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Dihydrochalcones (DHCs) including phlorizin (phloretin 2'-O-glucoside) and its positional isomer trilobatin (phloretin 4'-O-glucoside) are the most abundant phenylpropanoids in apple (Malus spp.). Transcriptional regulation of DHC production is poorly understood despite their importance in insect- and pathogen-plant interactions in human physiology research and in pharmaceuticals. In this study, segregation in hybrid populations and bulked segregant analysis showed that the synthesis of phlorizin and trilobatin in Malus leaves are both single-gene-controlled traits. Promoter sequences of PGT1 and PGT2, two glycosyltransferase genes involved in DHC glycoside synthesis, were shown to discriminate Malus with different DHC glycoside patterns. Differential PGT1 and PGT2 promoter activities determined DHC glycoside accumulation patterns between genotypes. Two transcription factors containing MYB-like DNA-binding domains were then shown to control DHC glycoside patterns in different tissues, with PRR2L mainly expressed in leaf, fruit, flower, stem, and seed while MYB8L mainly expressed in stem and root. Further hybridizations between specific genotypes demonstrated an absolute requirement for DHC glycoside production in Malus during seed development which explains why no Malus spp. with a null DHC chemotype have been reported.
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Malus , Humanos , Malus/genética , Florizina , Factores de Transcripción/genética , Floretina , Semillas/genética , Glucósidos , Regulación de la Expresión Génica de las PlantasRESUMEN
Motor disturbances predominantly characterize hypoxic-ischemic encephalopathy (HIE). Among its intervention methods, environmental enrichment (EE) is strictly considered a form of sensory intervention. However, limited research uses EE as a single sensory input intervention to validate outcomes postintervention. A Sprague-Dawley rat model subjected to left common carotid artery ligation and exposure to oxygen-hypoxic conditions is used in this study. EE was achieved by enhancing the recreational and stress-relief items within the cage, increasing the duration of sunlight, colorful items exposure, and introducing background music. JZL184 (JZL) was administered as neuroprotective drugs. EE was performed 21 days postoperatively and the rats were randomly assigned to the standard environment and EE groups, the two groups were redivided into control, JZL, and vehicle injection subgroups. The Western blotting and behavior test indicated that EE and JZL injections were efficacious in promoting cognitive function in rats following HIE. In addition, the motor function performance in the EE-alone intervention group and the JZL-alone group after HIE was significantly improved compared with the control group. The combined EE and JZL intervention group exhibited even more pronounced improvements in these performances. EE may enhance motor function through sensory input different from the direct neuroprotective effect of pharmacological treatment.NEW & NOTEWORTHY Rarely does literature assess motor function, even though it is common after hypoxia ischemic encephalopathy (HIE). Previously used environmental enrichment (EE) components have not been solely used as sensory inputs. Physical factors were minimized in our study to observe the effects of purely sensory inputs.
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Hipoxia-Isquemia Encefálica , Ratas Sprague-Dawley , Animales , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/fisiopatología , Ratas , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Masculino , Ambiente , Recuperación de la Función/fisiología , Actividad Motora/fisiologíaRESUMEN
Quorum sensing is a type of cell-cell communication that modulates various biological activities of bacteria. Previous studies indicate that quorum sensing contributes to the evolution of bacterial resistance to antibiotics, but the underlying mechanisms are not fully understood. In this study, we grew Pseudomonas aeruginosa in the presence of sub-lethal concentrations of ciprofloxacin, resulting in a large increase in ciprofloxacin minimal inhibitory concentration. We discovered that quorum sensing-mediated phenazine biosynthesis was significantly enhanced in the resistant isolates, where the quinolone circuit was the predominant contributor to this phenomenon. We found that production of pyocyanin changed carbon flux and showed that the effect can be partially inhibited by the addition of pyruvate to cultures. This study illustrates the role of quorum sensing-mediated phenotypic resistance and suggests a strategy for its prevention.
