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BACKGROUND: DEAD-box RNA helicase 19 A (DDX19A) is overexpressed in cervical squamous cell carcinoma. However, its role in gastric cancer remains unclear. The present study aimed to explore the role and underlying mechanism of DDX19A in the development of gastric cancer. METHODS: The expression of DDX19A in gastric cancer and paracancerous tissues was evaluated through quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The biological functions of DDX19A in gastric cancer were determined using CCK8, plate colony-forming, and Transwell migration assays. The specific mechanism of DDX19A in gastric cancer cells was studied using western blotting, RNA-binding protein immunoprecipitation, mRNA half-life detection, and nuclear and cytoplasmic RNA isolation. RESULTS: DDX19A was highly expressed in gastric cancer and positively associated with malignant clinicopathological features and poor prognosis. Additionally, DDX19A promoted gastric cancer cell proliferation, migration, and epithelial-mesenchymal transition phenotypes. Mechanistically, DDX19A activated the PI3K/AKT pathway by upregulating phosphatidylinositol-3-kinase (PIK3CA) expression. Furthermore, DDX19A interacted with PIK3CA mRNA, stabilized it, and facilitated its export from the nucleus. CONCLUSIONS: Our study reveals a novel mechanism whereby DDX19A promotes the proliferation and migration of gastric cancer cells by enhancing the stability and nuclear export of PIK3CA mRNA, thereby activating the PI3K/AKT pathway.
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Introduction: Intratumoral microbes play an important role in the development of colorectal cancer (CRC). However, studying intratumoral microbes in CRC faces technical challenges, as tumor microbe communities are often contaminated by fecal microbes due to the structure of the gut folds and villi. The present study aimed to develop a new method for isolating tumor cell-associated microbiota and comparing microbial populations from different compartments. Materials and methods: The distribution of intestinal bacteria was detected using immunohistochemistry combined with 5R-16s rRNA gene sequencing to explore the effects of the sampling site and number of washes on the detection of microbiota. The 5R-16s rRNA gene sequencing was performed using 44 samples from 11 patients with CRC, including CRC tumor tissues (TT), normal tissues adjacent to CRC (NT), tumor cells (TC), and normal cells (NC). TC and NC were obtained from the TT and NT using an enzymatic digestion method. The microbiota and their potential functions in the four groups were analyzed and compared to determine the differential microbiota related to CRC. Results: Bacteria were mainly distributed in the feces covering intestinal tissues and in the epithelial cells and macrophages within the tissues. Different sampling sites and number of washes led to detection of different microbiota distributions. Although the cleaning method could be controlled, sampling sites varied and led to different microbiota distributions. The phyla of Firmicutes and Bacteroidetes were highly abundant in the conventionally used tissue samples, whereas Proteobacteria was the most abundant phyla in the cell samples isolated with the new method (i.e., after cell enzymatic hydrolysis). Detection of CRC cell-associated microbiota using a cell enzymatic digestion method showed that some bacteria, such as Fusobacterium, Eikenella, Shewanella, and Listeria, were more abundant in TT than NT, whereas the abundance of Akkermansia was lower in TT than NT. The tumor/normal ratios of some bacteria, such as Gemella, Escherichia, Shigella, and Blautia, were different between the cell and tissue samples. Conclusion: The cell enzymatic digestion method reduced fecal bacterial contamination, enabling low biomass intratumoral microbiota to be detected and allowing prediction of bacterial distributions.
