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Biomanufacturing, driven by technologies such as synthetic biology, offers significant potential to advance the bioeconomy and promote sustainable development. It is anticipated to transform traditional manufacturing and become a key industry in future strategies. Cell factories are the core of biomanufacturing. The advancement of synthetic biology and growing market demand have led to the production of a greater variety of natural products and increasingly complex metabolic pathways. However, this progress also presents challenges, notably the conflict between natural product production and chassis cell growth. This conflict results in low productivity and yield, adverse side effects, metabolic imbalances, and growth retardation. Enzyme co-localization strategies have emerged as a promising solution. This article reviews recent progress and applications of these strategies in constructing cell factories for efficient natural product production. It comprehensively describes the applications of enzyme-based compartmentalization, metabolic pathway-based compartmentalization, and synthetic organelle-based compartmentalization in improving product titers. The article also explores future research directions and the prospects of combining multiple strategies with advanced technologies.

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The global rate of Amphotericin B (AmB) resistance in Candida auris has surpassed 12%. However, there is limited data on available clinical treatments and microevolutionary analyses concerning reduced AmB sensitivity. In this study, we collected 18 C. auris isolates from five patients between 2019 and 2022. We employed clinical data mining, genomic, and transcriptomic analyses to identify genetic evolutionary features linked to reduced AmB sensitivity in these isolates during clinical treatment. We identified six isolates with a minimum inhibitory concentration (MIC) of AmB below 0.5 µg/mL (AmB0.5) and 12 isolates with an AmB-MIC of 1 µg/mL (AmB1) or ≥ 2 µg/mL (AmB2). All five patients received 24-hour AmB (5 mg/L) bladder irrigation treatment. Evolutionary analyses revealed an ERG3 (c923t) mutation in AmB1 C. auris. Additionally, AmB2 C. auris was found to contain a t2831c mutation in the RAD2 gene. In the AmB1 group, membrane lipid-related gene expression (ERG1, ERG2, ERG13, and ERG24) was upregulated, while in the AmB2 group, expression of DNA-related genes (e.g. DNA2 and PRI1) was up-regulated. In a series of C.auris strains with reduced susceptibility to AmB, five key genes were identified: two upregulated (IFF9 and PGA6) and three downregulated (HGT7, HGT13,and PRI32). In this study, we demonstrate the microevolution of reduced AmB sensitivity in vivo and further elucidate the relationship between reduced AmB sensitivity and low-concentration AmB bladder irrigation. These findings offer new insights into potential antifungal drug targets and clinical markers for the "super fungus", C. auris.

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Anfotericina B , Antifúngicos , Candida auris , Candidiasis , Farmacorresistencia Fúngica , Pruebas de Sensibilidad Microbiana , Humanos , Anfotericina B/farmacología , Antifúngicos/farmacología , China/epidemiología , Farmacorresistencia Fúngica/genética , Candidiasis/microbiología , Candidiasis/tratamiento farmacológico , Candida auris/genética , Candida auris/efectos de los fármacos , Evolución Molecular , Masculino , Mutación , Femenino , Persona de Mediana Edad , Proteínas Fúngicas/genética

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BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes mellitus, and Prolyl 4-Hydroxylase Subunit Beta (P4HB) expression is increased in high glucose (HG)-induced renal tubular epithelial cells (TECs). But it's role in HG-induced TECs remains to be elucidated. METHODS: The HK-2 cells were induced using HG and transfected with SiRNA-P4HB. DCFH-DA staining was utilized for the detection of cellular levels of ROS. WB and immunofluorescence were utilized to detect the expression of P4HB, epithelial-mesenchymal transition (EMT), fibrosis, and TGFß/SMAD3-related proteins in HK-2 cells. Online databases were utilized for predicting the interaction target of P4HB, and immunoprecipitation (IP) experiments were employed to validate the binding of P4HB with the target. SiRNA and overexpression vectors of target gene were used to verify the mechanism of action of P4HB. RESULTS: HG induced an increase in the expression of P4HB and TGFß, p-SMAD3, and ROS in HK-2 cells. Furthermore, HG downregulated the expression of E-cadherin and upregulated the expression of N-cadherin, Vimentin, α-SMA, Fibronectin, Collagen IV, SNAIL, and SLUG in HK-2 cells. Interfering with P4HB significantly reversed the expression of these proteins. Database predictions and IP experiments showed that P4HB interacts with PRMT1, and the expression of PRMT1 was increased in HG-induced HK-2 cells. Interfering with PRMT1 inhibited the changes in expression of EMT and fibrosis related proteins induced by HG. However, overexpression of PRMT1 weakened the regulatory effect of P4HB interference on the EMT, fibrosis, and TGFß/SMAD3-related proteins in HK-2 cells. CONCLUSION: P4HB regulated the TGFß/SMAD3 signaling pathway through PRMT1 and thus participates in HG-induced EMT and fibrosis in HK-2 cells.