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Antibacterianos , Ciprofloxacina , Farmacorresistencia Bacteriana , Pruebas de Sensibilidad Microbiana , Fenazinas , Pseudomonas aeruginosa , Piocianina , Percepción de Quorum , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , Ciprofloxacina/farmacología , Percepción de Quorum/efectos de los fármacos , Fenazinas/farmacología , Fenazinas/metabolismo , Antibacterianos/farmacología , Piocianina/biosíntesis , Farmacorresistencia Bacteriana/genética , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Quinolonas/farmacologíaRESUMEN
BACKGROUND: Albuminuria, the presence of excess of protein in urine, is a well-known risk factor for early kidney damage among diabetic/prediabetic patients. There is a complex interaction between physical activity (PA) and albuminuria. However, the relationship of specific-domain PA and albuminuria remained obscure. METHODS: Albuminuria was defined as urinary albumin/creatinine ratio (ACR) > 30 mg/g. PA was self-reported by participants and classified into transportation-related PA (TPA), occupation-related PA (OPA), and leisure-time PA (LTPA). Weighted logistic regression was conducted to compute the odds ratios (ORs) and 95% confidence intervals (CIs). Restricted cubic spline (RCS) was used to evaluate the dose-response of PA domains with the risk of albuminuria. RESULTS: A total of 6739 diabetic/prediabetic patients (mean age: 56.52 ± 0.29 years) were enrolled in our study, including 3181 (47.20%) females and 3558 (52.80%) males. Of them, 1578 (23.42%) were identified with albuminuria, and 5161(76.58%) were without albuminuria. Diabetic/prediabetic patients who adhered the PA guidelines for total PA had a 22% decreased risk of albuminuria (OR = 0.78, 95%CI 0.64-0.95), and those met the PA guidelines for LTPA had a 28% decreased of albuminuria (OR = 0.72, 95%CI 0.57-0.92). However, OPA and TPA were both not associated with decreased risk of albuminuria. RCS showed linear relationship between the risk of albuminuria with LTPA. CONCLUSIONS: Meeting the PA guideline for LTPA, but not OPA and TPA, was inversely related to the risk of albuminuria among diabetic/prediabetic patients. Additionally, achieving more than 300 min/week of LTPA conferred the positive effects in reducing albuminuria among diabetic/prediabetic patients.
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Diabetes Mellitus , Estado Prediabético , Masculino , Femenino , Humanos , Persona de Mediana Edad , Estudios Transversales , Albuminuria/complicaciones , Ejercicio Físico/fisiologíaRESUMEN
BACKGROUND: Colorectal cancer (CRC) is a prevalent malignant malignancy affecting the gastrointestinal tract that is usually treated clinically with chemotherapeutic agents, whereas chemotherapeutic agents can cause severe gastrointestinal toxicity, which brings great pain to patients. Therefore, finding effective adjuvant agents for chemotherapy is crucial. METHODS: In this study, a CRC mouse model was successfully constructed using AOM/DSS, and the treatment was carried out by probiotic Bifidobacterium longum SX-1326 (B. longum SX-1326) in combination with irinotecan. Combining with various techniques of modern biomedical research, such as Hematoxylin and Eosin (H&E), Immunohistochemistry (IHC), Western blotting and 16S rDNA sequencing, we intend to elucidate the effect and mechanism of B. longum SX-1326 in improving the anticancer efficacy and reducing the side effects on the different levels of molecules, animals, and bacteria. RESULTS: Our results showed that B. longum SX-1326 enhanced the expression of Cleaved Caspase-3 (M vs. U = p < 0.01) and down-regulated the expression level of B-cell lymphoma-2 (Bcl-2) through up-regulation of the p53 signaling pathway in CRC mice, which resulted in an adjuvant effect on the treatment of CRC with irinotecan. Moreover, B. longum SX-1326 was also able to regulate the gut-brain-axis (GBA) by restoring damaged enterochromaffin cells, reducing the release of 5-hydroxytryptamine (5-HT) in brain tissue (I vs. U = 89.26 vs. 75.03, p < 0.05), and further alleviating the adverse effects of nausea and vomiting. In addition, B. longum SX-1326 reversed dysbiosis in CRC model mice by increasing the levels of Dehalobacterium, Ruminnococcus, and Mucispirillum. And further alleviated colorectal inflammation by downregulating the TLR4/MyD88/NF-κB signaling pathway. CONCLUSIONS: In conclusion, our work reveals that B. longum SX-1326 has a favorable effect in adjuvant irinotecan for CRC and amelioration of post-chemotherapy side effects, and also provides the theoretical basis and data for finding a safe and efficient chemotherapeutic adjuvant.