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BACKGROUND: G protein-coupled receptors play a critical role in atrial fibrillation (AF). Spexin is a novel ligand of galanin receptors (GALRs). In this study, we investigated the regulation of spexin and GALRs on AF and the underlying mechanisms. METHODS: Global spexin knockout (SPX-KO) and cardiomyocyte-specific GALRs knockout (GALR-cKO) mice underwent burst pacing electrical stimulation. Optical mapping was used to determine atrial conduction velocity and action potential duration. Atrial myocyte action potential duration and inward rectifying K+ current (IK1) were recorded using whole-cell patch clamps. Isolated cardiomyocytes were stained with Fluo-3/AM dye, and intracellular Ca2+ handling was examined by CCD camera. A mouse model of AF was established by Ang-II (angiotensin II) infusion. RESULTS: Spexin plasma levels in patients with AF were lower than those in subjects without AF, and knockout of spexin increased AF susceptibility in mice. In the atrium of SPX-KO mice, potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) and sarcolipin (SLN) were upregulated; meanwhile, IK1 current was increased and Ca2+ handling was impaired in isolated atrial myocytes of SPX-KO mice. GALR2-cKO mice, but not GALR1-cKO and GALR3-cKO mice, had a higher incidence of AF, which was associated with higher IK1 current and intracellular Ca2+ overload. The phosphorylation level of CREB (cyclic AMP responsive element binding protein 1) was upregulated in atrial tissues of SPX-KO and GALR2-cKO mice. Chromatin immunoprecipitation confirmed the recruitment of p-CREB to the proximal promoter regions of KCNJ2 and SLN. Finally, spexin treatment suppressed CREB signaling, decreased IK1 current and decreased intracellular Ca2+ overload, which thus reduced the inducibility of AF in Ang-II-infused mice. CONCLUSIONS: Spexin reduces atrial fibrillation susceptibility by inhibiting CREB phosphorylation and thus downregulating KCNJ2 and SLN transcription by GALR2 receptor. The spexin/GALR2/CREB signaling pathway represents a novel therapeutic avenue in the development of agents against atrial fibrillation.
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Fibrilación Atrial , Ratones Noqueados , Miocitos Cardíacos , Hormonas Peptídicas , Receptor de Galanina Tipo 2 , Animales , Femenino , Humanos , Masculino , Ratones , Potenciales de Acción/efectos de los fármacos , Fibrilación Atrial/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Hormonas Peptídicas/metabolismo , Receptor de Galanina Tipo 2/metabolismo , Receptor de Galanina Tipo 2/genética , Transducción de SeñalRESUMEN
BACKGROUND: Ubiquitination is an enzymatic modification involving ubiquitin chains, that can be reversed by deubiquitination (DUB) enzymes. Ubiquitin-specific protease 7 (USP7), which is also known as herpes virus-associated ubiquitin-specific protease (HAUSP), has been shown to play a vital role in cardiovascular diseases. However, the underlying molecular mechanism by which USP7 regulates cardiomyocyte function has not been reported. METHODS: To understand the physiological function of USP7 in the heart, we constructed cardiomyocyte-specific USP7 conditional knockout mice. RESULTS: We found that homozygous knockout mice died approximately three weeks after birth, while heterozygous knockout mice grew normally into adulthood. Severe cardiac dysfunction, hypertrophy, fibrosis, and cell apoptosis were observed in cardiomyocyte-specific USP7 knockout mice, and these effects were accompanied by disordered mitochondrial dynamics and cardiometabolic-related proteins. CONCLUSIONS: In summary, we investigated changes in the growth status and cardiac function of cardiomyocyte-specific USP7 knockout mice, and preliminarily explored the underlying mechanism.
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Animales Recién Nacidos , Ratones Noqueados , Miocitos Cardíacos , Peptidasa Específica de Ubiquitina 7 , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratones , Peptidasa Específica de Ubiquitina 7/metabolismo , Peptidasa Específica de Ubiquitina 7/genética , Biogénesis de Organelos , Dinámicas Mitocondriales/fisiología , Dinámicas Mitocondriales/genéticaRESUMEN
Chronic stress is a common emotional disorder in cancer patients. Chronic stress promotes progression of gastric cancer (GC) and leads to poor outcomes. However, the underlying mechanisms remain not clear. Herein, we explored the possible mechanisms of chronic stress in GC progression. The Cancer Genome Atlas (TCGA) datasets were analyzed for differentially expressed genes. Clinical data of GC were evaluated for their association with PlexinA1 using TCGA and Kaplan-Meier-plotter databases. Chronic stress of GC patients was evaluated using the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Chronic unpredictable mild stress (CUMS) was used to induce chronic stress in mice. Gastric xenograft tumor was constructed using the sewing method. Chronic stress-like behaviors were assessed using light/dark box and tail suspension tests. Protein expression was detected using immunohistochemistry and Western blot analysis. Analyses of TCGA and the Kaplan-Meier-plotter databases showed that patients with high levels of PlexinA1 in GC had worse overall survival than those with low levels of PlexinA1. A total of 36 GC patients were enrolled in the study, and about 33% of the patients had chronic stress. Compared with patients without chronic stress, higher expression levels of adrenoceptor beta 2 and PlexinA1 were observed in patients with chronic stress. The tumor size in mice under CUMS was significantly increased compared with the control mice. Adrenoceptor beta 2, PlexinA1, N-cadherin, and alpha-smooth muscle actin, as well as Ki67 were highly expressed in the tumors of CUMS group. However, E-cadherin was lowly expressed in the tumors of CUMS group. Importantly, chemical sympathectomy with 6-hydroxydopamine or treatment with a selective ß2 adrenergic receptor antagonist (ICI118,551) could reverse these effects. Our findings suggest that chronic stress plays an important role in GC progression and there is a potential for blocking the epinephrine-ß2AR/PlexinA1 pathway in the treatment of GC.
