmHg, HR = 1.06 [1.04-1.08]; SPRINT: SBP > 130 mmHg, HR = 1.04 [1.03-1.05]; SBP > 140 mmHg, HR = 1.05 [1.04-1.07]). Consistent results were found for diastolic blood pressure (DBP) burden (ACCORD: DBP > 80 mmHg, HR = 1.10 [1.06-1.15]; DBP > 90 mmHg, HR = 1.20 [1.11-1.30]. SPRINT: DBP > 80 mmHg, HR = 1.06 [1.02-1.09]; DBP > 90 mmHg, HR = 1.12 [1.06-1.18]). Significant associations were also observed for stroke, myocardial infarction, cardiovascular death, and all-cause mortality. CONCLUSION: Both time-weighted SBP and DBP independently influenced the risk of adverse cardiovascular events among patients with and without diabetes, regardless of the definition of hypertension (130/80 or <140/90 mmHg).
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Doenças Cardiovasculares , Diabetes Mellitus , Hipertensão , Humanos , Pressão Sanguínea , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Fatores de Risco , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Fatores de Risco de Doenças CardíacasRESUMO
BACKGROUND: The decline in the quantity and quality of mitochondria are closely associated with infertility, particularly in advanced maternal age. Transferring autologous mitochondria into the oocytes of infertile females represents an innovative and viable strategy for treating infertility, with no concerns regarding ethical considerations. As the donor cells of mitochondria, stem cells have biological advantages but research and evidence in this area are quite scarce. METHODS: To screen out suitable human autologous ooplasmic mitochondrial donor cells, we performed comprehensive assessment of mitochondrial physiology, function and metabolic capacity on a varity of autologous adipose, marrow, and urine-derived mesenchymal stromal cells (ADSC, BMSC and USC) and ovarian germline granulosa cells (GC). Further, to explore the biosafety, effect and mechanism of stem cell-derived mitochondria transfer on human early embryo development, randomized in-vitro basic studies were performed in both of the young and aged oocytes from infertile females. RESULTS: Compared with other types of mesenchymal stromal cells, USC demonstrated a non-fused spherical mitochondrial morphology and low oxidative stress status which resembled the oocyte stage. Moreover, USC mitochondrial content, activity and function were all higher than other cell types and less affected by age, and it also exhibited a biphasic metabolic pattern similar to the pre-implantation stage of embryonic development. After the biosafety identification of the USC mitochondrial genome, early embryos after USC mitochondrial transfer showed improvements in mitochondrial content, activity, and cytoplasmic Ca2+ levels. Further, aging embryos also showed improvements in embryonic morphological indicators, euploidy rates, and oxidative stress status. CONCLUSION: Autologous non-invasively derived USC mitochondria transfer may be an effective strategy to improve embryonic development and metabolism, especially in infertile females with advanced age or repeated pregnancy failure. It provides evidence and possibility for the autologous treatment of infertile females without invasive and ethical concerns.
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Infertilidade Feminina , Oócitos , Feminino , Humanos , Gravidez , Envelhecimento , Infertilidade Feminina/metabolismo , Infertilidade Feminina/terapia , Mitocôndrias , Oócitos/metabolismo , Células-TroncoRESUMO
Inflammation is a key factor in the pathogenesis of dry eye disease (DED). We aimed to investigate the role of microRNA-146a (miR-146a) in regulating corneal inflammation in a mouse model of benzalkonium chloride (BAC)-induced dry eye and the TNF-α-induced NF-κB signaling pathway in human corneal epithelial cells (HCECs). A mouse model of dry eye was established by administering with BAC to BALB/c mice, and the expression of TNF-α, IL-1ß, IL-6, IL-8, cyclooxygenase 2 (COX2), interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) in the corneas of dry eye model mice was significantly increased; this was accompanied by the upregulation of miR-146a and activation of the NF-κB pathway. In vitro, TNF-α induced miR-146a expression in HCECs, while the NF-κB inhibitor SC-514 reduced the expression of miR-146a. Overexpression of miR-146a decreased the expression of IRAK1 and TRAF6, which have been identified as targets of miR-146a. Furthermore, overexpression of miR-146a suppressed NF-κB p65 translocation from the cytoplasm to the nucleus. Moreover, overexpression of miR-146a attenuated the TNF-α-induced expression of IL-6, IL-8, COX2 and intercellular adhesion molecule 1 (ICAM1), while inhibition of miR-146a exerted the opposite effect. Our results suggest that miR-146a mediates the inflammatory response in DED. MiR-146a negatively regulates inflammation in HCECs through the IRAK1/TRAF6/NF-κB pathway, and this may serve as a potential therapeutic approach for the treatment of DED.