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Bifidobacterium longum , Microbioma Gastrointestinal , Animales , Humanos , Ratones , Eje Cerebro-Intestino , Irinotecán/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/farmacologíaRESUMEN
INTRODUCTION: Cognitive dysfunction due to reduced neuronal transmission in the brain is a major emerging complication in diabetes. However, recent neuroimaging studies have demonstrated non-linear changes including hyperactivity in the hippocampus during the early stage of diabetes. This study aimed to determine the changes in neuronal activity at a single-cell level in hippocampal CA1 pyramidal neurons in the early stage of streptozotocin-induced type 1 diabetes in mice. METHODS: Whole-cell patch-clamp recordings from acute brain slices were performed in mice over 4 consecutive weeks following the induction of hyperglycaemia using streptozotocin. In addition, microdialysate was collected from CA1 area while the mice were in an arousal state. The concentrations of glutamate and GABA in the microdialysate were then measured using ultra-performance liquid chromatography with mass spectrometry. RESULTS: CA1 neurons in streptozotocin-induced diabetic mice exhibited higher membrane potentials (p = 0.0052), higher frequency of action potentials (p = 0.0052), and higher frequency of spontaneous excitatory post-synaptic currents (p = 0.037) compared with controls during the second week after hyperglycaemia was established. No changes in electrophysiological parameters were observed during the first, the third, and the fourth week. Moreover, the diabetic mice had higher extracellular glutamate concentration in CA1 area compared with controls (p = 0.021) during the second week after the initiation of diabetes. No change in the extracellular GABA concentration was observed. CONCLUSION: Our study demonstrated a temporary state of neuronal hyperactivity at the single-cell level in the hippocampal CA1 region during the early stage of diabetes. This neuronal hyperactivity might be related to altered glutamate metabolism and provide clues for future brain-target intervention.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Hiperglucemia , Ratones , Animales , Estreptozocina/toxicidad , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hipocampo/metabolismo , Neuronas , Transmisión Sináptica/fisiología , Ácido Glutámico/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Hiperglucemia/metabolismoRESUMEN
OBJECTIVES: We aimed to explore the imaging profile of coronary atherosclerosis, perivascular inflammation, myocardial perfusion, and interstitial fibrosis in diabetes stratified by lipoprotein(a) [Lp(a)] levels. METHODS: In this prospective study, we enrolled diabetic patients who had undergone computed tomography (CT) angiography, stress CT-myocardial perfusion imaging, and late iodine enhancement in 20 months. Then, we categorized them into elevated and normal groups based on an Lp(a) cutoff level of 30 mg/dL. All imaging data, including coronary atherosclerosis parameters, pericoronary adipose tissue (PCAT) density, stress myocardial blood flow (MBF), and extracellular volume (ECV), were collected for further analysis. RESULTS: In total, 207 participants (mean age: 59.1 ± 12.0 years, 111 males) were included in this study. Patients with elevated Lp(a) level had more pronounced percent atheroma volume (2.55% (1.01-9.01%) versus 1.30% (0-4.95%), p = 0.010), and demonstrated a higher incidence of positive remodeling, spotty calcification, and high-risk plaque (HRP) than those with normal Lp(a) levels (75.6% versus 54.8%, p = 0.015; 26.8% versus 9.6%, p = 0.003; 51.2% versus 30.1%, p = 0.011, respectively). Results of the multivariate analysis revealed that after adjusting for all clinical characteristics, elevated Lp(a) levels were an independent parameter associated with HRP (odds ratio = 2.608; 95% confidence interval: 1.254-5.423, p = 0.010). However, no significant difference was found between the two groups in terms of PCAT density, stress MBF, and ECV. CONCLUSIONS: Elevated Lp(a) levels are associated with extensive coronary atherosclerosis and HRP development. However, they are not related to perivascular inflammation, decreased myocardial perfusion, and interstitial fibrosis in diabetes. CLINICAL RELEVANCE STATEMENT: Elevated lipoprotein(a) levels are associated with extensive coronary atherosclerosis and a high incidence of HRPs. However, they are not related to perivascular inflammation, decreased myocardial perfusion, and interstitial fibrosis in diabetes. KEY POINTS: Diabetes is a known risk factor that accelerates cardiovascular disease progression. Diabetics with elevated lipoprotein(a) (Lp(a)) levels had a higher percent atheroma volume and positive remodeling, spotty calcification, and HRPs. Patients with diabetes should be screened for elevated Lp(a) using CCTA for comprehensive evaluation of atherosclerotic characteristics.