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Neoplasias Gástricas , Humanos , Animales , Ratones , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Receptores AdrenérgicosRESUMEN
Ailanthone (AIL), a monomer derived from ailanthus in Chinese medicine, has been demonstrated to have antitumor effects, albeit the underlying mechanism is unknown. Autophagy and ferroptosis are two modes of cell death that have been championed as potential mechanisms implicated in the antitumor effects of various drugs. The present study demonstrated that AIL effectively suppresses the Lewis cell proliferation in non-small cell lung cancer using MTT and colony formation assays. Autophagy and ferroptosis were verified using western blotting, immunofluorescence and ferroptosis detection. Additionally, the findings revealed that regulating the AMPK/mTOR/p70S6k signaling pathway may be the underlying mechanism for the antitumor effect of AIL. The present study established a theoretical foundation for further research into the utilization of AIL as a novel antitumor approach.
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Cardiomyocyte maturation is the final stage of heart development, and abnormal cardiomyocyte maturation will lead to serious heart diseases. CXXC zinc finger protein 1 (Cfp1), a key epigenetic factor in multi-lineage cell development, remains underexplored in its influence on cardiomyocyte maturation. This study investigates the role and mechanisms of Cfp1 in this context. Cardiomyocyte-specific Cfp1 knockout (Cfp1-cKO) mice died within 4 weeks of birth. Cardiomyocytes derived from Cfp1-cKO mice showed an inhibited maturation phenotype, characterized by structural, metabolic, contractile, and cell cycle abnormalities. In contrast, cardiomyocyte-specific Cfp1 transgenic (Cfp1-TG) mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) overexpressing Cfp1 displayed a more mature phenotype. Mechanistically, deficiency of Cfp1 led to a reduction in trimethylation on lysine 4 of histone H3 (H3K4me3) modification, accompanied by the formation of ectopic H3K4me3. Furthermore, Cfp1 deletion decreased the level of H3K4me3 modification in adult genes and increased the level of H3K4me3 modification in fetal genes. Collectively, Cfp1 modulates the expression of genes crucial to cardiomyocyte maturation by regulating histone H3K4me3 modification, thereby intricately influencing the maturation process. This study implicates Cfp1 as an important molecule regulating cardiomyocyte maturation, with its dysfunction strongly linked to cardiac disease.
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Histonas , Células Madre Pluripotentes Inducidas , Animales , Humanos , Ratones , Histonas/genética , Células Madre Pluripotentes Inducidas/metabolismo , Miocitos Cardíacos/metabolismo , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
Two-dimensional Layered double hydroxides (LDHs) are highly used in the biomedical domain due to their biocompatibility, biodegradability, controlled drug loading and release capabilities, and improved cellular permeability. The interaction of LDHs with biological systems could facilitate targeted drug delivery and make them an attractive option for various biomedical applications. Rheumatoid Arthritis (RA) requires targeted drug delivery for optimum therapeutic outcomes. In this study, stacked double hydroxide nanocomposites with dextran sulphate modification (LDH-DS) were developed while exhibiting both targeting and pH-sensitivity for rheumatological conditions. This research examines the loading, release kinetics, and efficiency of the therapeutics of interest in the LDH-based drug delivery system. The mean size of LDH-DS particles (300.1 ± 8.12 nm) is -12.11 ± 0.4 mV. The encapsulation efficiency was 48.52%, and the loading efficacy was 16.81%. In vitro release tests indicate that the drug's discharge is modified more rapidly in PBS at pH 5.4 compared to pH 5.6, which later reached 7.3, showing the case sensitivity to pH. A generative adversarial network (GAN) is used to analyze the drug delivery system in rheumatology. The GAN model achieved high accuracy and classification rates of 99.3% and 99.0%, respectively, and a validity of 99.5%. The second and third administrations resulted in a significant change with p-values of 0.001 and 0.05, respectively. This investigation unequivocally demonstrated that LDH functions as a biocompatible drug delivery matrix, significantly improving delivery effectiveness.