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Síndromes do Olho Seco , MicroRNAs , Animais , Humanos , Camundongos , Compostos de Benzalcônio , Ciclo-Oxigenase 2/genética , Modelos Animais de Doenças , Inflamação/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Interleucina-6 , Interleucina-8 , MicroRNAs/genética , NF-kappa B , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/genética , Fator de Necrose Tumoral alfaRESUMO
The outgrowth of epithelial bud followed by reiterated bifurcations during renal development is driven by the ligand-receptor interactions between the epithelium and the surrounding mesenchyme. Here, by exploring ligand-receptor interactions in E10.5 and E11.5 kidneys by single cell RNA-seq, we find that Isthmin1 (Ism1), a secreted protein, resembles Gdnf expression and modulates kidney branching morphogenesis. Mice deficient for Ism1 exhibit defective ureteric bud bifurcation and impaired metanephric mesenchyme condensation in E11.5 embryos, attributable to the compromised Gdnf/Ret signaling, ultimately leading to renal agenesis and hypoplasia/dysplasia. By HRP-induced proximity labelling, we further identify integrin α8ß1 as a receptor of Ism1 in E11.5 kidney and demonstrate that Ism1 promoted cell-cell adhesion through interacting with Integrin α8ß1, the receptor whose activation is responsible for Gdnf expression and mesenchyme condensation. Taken together, our work reveals Ism1 as a critical regulator of cell-cell interaction that modulates Gdnf/Ret signaling during early kidney development.
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Fator Neurotrófico Derivado de Linhagem de Célula Glial , Proteínas Proto-Oncogênicas c-ret , Camundongos , Animais , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Ligantes , Rim/metabolismo , Morfogênese , Mesoderma/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismoRESUMO
SUMO adducts occur in Aspergillus flavus, and are implicated in fungal biology, while the underlying mechanism and the SUMOylation apparatus components in this saprophytic food spoilage mould, remain undefined. Herein, genes encoding SUMOylation cascade enzymes in A. flavus, including two heterodimeric SUMO E1 activating enzymes, a unique SUMO E2 conjugating enzyme, and one of SUMO E3 ligases, were identified and functionally analyzed. Global SUMO adducts immunoassay, multiple morphological comparison, aflatoxin attributes test, fungal infection and transcriptomic analyses collectively revealed that: E1 and E2 were essential for intracellular SUMOylation, and contributed to both stress response and fungal virulence-related events, including sporulation, colonization, aflatoxins biosynthesis; the primary E3 in this fungus, AfSizA, might serve as the molecular linkage of SUMOylation pathway to fungal virulence rather than SUMOylation-mediated stress adaptation. These findings demonstrated that SUMOylation machinery in A. flavus was functionally intact and contributed to multiple pathobiological processes, hence offering ideas and targets to control food contamination by this mycotoxigenic fungus.
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Aflatoxinas , Aspergillus flavus , Aspergillus flavus/metabolismo , Aflatoxinas/metabolismo , Sumoilação , AlimentosRESUMO
Accurate segmentation of the left ventricle (LV) is crucial for evaluating myocardial perfusion SPECT (MPS) and assessing LV functions. In this study, a novel method combining deep learning with shape priors was developed and validated to extract the LV myocardium and automatically measure LV functional parameters. The method integrates a three-dimensional (3D) V-Net with a shape deformation module that incorporates shape priors generated by a dynamic programming (DP) algorithm to guide its output during training. A retrospective analysis was performed on an MPS dataset comprising 31 subjects without or with mild ischemia, 32 subjects with moderate ischemia, and 12 subjects with severe ischemia. Myocardial contours were manually annotated as the ground truth. A 5-fold stratified cross-validation was used to train and validate the models. The clinical performance was evaluated by measuring LV end-systolic volume (ESV), end-diastolic volume (EDV), left ventricular ejection fraction (LVEF), and scar burden from the extracted myocardial contours. There were excellent agreements between segmentation results by our proposed model and those from the ground truth, with a Dice similarity coefficient (DSC) of 0.9573 ± 0.0244, 0.9821 ± 0.0137, and 0.9903 ± 0.0041, as well as Hausdorff distances (HD) of 6.7529 ± 2.7334 mm, 7.2507 ± 3.1952 mm, and 7.6121 ± 3.0134 mm in extracting the LV endocardium, myocardium, and epicardium, respectively. Furthermore, the correlation coefficients between LVEF, ESV, EDV, stress scar burden, and rest scar burden measured from our model results and the ground truth were 0.92, 0.958, 0.952, 0.972, and 0.958, respectively. The proposed method achieved a high accuracy in extracting LV myocardial contours and assessing LV functions.