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Células Epiteliales , Transición Epitelial-Mesenquimal , Fibrosis , Glucosa , Túbulos Renales , Proteína-Arginina N-Metiltransferasas , Proteínas Represoras , Transducción de Señal , Proteína smad3 , Factor de Crecimiento Transformador beta , Humanos , Proteína smad3/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Glucosa/farmacología , Glucosa/toxicidad , Glucosa/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Factor de Crecimiento Transformador beta/metabolismo , Túbulos Renales/patología , Túbulos Renales/metabolismo , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Línea Celular , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Especies Reactivas de Oxígeno/metabolismo

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Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A>G and ND6 14484T>C mutations in three Chinese families affected by LHON is investigated. The m.14693A>G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T>C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual-mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.

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BACKGROUND: Inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) are autoimmune diseases that often coexist clinically. This phenomenon might be due to shared genetic components. METHODS: Genome-wide association study (GWAS) data for IBD and SLE were analyzed to determine both global and local genetic correlations using three methodologies: linkage disequilibrium score regression (LDSC), genetic covariance analyzer (GNOVA), and SUPERGNOVA. The genetic overlap and risk loci were subsequently examined using the conditional/conjunctional false discovery rate (cond/conjFDR) statistical framework. Furthermore, a multi-trait analysis of MTAG was employed to validate the loci, followed by an LDSC analysis focusing on tissue-specific gene expression. RESULTS: GWAS findings demonstrated a marked global genetic correlation between IBD (including Crohn's disease and ulcerative colitis) and SLE. Locally, SLE showed a strong association with IBD and Crohn's disease on chromosomes 10, 19, and 22. ConjFDR analysis confirmed the genetic overlap and identified relevant genetic risk loci. MTAG further validated several shared susceptibility genes. Additionally, the LDSC-SEG analysis results indicate that IBD (including CD and UC) and SLE are jointly enriched in the tissues of Spleen and Whole Blood. CONCLUSION: This study confirms a genetic overlap between IBD and SLE, identifying marked comorbid genes and offering new insights for treating these diseases.

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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades Inflamatorias del Intestino , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico , Lupus Eritematoso Sistémico/genética , Humanos , Enfermedades Inflamatorias del Intestino/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo

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Introduction: Gan-jiang-ling-zhu (GJLZ) decoction is a classical traditional Chinese medicine prescription. Through invigorating yang, activating qi and dissipating dampness, GJLZ decoction is widely applied for the treatment of chronic digestive disease, including nonalcoholic fatty liver disease. However, efficacy and mechanism of GJLZ decoction behind nonalcoholic steatohepatitis (NASH) treatment remains unelucidated. Methods: NASH was induced in mice, followed by treatment with GJLZ decoction. Various methods including hematoxylin-eosin, oil red O staining, and triglyceride analysis were employed to evaluate the treatment effects of GJLZ decoction on NASH. Gut microbiota, metabolomics, cell viability assays, immunofluorescence and Western blotting were performed to unveil the mechanism behind GJLZ decoction. Results: GJLZ decoction treatment significantly improved hepatic steatosis in mice with NASH. It led to remodeling of gut flora and metabolite structures, including the 12-tridecenoic acid level. 12-Tridecenoic acid aggravated hepatic steatosis by promoting acetyl-coenzyme A carboxylase alpha (ACC) expression and inhibiting carnitine palmitoyltransferase 1A (CPT1A) expression. GJLZ decoction treatment reduced the 12-tridecenoic acid level, inhibited ACC activity and promoted CPT1A expression. Conclusion: Our results demonstrated that 12-tridecenoic acid aggravated hepatic steatosis by affecting the ACC-CPT1A axis and GJLZ decoction treatment effectively reduced the 12-tridecenoic acid level and improved steatosis.