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Nanocompuestos , Reumatología , Hidróxidos/química , Sistemas de Liberación de Medicamentos/métodos , Nanocompuestos/química , NanotecnologíaRESUMEN
BACKGROUND: The morphology of the adrenal tumor and the clinical statistics of the adrenal tumor area are two crucial diagnostic and differential diagnostic features, indicating precise tumor segmentation is essential. Therefore, we build a CT image segmentation method based on an encoder-decoder structure combined with a Transformer for volumetric segmentation of adrenal tumors. METHODS: This study included a total of 182 patients with adrenal metastases, and an adrenal tumor volumetric segmentation method combining encoder-decoder structure and Transformer was constructed. The Dice Score coefficient (DSC), Hausdorff distance, Intersection over union (IOU), Average surface distance (ASD) and Mean average error (MAE) were calculated to evaluate the performance of the segmentation method. RESULTS: Analyses were made among our proposed method and other CNN-based and transformer-based methods. The results showed excellent segmentation performance, with a mean DSC of 0.858, a mean Hausdorff distance of 10.996, a mean IOU of 0.814, a mean MAE of 0.0005, and a mean ASD of 0.509. The boxplot of all test samples' segmentation performance implies that the proposed method has the lowest skewness and the highest average prediction performance. CONCLUSIONS: Our proposed method can directly generate 3D lesion maps and showed excellent segmentation performance. The comparison of segmentation metrics and visualization results showed that our proposed method performed very well in the segmentation.
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Neoplasias de las Glándulas Suprarrenales , Redes Neurales de la Computación , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagenRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality. The current study aims to explore the role of Cullin-associated and neddylation-dissociated protein 1 (CAND1) in the development of NAFLD and the underlying mechanisms. CAND1 is reduced in the liver of NAFLD male patients and high fat diet (HFD)-fed male mice. CAND1 alleviates palmitate (PA) induced lipid accumulation in vitro. Hepatocyte-specific knockout of CAND1 exacerbates HFD-induced liver injury in HFD-fed male mice, while hepatocyte-specific knockin of CAND1 ameliorates these pathological changes. Mechanistically, deficiency of CAND1 enhances the assembly of Cullin1, F-box only protein 42 (FBXO42) and acetyl-CoA acyltransferase 2 (ACAA2) complexes, and thus promotes the ubiquitinated degradation of ACAA2. ACAA2 overexpression abolishes the exacerbated effects of CAND1 deficiency on NAFLD. Additionally, androgen receptor binds to the -187 to -2000 promoter region of CAND1. Collectively, CAND1 mitigates NAFLD by inhibiting Cullin1/FBXO42 mediated ACAA2 degradation.
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Proteínas Cullin , Enfermedad del Hígado Graso no Alcohólico , Masculino , Animales , Ratones , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Aciltransferasas , Factores de Transcripción/metabolismo , Ubiquitina , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Hígado/metabolismoRESUMEN
In digital subtraction angiography (digital subtraction total cerebral angiography), cardiac and macrovascular cardiography, anorectal radiology, fluoroscopy, and computed tomography (CT), a prior knowledge to X-ray energy spectrum is crucial for assessing the image quality and also calculating patient X-ray dosage. The present investigation's main objective is to propose an intelligent technique for faster calculating X-ray energy spectrum of medical imaging systems with different exposure settings of tube voltage, filter material, and thickness based on limited specific spectra. In this study, Monte Carlo N Particle (MCNP) simulation code was initially used to generate some limited X-ray spectra for tube voltages of 20, 30, 40, 50, 80, 100, 130, and 150 kV for two different filters of beryllium and aluminum with thicknesses of 0. 4, 0.8, 1.2, 1.6 and 2 mm. Tube voltage, type, and thickness of filter were used as the 3 inputs of 150 Radial Basis Function Neural Network (RBFNN) to forecast point by point of the X-ray spectrum. After training, the RBFNNs could forecast most of the X-ray spectra for tube voltages in the range of 20-150 kV and two various filters of aluminum and beryllium with thicknesses in the range of 0-2 mm.