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AIM: We investigated the relationship between the complexity of the glucose time series index (CGI) during pregnancy and adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM). MATERIALS AND METHODS: In this retrospective cohort study, 388 singleton pregnant women with GDM underwent continuous glucose monitoring (CGM) at a median of 26.86 gestational weeks. CGI was calculated using refined composite multiscale entropy based on CGM data. The participants were categorized into tertiles according to their baseline CGI (CGI <2.32, 2.32-3.10, ≥3.10). Logistic regression was used to assess the association between CGI and composite adverse outcomes or large for gestational age (LGA). The discrimination performance of CGI was estimated using receiver operating characteristic analysis. RESULTS: Of the 388 participants, 71 (18.3%) had LGA infants and 63 (16.2%) had composite adverse outcomes. After adjustments were made for confounders, compared with those with a high CGI (CGI ≥3.10), participants with a low CGI (CGI <2.32) had a higher risk of composite adverse outcomes (odds ratio: 12.10, 95% confidence interval: 4.41-33.18) and LGA (odds ratio: 12.68, 95% confidence interval: 4.04-39.75). According to the receiver operating characteristic analysis, CGI was significantly better than glycated haemoglobin and conventional CGM indicators for the prediction of adverse pregnancy outcomes (all p < .05). CONCLUSION: A lower CGI during pregnancy was associated with composite adverse outcomes and LGA. CGI, a novel glucose homeostasis predictor, seems to be superior to conventional glucose indicators for the prediction of adverse pregnancy outcomes in women with GDM.
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Automonitorización de la Glucosa Sanguínea , Glucemia , Diabetes Gestacional , Resultado del Embarazo , Humanos , Embarazo , Femenino , Diabetes Gestacional/sangre , Adulto , Estudios Retrospectivos , Glucemia/análisis , Glucemia/metabolismo , Resultado del Embarazo/epidemiología , Macrosomía Fetal/epidemiología , Macrosomía Fetal/etiología , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Recién NacidoRESUMEN
BACKGROUND: Blood shortage is a global challenge, impacting elective surgeries with high bleeding risk. Predicting intraoperative blood use, optimizing resource allocation, and ensuring safe elective surgery are vital. This study targets identifying key bleeding risk factors in Aortic Valve Replacement (AVR) through machine learning. METHODS: Data from 702 AVR patients were split into 70% training and 30% test sets. Thirteen models predicted RBC transfusion. SHapley Additive exPlanations (SHAP) analyzed risk factors. RESULTS: Logistic Regression excelled, with Area Under Curve (AUC) 0.872 and 81.0% accuracy on the test set. Notably, female gender, Hemoglobin (HGB) < 131.91 g/L, Hematocrit (HCT) < 0.41L/L, weight < 59.49 kg, age > 54.47 year, Mean Corpuscular Hemoglobin (MCH) < 29.15 pg, Total Protein (TP) > 69.7 g/L, FIB > 2.61 g/L, height < 160 cm, and type of operation is Surgical Aortic Valve Replacement (SAVR) were significant RBC transfusion predictors. CONCLUSIONS: The study's model accurately forecasts AVR-related RBC transfusions. This informs presurgery blood preparations, reducing resource waste and aiding clinicians in optimizing patient care.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Humanos , Femenino , Válvula Aórtica/cirugía , Transfusión de Eritrocitos , Factores de Riesgo , Aprendizaje Automático , Estudios RetrospectivosRESUMEN
Bayesian tensor decomposition has been widely applied in channel parameter estimations, particularly in cases with the presence of interference. However, the types of interference are not considered in Bayesian tensor decomposition, making it difficult to accurately estimate the interference parameters. In this paper, we present a robust tensor variational method using a CANDECOMP/PARAFAC (CP)-based additive interference model for multiple input-multiple output (MIMO) with orthogonal frequency division multiplexing (OFDM) systems. A more realistic interference model compared to traditional colored noise is considered in terms of co-channel interference (CCI) and front-end interference (FEI). In contrast to conventional algorithms that filter out interference, the proposed method jointly estimates the channel and interference parameters in the time-frequency domain. Simulation results validate the correctness of the proposed method by the evidence lower bound (ELBO) and reveal the fact that the proposed method outperforms traditional information-theoretic methods, tensor decomposition models, and robust model based on CP (RCP) in terms of estimation accuracy. Further, the interference parameter estimation technique has profound implications for anti-interference applications and dynamic spectrum allocation.