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Background: Glycosylated hemoglobin (HbA1c) variability is a risk factor for cardiovascular complications in patients with Type 2 diabetes mellitus (T2DM), but its relationship with the severity of coronary artery disease (CAD) is unclear. Methods: Patients with T2DM who underwent coronary angiography due to angina were enrolled. HbA1c variability was expressed as coefficient of variation (CV), standard deviation (SD), variability independent of mean (VIM), and time in range (TIR). The severity of CAD was expressed by the number of involved vessels and Gensini score. Multivariate regression models were constructed to test the relationship between HbA1c variability, number of involved vessels, and the Gensini score, followed by linear regression analysis. Results: A total of 147 patients were included. In multivariate analysis, VIM-HbA1c (OR = 2.604; IQR: 1.15, 5.90; r = 0.026) and HbA1cTIR (OR = 0.13; IQR: 0.04, 0.41; r < 0.001) were independent risk factors for the number of involved vessels. After adjustment, HbA1cTIR (OR = 0.01; IQR: 0.002, 0.04; r < 0.001), SD-HbA1c (OR = 4.12, IQR: 1.64, 10.35; r = 0.001), CV-HbA1c (OR = 1.41, IQR: 1.04, 1.92; r = 0.007), and VIM-HbA1c (OR = 3.26; IQR: 1.43, 7.47; r = 0.003) were independent risk factors for the Gensini score. In the linear analysis, the Gensini score was negatively correlated with HbA1cTIR (ß = -0.629; r < 0.001) and positively correlated with SD-HbA1c (ß = 0.271; r = 0.001) and CV-HbA1c (ß = 0.176; r = 0.033). After subgroup analysis, HbA1cTIR was a risk factor for the number of involved vessels. The Gensini score was negatively correlated with HbA1cTIR and positively correlated with SD-HbA1c at subgroups of subjects with a mean HbA1c ≤ 7%. Conclusions: Our analysis indicates that HbA1c variability, especially HbA1cTIR, plays a role for the severity of CAD in patients with T2DM. HbA1c variability may provide additional information and require management even at the glycemic target. Translational Aspects: Studies have shown that HbA1c variability is related to cardiovascular complications. Further, we explore the correlation between HbA1c variability and the severity of CAD. HbA1c variability is a risk factor for coronary stenosis in T2DM. It may be a potential indicator reflecting glycemic control for the prevention and treatment of cardiovascular complications.

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Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Hemoglobina Glucada , Índice de Severidad de la Enfermedad , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/sangre , Hemoglobina Glucada/metabolismo , Hemoglobina Glucada/análisis , Masculino , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Persona de Mediana Edad , Anciano , Factores de Riesgo , Análisis Multivariante

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Endocrine tumors like thyroid carcinoma are becoming more frequent. No clinically informative predictors were found. Thus, effective gene networks and representative biomarkers can illuminate thyroid cancer prevention molecular mechanisms. TBC1D4 is an activating protein molecule that plays an important role in regulating cell metabolism and signal transduction. The aim of this study was to investigate the expression characteristics of TBC1D4 activating protein molecules and identify key module genes that prevent thyroid cancer progression. GSE65144 data were downloaded from GEO. "limma" in R found DEGs with a false discovery rate < 0.05 and a log2 fold change <1. WGCNA builds gene co-expression networks, screens key modules, and filters hub genes. Overlapping genes become hub genes. Hub genes underwent GO and KEGG pathway enrichment analysis. We used Lasso to extract hub gene expression results' distinctive genes. Key genes. GEPIA database determined expression and survival impact. A total of 3220 DEGs. Thyroid cancer was mostly associated with darkred, darkturquoise, and green modules. Venn screened 639 hub genes. Cytokine-cytokine receptor interaction was the primary KEGG enrichment. Hub genes were 14. Finally, ARHGAP6, TBC1D4, and TC2N were important genes. Through gene screening and functional enrichment analysis, we identified a group of genes related to TBC1D4 activating protein and constructed the corresponding protein interaction network.