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Aluminio , Berilio , Humanos , Rayos X , Radiografía , Redes Neurales de la Computación , Fantasmas de Imagen , Dosis de Radiación , Método de MontecarloRESUMEN
Speckle-type pox virus and zinc finger (POZ) protein (SPOP), a substrate recognition adaptor of cullin-3 (CUL3)/RING-type E3 ligase complex, is investigated for its role in cardiac fibrosis in our study. Cardiac fibroblasts (CFs) activation was achieved with TGF-ß1 (20 ng/mL) and MI mouse model was established by ligation of the left anterior descending coronary, and lentivirus was employed to mediate interference of SPOP expression. SPOP was increased both in fibrotic post-MI mouse hearts and TGF-ß1-treated CFs. The gain-of-function of SPOP promoted myofibroblast transformation in CFs, and exacerbated cardiac fibrosis and cardiac dysfunction in MI mice, while the loss-of-function of SPOP exhibited the opposite effects. Mechanistically, SPOP bound to the receptor of activated protein C kinase 1 (RACK1) and induced its ubiquitination and degradation by recognizing Ser/Thr-rich motifs on RACK1, leading to Smad3-mediated activation of CFs. Forced RACK1 expression canceled the effects of SPOP on cardiac fibrosis. The study reveals therapeutic targets for fibrosis-related cardiac diseases.
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Infarto del Miocardio , Factor de Crecimiento Transformador beta1 , Animales , Ratones , Fibrosis , Infarto del Miocardio/complicaciones , Infarto del Miocardio/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Receptores de Cinasa C Activada , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
One of the major health issues facing people worldwide is liver fibrosis. Liver fibrosis may be brought on by long-term exposure to harmful substances, medicines, and microorganisms. The development of liver fibrosis in children was particularly worrying due to their longer life-span, which was possibly related to a great risk of developing long-term complications. Marine algae species have provided a biological variety in the research phase of novel approaches to the treatment of numerous ailments. Marine macroalgae have recently been the subject of research due to their rich bioactive chemical composition and potential for the production of various nutraceuticals. Macroalgae are potentially excellent sources of bioactive substances with particular and distinct biological activity when compared to their terrestrial equivalents. Macroalgae in diverse marine cases offer a few biologically active metabolites, comprising sterols, polyunsaturated fatty acids, carotenoids, oligosaccharides, polysaccharides, proteins, polyphenols, vitamins, and minerals. Accordingly, there is great interest in their high potential for supporting immunomodulatory, antimicrobial, antidiabetic, antitumoral, anti-inflammatory, antiangiogenic, and neuroprotective properties. Using an experimental model, the current research intends to collect data on the therapeutic value of macroalgae nanoparticles for fatty liver disease. The researchers' goal of predicting illnesses from the extensive medical datasets is quite difficult. The purpose of this research is to assess the protective effects of a seaweed, Padina pavonia (PP), on liver fibrosis caused by carbon tetrachloride (CCl4). This research presents two models of logistic regression (LR) and support vector machines (SVM) for predicting the likelihood of liver disease incidence. The performance of the model was evaluated using a dataset. PP macro-algae considerably reduce the high blood concentrations of aminotransferases, alkaline phosphatases, and lactate dehydrogenases, as well as causing a considerable (p < 0.05) decrease in serum bilirubin levels. In addition to improving kidney function (urea and creatinine), algal extracts enhance fat metabolism (triglycerides and cholesterol). With an accuracy rate of 70.2%, a sensitivity of 92.3%, a specificity of 74.7%, a type I error of 9.1%, and a type II error of 21.0%, the predictive model has demonstrated excellent performance. The model validated laboratory tests' ability to predict illness (age; direct bilirubin (DB), total proteins (TP), and albumin (ALB). These classifier methods are compared on the basis of their execution time and classification accuracy.