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The accurate pollutant prediction by Machine Learning (ML) is significant to efficient environmental monitoring and risk assessment. However, application of ML in soil is under studied. In this study, a Positive Matrix Factorization (PMF) assisted prediction method was developed with Support Vector Machine (SVM) and Random Forest (RF) for heavy metals (HMs) prediction in mining farmland. Principal Component Analysis (PCA) and Redundancy Analysis (RDA) were selected to pretreat data. Experiment results illustrated Cd was the main pollutant with heavy risks in the study area and Pb was easy to migrate. The method effects of HMs total concentration predicting were PMF > Simple > PCA > PCA - PMF, and RF predicted better than SVM. Data pretreatment by RDA prior inspection improved the model results. Characteristic HMs Tessier fractions prediction received good effects with average R value as 0.86. Risk classification prediction performed good in Cd, Cu, Ni and Zn, however, Pb showed weak effect by simple model. The best classifier method for Pb was PMF - RF method with relatively good effect (Area under ROC Curve = 0.896). Overall, our study suggested the combination between PMF and ML can assist the prediction of HMs in soil. Spatial weighted attribute of HMs can be provided by PMF.
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Contaminantes Ambientales , Metales Pesados , Contaminantes del Suelo , Granjas , Cadmio , Plomo , Contaminantes del Suelo/análisis , Metales Pesados/análisis , Suelo , Monitoreo del Ambiente/métodos , Aprendizaje Automático , Medición de Riesgo , ChinaRESUMEN
The CRISPR/Cas13b system has been demonstrated as a robust tool for versatile RNA studies and relevant applications. New strategies enabling precise control of Cas13b/dCas13b activities and minimal interference with native RNA activities will further facilitate the understanding and regulation of RNA functions. Here, we engineered a split Cas13b system that can be conditionally activated and deactivated under the induction of abscisic acid (ABA), which achieved the downregulation of endogenous RNAs in dosage- and time-dependent manners. Furthermore, an ABA inducible split dCas13b system was generated to achieve temporally controlled deposition of m6A at specific sites on cellular RNAs through conditional assembly and disassembly of split dCas13b fusion proteins. We also showed that the activities of split Cas13b/dCas13b systems can be modulated by light via using a photoactivatable ABA derivative. Overall, these split Cas13b/dCas13b platforms expand the existing repertoire of the CRISPR and RNA regulation toolkit to achieve targeted manipulation of RNAs in native cellular environments with minimal functional disruption to these endogenous RNAs.
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Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , ARN , ARN/metabolismo , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Sistemas CRISPR-Cas/genéticaRESUMEN
Invasive glioma usually disrupts the integrity of the blood-brain barrier (BBB), making the delivery of nanodrugs across the BBB possible, but sufficient targeting ability is still avidly needed to improve drug accumulation in glioma. Membrane-bound heat shock protein 70 (Hsp70) is expressed on the membrane of glioma cells rather than adjacent normal cells, therefore it can serve as a specific glioma target. Meanwhile, prolonging the retention in tumors is important for active-targeting nanoparticles to overcome receptor-binding barriers. Herein, the Hsp70-targeting and acid-triggered self-assembled gold nanoparticles (D-A-DA/TPP) are proposed to realize selective delivery of doxorubicin (DOX) to glioma. In the weakly acidic glioma matrix, D-A-DA/TPP formed aggregates to prolong retention, improve receptor-binding efficiency and facilitate acid-responsive DOX release. DOX accumulation in glioma induced immunogenic cell death (ICD) to promote antigen presentation. Meanwhile, combination with the PD-1 checkpoint blockade further activate T cells and provokes robust anti-tumor immunity. The results showed that D-A-DA/TPP can induce more glioma apoptosis. Furthermore, in vivo studies indicated D-A-DA/TPP plus PD-1 checkpoint blockade significantly improved median survival time. This study offeres a potential nanocarrier combining size-tunable strategy with active targeting ability to increase drug enrichment in glioma and synergizes with PD-1 checkpoint blockade to achieve chemo-immunotherapy.