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Proteínas Activadoras de GTPasa , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Biología Computacional/métodos , Mapas de Interacción de Proteínas/genética

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Background: Gestational diabetes mellitus (GDM) is a pregnancy-related diabetic condition that may cause serious complications. However, its pathogenesis remains unclear. Placental damage due to GDM may lead to several health issues that cannot be ignored. Thus, we aimed to identify the mechanisms underlying GDM by screening differentially expressed genes (DEGs) related to vascular endothelial cells in the GDM databases and verify the expression of these DEGs in the placentas of women afflicted by GDM. Methods: We used GDM microarray datasets integrated from the Gene Expression Omnibus (GEO) database. Functional annotation and protein-protein interaction (PPI) analyses were used to screen DEGs. Placental tissues from 20 pregnant women with GDM and 20 healthy pregnant women were collected, and differential gene expression in the placental tissues was verified via qRT-PCR, western blotting, and immunofluorescence. Results: Bioinformatics analysis revealed three significant DEGs: SNAIL2, PAPP-A, and TGFß1. These genes were all predicted to be underexpressed in patients with GDM. The results of qRT-PCR, western blot, and immunofluorescence analyses indicated that SNAIL2 and PAPP-A in the placenta tissue of patients with GDM were significantly underexpressed. However, TGFß1 in the placenta tissues of GDM was significantly overexpressed. Conclusion: SNAIL2, TGFß1, and PAPP-A may affect the placentas of pregnant women with GDM, warranting further investigation.

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Diabetes Gestacional , Placenta , Proteína Plasmática A Asociada al Embarazo , Factores de Transcripción de la Familia Snail , Factor de Crecimiento Transformador beta1 , Humanos , Diabetes Gestacional/metabolismo , Diabetes Gestacional/genética , Embarazo , Femenino , Placenta/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , Adulto , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Proteína Plasmática A Asociada al Embarazo/genética , Proteína Plasmática A Asociada al Embarazo/metabolismo , Perfilación de la Expresión Génica , Biología Computacional , Estudios de Casos y Controles , Mapas de Interacción de Proteínas

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Background: Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in coronary artery disease (CAD) and diabetes. This study aimed to determine the prognostic value of ET-1 in the patients with stable CAD under different glucose metabolism states. Methods: In this prospective, large-cohort study, we consecutively enrolled 7,947 participants with angiography-diagnosed stable CAD from April 2011 to April 2017. Patients were categorized by baseline glycemic status into three groups (normoglycemia, prediabetes, and diabetes) and further divided into nine groups by circulating ET-1 levels. Patients were followed for the occurrence of cardiovascular events (CVEs), including nonfatal myocardial infarction, stroke, and cardiovascular mortality. Results: Of the 7,947 subjects, 3,352, 1,653, and 2,942 had normoglycemia, prediabetes, and diabetes, respectively. Over a median follow-up of 37.5 months, 381 (5.1%) CVEs occurred. The risk for CVEs was significantly higher in patients with elevated ET-1 levels after adjustment for potential confounders. When patients were categorized by both status of glucose metabolism and plasma ET-1 levels, the high ET-1 levels were associated with higher risk of CVEs in prediabetes (adjusted hazard ratio [HR], 2.089; 95% confidence interval [CI], 1.151 to 3.793) and diabetes (adjusted HR, 2.729; 95% CI, 1.623 to 4.588; both P<0.05). Conclusion: The present study indicated that baseline plasma ET-1 levels were associated with the prognosis in prediabetic and diabetic patients with stable CAD, suggesting that ET-1 may be a valuable predictor in CAD patients with impaired glucose metabolism.

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[This corrects the article DOI: 10.3389/fpubh.2024.1351972.].

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Macroautophagy/autophagy is primarily accountable for the degradation of damaged organelles and toxic macromolecules in the cells. Regarding the essential function of autophagy for preserving cellular homeostasis, changes in, or dysfunction of, autophagy flux can lead to disease development. In the current paper, the complicated function of autophagy in aging-associated pathologies and cancer is evaluated, highlighting the underlying molecular mechanisms that can affect longevity and disease pathogenesis. As a natural biological process, a reduction in autophagy is observed with aging, resulting in an accumulation of cell damage and the development of different diseases, including neurological disorders, cardiovascular diseases, and cancer. The MTOR, AMPK, and ATG proteins demonstrate changes during aging, and they are promising therapeutic targets. Insulin/IGF1, TOR, PKA, AKT/PKB, caloric restriction and mitochondrial respiration are vital for lifespan regulation and can modulate or have an interaction with autophagy. The specific types of autophagy, such as mitophagy that degrades mitochondria, can regulate aging by affecting these organelles and eliminating those mitochondria with genomic mutations. Autophagy and its specific types contribute to the regulation of carcinogenesis and they are able to dually enhance or decrease cancer progression. Cancer hallmarks, including proliferation, metastasis, therapy resistance and immune reactions, are tightly regulated by autophagy, supporting the conclusion that autophagy is a promising target in cancer therapy.