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Algas Marinas , Niño , Humanos , Algas Marinas/química , Algas Marinas/metabolismo , Máquina de Vectores de Soporte , Modelos Logísticos , Cirrosis Hepática , Bilirrubina/metabolismoRESUMEN
Cardiac fibrosis is a common pathological manifestation in multiple cardiovascular diseases and often results in myocardial stiffness and cardiac dysfunctions. LncRNA (long noncoding RNA) participates in a number of pathophysiological processes. However, its role in cardiac fibrosis remains unclear. The purpose of this study was to investigate the role and molecular mechanism of MetBil in regulating cardiac fibrosis. Our data showed that METTL3 binding lncRNA (MetBil) was significantly increased both in fibrotic tissue following myocardial infarction (MI) in mice and in cardiac fibroblasts (CFs) exposed to TGF-ß1 (20 ng/mL) or 20% FBS. Overexpression of MetBil augmented collagen deposition, CF proliferation and activation while silencing MetBil exhibited the opposite effects. Importantly, heterozygous knockout of MetBil alleviated cardiac fibrosis and improved cardiac function after MI. RNA pull-down and RNA-binding protein immunoprecipitation assay showed that METTL3 is a direct downstream target of MetBil; consistently, MetBil and METTL3 were co-localized in both the nucleus and cytoplasm of CFs. Interestingly, MetBil regulated METTL3 expression at protein level, but not mRNA level, in ubiquitin-proteasome pathway. Enforced expression of METTL3 canceled the antifibrotic effects of silencing MetBil reflected by increased collagen production, CF proliferation and activation. Most notably, the m6A-modified fibrosis-regulated genes mediated by METTL3 are profoundly involved in the regulation of MetBil in the cardiac fibrosis following MI. Our study reveals that MetBil as a novel regulator of fibrosis promotes cardiac fibrosis via interacting with METTL3 and regulating the expression of the methylated fibrosis-associated genes, providing a new intervening target for fibrosis-associated cardiac diseases.
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Cardiopatías , Infarto del Miocardio , ARN Largo no Codificante , Ratones , Animales , ARN Largo no Codificante/genética , Infarto del Miocardio/metabolismo , Fibrosis , Metiltransferasas/genética , Metiltransferasas/metabolismo , Colágeno/genética , Colágeno/metabolismoRESUMEN
The air kerma is a key parameter in medical diagnostic radiology. Radiologists use the air kerma parameter to evaluate organ doses and any associated patient hazards. The air kerma can be simply described as the deposited kinetic energy once a photon passes through the air, and it represents the intensity of the radiation beam. Due to the heel effect in the X-ray sources of medical imaging systems, the air kerma is not uniform within the X-ray beam's field of view. Additionally, the X-ray tube voltage can also affect this nonuniformity. In this investigation, an intelligent technique based on the radial basis function neural network (RBFNN) is presented to predict the air kerma at every point within the fields of view of the X-ray beams of medical diagnostic imaging systems based on discrete and limited measured data. First, a diagnostic imaging system was modeled with the help of the Monte Carlo N Particle X version (MCNPX) code. It should be noted that a tungsten target and beryllium window with a thickness of 1 mm (no extra filter was applied) were used for modeling the X-ray tube. Second, the air kerma was calculated at various discrete positions within the conical X-ray beam for tube voltages of 40 kV, 60 kV, 80 kV, 100 kV, 120 kV, and 140 kV (this range covers most medical X-ray imaging applications) to provide the adequate dataset for training the network. The X-ray tube voltage and location of each point at which the air kerma was calculated were used as the RBFNN inputs. The calculated air kerma was also assigned as the output. The trained RBFNN model was capable of estimating the air kerma at any random position within the X-ray beam's field of view for X-ray tube voltages within the range of medical diagnostic radiology (20-140 kV).