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Aprendizado Profundo , Ventrículos do Coração , Humanos , Volume Sistólico , Estudos Retrospectivos , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Cicatriz , Função Ventricular Esquerda , Isquemia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , PerfusãoRESUMO
BACKGROUND: Single photon emission computed tomography (SPECT) myocardial perfusion images (MPI) can be displayed both in traditional short-axis (SA) cardiac planes and polar maps for interpretation and quantification. It is essential to reorient the reconstructed transaxial SPECT MPI into standard SA slices. This study is aimed to develop a deep-learning-based approach for automatic reorientation of MPI. METHODS: A total of 254 patients were enrolled, including 226 stress SPECT MPIs and 247 rest SPECT MPIs. Fivefold cross-validation with 180 stress and 201 rest MPIs was used for training and internal validation; the remaining images were used for testing. The rigid transformation parameters (translation and rotation) from manual reorientation were annotated by an experienced nuclear cardiologist and used as the reference standard. A convolutional neural network (CNN) was designed to predict the transformation parameters. Then, the derived transform was applied to the grid generator and sampler in spatial transformer network (STN) to generate the reoriented image. A loss function containing mean absolute errors for translation and mean square errors for rotation was employed. A three-stage optimization strategy was adopted for model optimization: (1) optimize the translation parameters while fixing the rotation parameters; (2) optimize rotation parameters while fixing the translation parameters; (3) optimize both translation and rotation parameters together. RESULTS: In the test set, the Spearman determination coefficients of the translation distances and rotation angles between the model prediction and the reference standard were 0.993 in X axis, 0.992 in Y axis, 0.994 in Z axis, 0.987 along X axis, 0.990 along Y axis and 0.996 along Z axis, respectively. For the 46 stress MPIs in the test set, the Spearman determination coefficients were 0.858 in percentage of profusion defect (PPD) and 0.858 in summed stress score (SSS); for the 46 rest MPIs in the test set, the Spearman determination coefficients were 0.9 in PPD and 0.9 in summed rest score (SRS). CONCLUSIONS: Our deep learning-based LV reorientation method is able to accurately generate the SA images. Technical validations and subsequent evaluations of measured clinical parameters show that it has great promise for clinical use.
Assuntos
Aprendizado Profundo , Imagem de Perfusão do Miocárdio , Humanos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Coração , Perfusão , Imagem de Perfusão do Miocárdio/métodosRESUMO
A robust and porous Ni-based metal-organic framework (MOF), NiL1, was assembled from Ni(II) ions and a dipyrazolate linker (L12-). A Ni(II)-anchored MOF catalyst Ni@NiL1-Sal has been successfully prepared by post-synthetic modification (PSM) condensation between NiL1 with salicylaldehyde, followed by chelation of Ni(II) ions by salicylaldimine as a secondary active site. Ni@NiL1-Sal with carbon black was found to exhibit enhanced electrocatalytic hydrogen evolution reaction (HER) performance (the smallest overpotential, 384 mV, and Tafel slope, 87 mV dec-1) when compared with primitive NiL1 and NiL1-Sal. Such improvement in HER highlights the creation of unambiguous secondary active sites as an avenue to the rational design of a functional MOF-based electrocatalyst.
RESUMO
PURPOSE: Left bundle branch pacing (LBBP) is as an innovative physiological pacing approach. The research on LBBP in non-obstructive hypertrophic cardiomyopathy (NOHCM) patients is scarce. This study aimed to assess the feasibility, safety, and effect of LBBP in bradycardia NOHCM patients with permanent pacemaker (PPM) implantation indication. METHODS: Thirteen consecutive patients with NOHCM who received LBBP were retrospectively enrolled as a hypertrophic cardiomyopathy (HCM) group. Following 1:3 matching, 39 patients without HCM were randomly matched as a control group. Echocardiographic index and pacing parameters were collected. RESULTS: The successful LBBP was achieved in 96.2% of all cases (50/52), and the success rate of the HCM group was 92.3% (12/13). In the HCM group, the paced QRS duration (from the pacing stimulus to QRS end) was 145.6±20.8 ms. The stimulus to left ventricular activation time (s-LVAT) was 87.4±15.2 ms. In the control group, the paced QRS duration was 139.4±17.2 ms, and the s-LVAT was 79.9±14.1 ms. During the implantation, R-wave sensing and the pacing threshold of the HCM group were significantly higher than the control group (20.2±10.5 vs 12.5±5.9 mV, P < 0.05; 0.8±0.3 vs 0.6±0.2V/0.4 ms, P < 0.05). In addition, the fluoroscopic duration and procedural duration were longer in the HCM group (14.8±8.3 vs 10.3±6.6min, P = 0.07; 131.8±50.5 vs 101.4±41.6 min, P < 0.05). The lead insertion depth was 15±2 mm in the HCM group, and no procedure-related complications occurred. During the 12-month follow-up, pacing parameters remained stable and were of no significance in the two groups. The cardiac function did not deteriorate, and the left ventricular outflow tract gradient (LVOTG) did not increase in the follow-up. CONCLUSION: LBBP might be feasible and safe for NOHCM patients with conventional bradycardia pacing indication, and there is no deterioration in cardiac function and LVOTG of patients with NOHCM.