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Glioma , Nanopartículas del Metal , Nanopartículas , Humanos , Receptor de Muerte Celular Programada 1 , Oro/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/patología , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Línea Celular TumoralRESUMEN
OBJECTIVES: To investigate the prognostic value of computed tomography fractional flow reserve (CT-FFR) in patients with diabetes and to establish a risk stratification model for major adverse cardiac event (MACE). METHODS: Diabetic patients with intermediate pre-test probability of coronary artery disease were prospectively enrolled. All patients were referred for coronary computed tomography angiography and followed up for at least 2 years. In the training cohort comprising of 957 patients, two models were developed: model1 with the inclusion of clinical and conventional imaging parameters, model2 incorporating the above parameters + CT-FFR. An internal validation cohort comprising 411 patients and an independent external test cohort of 429 patients were used to validate the proposed models. RESULTS: 1797 patients (mean age: 61.0 ± 7.0 years, 1031 males) were finally included in the present study. MACE occurred in 7.18% (129/1797) of the current cohort during follow- up. Multivariate Cox regression analysis revealed that CT-FFR ≤ 0.80 (hazard ratio [HR] = 4.534, p < 0.001), HbA1c (HR = 1.142, p = 0.015) and low attenuation plaque (LAP) (HR = 3.973, p = 0.041) were the independent predictors for MACE. In the training cohort, the Log-likelihood test showed statistical significance between model1 and model2 (p < 0.001). The C-index of model2 was significantly larger than that of model1 (C-index = 0.82 [0.77-0.87] vs. 0.80 [0.75-0.85], p = 0.021). Similar findings were found in internal validation and external test cohorts. CONCLUSION: CT-FFR was a strong independent predictor for MACE in diabetic cohort. The model incorporating CT-FFR, LAP and HbA1c yielded excellent performance in predicting MACE.
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Enfermedad de la Arteria Coronaria , Estenosis Coronaria , Diabetes Mellitus , Reserva del Flujo Fraccional Miocárdico , Placa Aterosclerótica , Masculino , Humanos , Persona de Mediana Edad , Anciano , Angiografía Coronaria/métodos , Hemoglobina Glucada , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Vasos Coronarios , Tomografía Computarizada por Rayos X , Valor Predictivo de las Pruebas , Angiografía por Tomografía Computarizada/métodosRESUMEN
BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are recognized as a potential cell-based therapy for regenerative medicine. Short-term inflammatory cytokine pre-stimulation (cytokine priming) is a promising approach to enhance regenerative efficacy of MSCs. However, it is unclear whether their intrinsic heterogenic nature causes an unequal response to cytokine priming, which might blunt the accessibility of clinical applications. METHODS: In this study, by analyzing the single-cell transcriptomic landscape of human bone marrow MSCs from a naïve to cytokine-primed state, we elucidated the potential mechanism of superior therapeutic potential in cytokine-primed MSCs. RESULTS: We found that cytokine-primed MSCs had a distinct transcriptome landscape. Although substantial heterogeneity was identified within the population in both naïve and primed states, cytokine priming enhanced the several characteristics of MSCs associated with therapeutic efficacy irrespective of heterogeneity. After cytokine-priming, all sub-clusters of MSCs possessed high levels of immunoregulatory molecules, trophic factors, stemness-related genes, anti-apoptosis markers and low levels of multi-lineage and senescence signatures, which are critical for their therapeutic potency. CONCLUSIONS: In conclusion, our results provide new insights into MSC heterogeneity under cytokine stimulation and suggest that cytokine priming reprogrammed MSCs independent of heterogeneity.