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OBJECTIVE: ASPP1 (apoptosis stimulating of p53 protein 1) is critical in regulating cell apoptosis as a cofactor of p53 to promote its transcriptional activity in the nucleus. However, whether cytoplasmic ASPP1 affects p53 nuclear trafficking and its role in cardiac diseases remains unknown. This study aims to explore the mechanism by which ASPP1 modulates p53 nuclear trafficking and the subsequent contribution to cardiac ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: The immunofluorescent staining showed that under normal condition ASPP1 and p53 colocalized in the cytoplasm of neonatal mouse ventricular cardiomyocytes, while they were both upregulated and translocated to the nuclei upon hypoxia/reoxygenation treatment. The nuclear translocation of ASPP1 and p53 was interdependent, as knockdown of either ASPP1 or p53 attenuated nuclear translocation of the other one. Inhibition of importin-ß1 resulted in the cytoplasmic sequestration of both p53 and ASPP1 in neonatal mouse ventricular cardiomyocytes with hypoxia/reoxygenation stimulation. Overexpression of ASPP1 potentiated, whereas knockdown of ASPP1 inhibited the expression of Bax (Bcl2-associated X), PUMA (p53 upregulated modulator of apoptosis), and Noxa, direct apoptosis-associated targets of p53. ASPP1 was also increased in the I/R myocardium. Cardiomyocyte-specific transgenic overexpression of ASPP1 aggravated I/R injury as indicated by increased infarct size and impaired cardiac function. Conversely, knockout of ASPP1 mitigated cardiac I/R injury. The same qualitative data were observed in neonatal mouse ventricular cardiomyocytes exposed to hypoxia/reoxygenation injury. Furthermore, inhibition of p53 significantly blunted the proapoptotic activity and detrimental effects of ASPP1 both in vitro and in vivo. CONCLUSIONS: Binding of ASPP1 to p53 triggers their nuclear cotranslocation via importin-ß1 that eventually exacerbates cardiac I/R injury. The findings imply that interfering the expression of ASPP1 or the interaction between ASPP1 and p53 to block their nuclear trafficking represents an important therapeutic strategy for cardiac I/R injury.
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Proteínas Adaptadoras Transductoras de Señales , Daño por Reperfusión , Proteína p53 Supresora de Tumor , Animales , Ratones , Apoptosis/fisiología , Hipoxia/metabolismo , Isquemia/metabolismo , Carioferinas , Miocitos Cardíacos/metabolismo , Daño por Reperfusión/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
A significant portion of the solid waste filling landfills worldwide is debris from construction and demolition projects. Across the world, a significant portion of the solid waste filling landfills is made up of construction and demolition waste. Recycling construction waste may help cut down on the quantity of waste sent to landfills and the requirement for energy and other natural resources. To help with construction waste reduction, a management hierarchy that begins with rethink, reduce, redesign, refurbish, reuse, incineration, composting, recycle, and eventually disposal is likely to be effective. The objective of this research is to investigate the viability of the Analytic Hierarchy Process (AHP) as a data gathering instrument for the development of a solid waste management assessment tool, followed by an examination of an artificial neural network (ANN). Using a standardized questionnaire, all data was gathered from waste management practitioners in three industry sectors. The survey data was subsequently analyzed using ANN and later AHP. The suggested framework consisted of four components: (1) the development of different level structures for fluffy AHP, (2) the calculation of weights, (3) the collection of data, and (4) the making of decisions. An ANN feedforward with error back propagation (EBP) learning computation is coupled to identify the association between the items and the store execution. It was found that the combination of AHP and ANN has emerged as a key decision support tool for landfilling, incineration, and composting waste management strategies, taking into account the environmental profile and economic and social characteristics of each choice. Composting has the highest sustainable performance when a balanced weight distribution of criteria is assumed, especially if the environmental component is considered in comparison to the other criteria. However, if social and economic features are addressed, incineration or landfilling have more favorable characteristics, respectively.