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Citocinas , Células Madre Mesenquimatosas , Humanos , Análisis de Expresión Génica de una Sola Célula , Transcriptoma , Perfilación de la Expresión GénicaRESUMEN
OBJECTIVES: To investigate the predictive value of peri-coronary adipose tissue (PCAT) attenuation for microvascular complications in diabetic patients without significant stenosis and to develop a prediction model for early risk stratification. METHODS: This study retrospectively included patients clinically identified for coronary computed tomography angiography (CCTA) and type 2 diabetes between January 2017 and December 2020. All patients were followed up for at least 1 year. The clinical data and CCTA-based imaging characteristics (including PCAT of major epicardial vessels, high-risk plaque features) were recorded. In the training cohort comprising of 579 patients, two models were developed: model 1 with the inclusion of clinical factors and model 2 incorporating clinical factors + RCAPCAT using multivariable logistic regression analysis. An internal validation cohort comprising 249 patients and an independent external validation cohort of 269 patients were used to validate the proposed models. RESULTS: Microvascular complications occurred in 69.1% (758/1097) of the current cohort during follow-up. In the training cohort, model 2 exhibited improved predictive power over model 1 based on clinical factors (AUC = 0.820 versus 0.781, p = 0.003) with lower prediction error (Brier score = 0.146 versus 0.164) compared to model 1. Model 2 accurately categorized 78.58% of patients with diabetic microvascular complications. Similar performance of model 2 in the internal validation cohort and the external validation cohort was further confirmed. CONCLUSIONS: The model incorporating clinical factors and RCAPCAT predicts the development of microvascular complications in diabetic patients without significant coronary stenosis. KEY POINTS: ⢠Hypertension, HbA1c, duration of diabetes, and RCAPCAT were independent risk factors for microvascular complications. ⢠The prediction model integrating RCAPCAT exhibited improved predictive power over the model only based on clinical factors (AUC = 0.820 versus 0.781, p = 0.003) and showed lower prediction error (Brier score=0.146 versus 0.164).
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Enfermedad de la Arteria Coronaria , Estenosis Coronaria , Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Estudios Retrospectivos , Angiografía Coronaria/métodos , Medición de Riesgo , Valor Predictivo de las Pruebas , Estenosis Coronaria/complicaciones , Estenosis Coronaria/diagnóstico por imagen , Angiografía por Tomografía Computarizada/métodos , Complicaciones de la Diabetes/diagnóstico por imagen , Tejido Adiposo/diagnóstico por imagen , Vasos CoronariosRESUMEN
This study aims to experimentally and theoretically investigate the roles of a threaded nozzle and yield stress in the coaxial air blast atomization of a gelled jet by means of rheological tests and high-speed flow visualization techniques. Similar to the breakup types of Newtonian fluids, a gelled jet will gradually exhibit an oscillation mode, membrane-type breakup, fiber-type breakup and a superpulsating submode as the airflow velocity increases. The transition conditions for each type are determined and plotted in the dimensionless map of We-Oh. For the jet spray angle, the maximum occurs when We = 600 and is clearly enlarged by the gas-side thread in the nozzle. The numerical results of the linear stability analysis indicate that a smaller dominant unstable growth rate is acquired by swelling the yield stress, while the higher dominant unstable growth rate and truncated wavenumber appear as the rotational airflow is acquired through the gas-side threaded nozzle.