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Eliminación de Residuos , Administración de Residuos , Residuos Sólidos/análisis , Proceso de Jerarquía Analítica , Incineración , Instalaciones de Eliminación de ResiduosRESUMEN
BACKGROUND: Cationic lipids can be used as nonviral vectors in gene delivery therapy. Most cationic lipids contain quaternary ammonium that can bind to negative phosphates of the plasmid. In this study, sulfonium-a trialkylated sulfur cation was adopted in the synthesis of a series of cationic lipids which were evaluated for their ability to function as gene delivery vectors. METHODS: The sulfonium lipids were synthesized by condensing cyclic thioether and aliphatic carbon chains with ethoxy linkage and the structure was characterized by NMR and mass. The DNA condensing abilities of sulfonium lipids were evaluated using a gel retardation experiment. Sulfonium lipids/ DNA condensates were measured for particle size and Zeta potential. The cytotoxicity of sulfoniums was evaluated with the MTT assay. The intracellular uptake of sulfonium lipid/DNA complexes was observed with a fluorescence microscope. RESULTS: The results showed that the sulfonium head can effectively bind to the phosphate of DNA. When the S/P ratio is larger than 10/1, sulfonium lipids with longer carbon chains can completely condense DNA to form a nanoparticle with particle size ranging from 135 nm to 155 nm and zeta potential ranging from 28 mV to 42 mV. The IC50 of sulfonium lipids on HepG2 cells ranged from 2.37 µg/mL to 3.67 µg/mL. Cellular uptake experiments showed that sulfonium lipids/DNA condensate can be taken into cells. CONCLUSION: Sulfonium lipids can effectively condense DNA and transfer DNA into cells. The sulfonium compound is worth further development to reduce the cytotoxicity and increase the transfection rate as gene vectors.
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Vectores Genéticos , Lípidos , Lípidos/química , Transfección , Técnicas de Transferencia de Gen , Plásmidos , ADN , Cationes/química , Tamaño de la PartículaRESUMEN
Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease that occurs in the intestinal tract. It is mainly divided into two subtypes, i.e., the Crohn's disease (CD) and ulcerative colitis (UC). At present, its pathogenesis has not been fully elucidated, but it has been generally believed that the environment, immune disorders, genetic susceptibility, and intestinal microbes are the main factors for the disease pathogenesis. With the development of the sequencing technology, microbial factors have received more and more attention. The gut microbiota is in a state of precise balance with the host, in which the host immune system is tolerant to immunogenic antigens produced by gut commensal microbes. In IBD patients, changes in the balance between pathogenic microorganisms and commensal microbes lead to changes in the composition and diversity of gut microbes, and the balance between microorganisms and the host would be disrupted. This new state is defined as dysbiosis. It has been confirmed, in both clinical and experimental settings, that dysbiosis plays an important role in the occurrence and development of IBD, but the causal relationship between dysbiosis and inflammation has not been elucidated. On the other hand, as a classic research method for pathogen identification, the Koch's postulates sets the standard for verifying the role of pathogens in disease. With the further acknowledgment of the disease pathogenesis, it is realized that the traditional Koch's postulates is not applicable to the etiology research (determination) of infectious diseases. Thus, many researchers have carried out more comprehensive and complex elaboration of Koch's postulates to help people better understand and explain disease pathogenesis through the improved Koch's postulates. Therefore, focusing on the new perspective of the improved Koch's postulates is of great significance for deeply understanding the relationship between dysbiosis and IBD. This article has reviewed the studies on dysbiosis in IBD, the use of microbial agents in the treatment of IBD, and their relationship to the modified Koch's postulates.
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Around the world, the COVID-19 pandemic has created significant obstacles for education, driving people to discover workarounds to maintain education. Because of the excellent benefit of cheap-cost information distribution brought about by the advent of the Internet, some offline instructional activity started to go online in an effort to stop the spread of the disease. How to guarantee the quality of teaching and promote the steady progress of education has become more and more important. Currently, one of the ways to guarantee the quality of online learning is to use independent online learning behavior data to build learning performance predictors, which can provide real-time monitoring and feedback during the learning process. This method, however, ignores the internal correlation between e-learning behaviors. In contrast, the e-learning behavior classification model (EBC model) can reflect the internal correlation between learning behaviors. Therefore, this study proposes an online learning performance prediction model, SA-FEM, based on adaptive feature fusion and feature selection. The proposed method utilizes the relationship among features and fuses features according to the category that achieved better performance. Through the analysis of experimental results, the feature space mined by the fine-grained differential evolution algorithm and the adaptive fusion of features combined with the differential evolution algorithm can better support online learning performance prediction, and it is also verified that the adaptive feature fusion strategy based on the EBC model proposed in this paper outperforms the benchmark method.