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While there is good evidence that exercise is an effective adjunct therapy to cancer care, little is known about its value for money. The aim of this systematic review is to explore the available evidence pertaining to the cost-effectiveness of exercise interventions following cancer. A search of eight online databases (CINAHL, the Cochrane Library (NHSEED), Econlit, Embase, PsycInfo, PubMed, Scopus, Web of science) was first conducted on 26 March 2021 and updated on 8 March 2022. Only economic evaluations with results in the form of incremental cost-effectiveness ratio (ICER) were included. The Consolidated Health Economics Evaluation Reporting Standards (CHEERS) was used to appraise the quality of reporting in the studies. The study protocol was registered in PROSPERO. Sixteen studies comprising seven (44%) cost-utility analyses (CUA), one (6%) cost-effectiveness analyses (CEA) and eight (50%) combined CUA and CEA were identified. These studies explored exercise in five cancer types (breast, colon, lung, prostate, and blood), with half (50%) in breast cancer. Seven studies (44%) adopted societal perspectives. Exercise interventions were found to be cost-effective in five of ten (50%) trial-based economic evaluations and in five of the six (83%) model-based economic evaluations. Most exercise interventions included were supervised, while close supervision and individualized exercise sessions incurred higher costs. Exercise interventions in cancer care are cost-effective for various cancer types despite considerable heterogeneity in exercise delivery and the type of analysis used for economic evaluation. There is clear value in using decision-analytic modelling to account for the long-term benefits of exercise in cancer care.
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Neoplasias de la Mama , Masculino , Humanos , Análisis Costo-Beneficio , Análisis de Costo-Efectividad , Ejercicio Físico , Terapia por EjercicioRESUMEN
PURPOSE: Cardiovascular disease (CVD) is the leading cause of death after treatment for endometrial cancer (EC). There is clinical evidence that exercise significantly reduces the risks of CVD and cancer recurrence in this population; however, it is unclear whether there is value for money in integrating exercise into cancer recovery care for women treated for EC. This paper assesses the long-term cost-effectiveness of a 12-week supervised exercise intervention, as compared with standard care, for women diagnosed with early-stage EC. METHOD: A cost-utility analysis was conducted from the Australian health system perspective for a time horizon of 5 years. A Markov cohort model was designed with six mutually exclusive health states: (i) no CVD, (ii) post-stroke, (iii) post-coronary heart disease (CHD), (iv) post-heart failure, (v) post-cancer recurrence, and (vi) death. The model was populated using the best available evidence. Costs and quality-adjusted life years (QALYs) were discounted at 5% annual rate. Uncertainty in the results was explored using one-way and probabilistic sensitivity analyses (PSA). RESULT: The incremental cost of supervised exercise versus standard care was AUD $358, and the incremental QALY was 0.0789, resulting in an incremental cost-effectiveness ratio (ICER) of AUD $5184 per QALY gained. The likelihood that the supervised exercise intervention was cost-effective at a willingness-to-pay threshold of AUD $50,000 per QALY was 99.5%. CONCLUSION: This is the first economic evaluation of exercise after treatment for EC. The results suggest that exercise is cost-effective for Australian EC survivors. Given the compelling evidence, efforts could now focus on the implementation of exercise as part of cancer recovery care in Australia.
Asunto(s)
Supervivientes de Cáncer , Enfermedades Cardiovasculares , Neoplasias Endometriales , Femenino , Humanos , Análisis Costo-Beneficio , Australia , Neoplasias Endometriales/terapia , Terapia por EjercicioRESUMEN
Biofilm formation is likely to contribute greatly to antibiotic resistance in bacteria and therefore the efficient removal of bacterial biofilms needs addressing urgently. Here, we reported that the supplement of non-inhibitory concentration of N-acetyl-L-cysteine (NAC), a common reactive oxygen species (ROS) scavenger, can significantly reduce the biomass of mature Pseudomonas aeruginosa biofilms (corroborated by crystal violet assay and laser scanning confocal microscopy). 1 mM NAC increased the cheater (ΔlasR mutant) frequency to 89.4 ± 1.5% in the evolved PAO1 after the 15-day treatment. Scavenging of ROS by NAC induced the collapse of P. aeruginosa biofilms, but it did not alter quorum sensing-regulated genes expression (e.g., hcnC and cioAB) and hydrogen cyanide production. The replenishment of public good protease contributed to the recovery of biofilm biomass, indicating the role of disrupting policing in biofilm inhibition. Furthermore, 7 typical ROS scavengers (e.g., superoxide dismutase, catalase and peroxidase, etc.) also effectively inhibited mature P. aeruginosa biofilms. This study demonstrates that scavenging of ROS can promote the selective control of P. aeruginosa biofilms through policing disruption as a targeted biofilm control strategy in complex water environments.