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Envejecimiento , Autofagia , Neoplasias , Humanos , Autofagia/fisiología , Neoplasias/terapia , Neoplasias/patología , Neoplasias/metabolismo , Envejecimiento/fisiología , Envejecimiento/patología , Envejecimiento/metabolismo , Animales

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BACKGROUND AND AIM: The incidence of rectal neuroendocrine tumors (R-NETs) has increased in recent years. However, the predictors of lymph node (LN) metastasis and clinical outcomes, particularly following endoscopic treatment, remain unclear. Our study aims to elucidate the potential risk factors for LN metastasis and the clinical outcomes of patients undergoing endoscopic resection in R-NETs. METHODS: A total of 128 patients with R-NETs were retrospectively identified from a single center between June 2012 and December 2021. Risk factors for LN metastasis in R-NETs were analyzed using multivariate analysis. Additionally, the clinical outcomes of endoscopic resections in patients with R-NETs were assessed. RESULTS: In our study, 128 patients with R-NETs were retrospectively analyzed. The risk factors for LN metastasis determined by multivariate analysis were tumor size and patient age at diagnosis. Among the 111 patients treated with endoscopic resection and with tumor margin records available, 92 underwent endoscopic submucosal dissection (ESD) and 19 underwent conventional endoscopic mucosal resection (EMR). There was no significant difference between the two groups regarding the positive rates of basal tumor margin and lateral tumor margin. Furthermore, 64 patients who underwent endoscopic resection for R-NETs were successfully followed up (range, 1.64-76.71 months), during which only one patient developed local recurrence. CONCLUSION: Tumor size and age at diagnosis were predictors for LN metastasis of R-NETs. Both ESD and EMR are alternative techniques with a favorable prognosis for R-NETs, even in cases with positive resection margins. However, due to the relatively small number of patients undergoing EMR and missing data in follow-up protocols, definitive conclusions require further large-scale studies.

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Resección Endoscópica de la Mucosa , Metástasis Linfática , Tumores Neuroendocrinos , Neoplasias del Recto , Humanos , Masculino , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Estudios Retrospectivos , Femenino , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/secundario , Persona de Mediana Edad , Resección Endoscópica de la Mucosa/métodos , Anciano , Adulto , Factores de Riesgo , Resultado del Tratamiento , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Márgenes de Escisión

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Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a leading cause of several chronic diseases, imposing a significant global economic burden. The Mediterranean diet (MD) and low-fat diet (LFD) are the two primary recommended dietary patterns that exhibit distinct positive effects on treating NAFLD. Objective: To investigate which of the two diets, MD and LFD, is more effective in the treatment of NAFLD. Methods: Randomized controlled trials (RCTs) up to April 2024 were searched for in PubMed, Web of Science, Medline, Scopus and Embase. Interventions included MD or LFD, with primary outcome measures being intrahepatic lipid, liver stiffness, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, gamma-glutamyl transferase, and homeostasis model assessment of insulin resistance. Secondary outcomes included weight, waist circumference, and body mass index. Use of random effects meta-analysis to assess outcomes of interest. Results: meta-analysis revealed no significant differences between MD and LFD in improving liver enzymes, liver fat, and related indices in NAFLD patients. Our findings provide compelling evidence for patients and healthcare professionals, allowing patients to choose a dietary pattern that aligns with their preferences and disease conditions. In summary, both MD and LFD can equivalently ameliorate NAFLD in the short term. Conclusions: Our results show that MD and LFD have similar therapeutic effects on liver enzymes and liver fat content in patients with NAFLD in the short term. Furthermore, our meta-analysis results have also opened up a new avenue of thought as to whether similar effects are achieved by alternating MD and LFD on alternate days.

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Dieta con Restricción de Grasas , Dieta Mediterránea , Hígado , Enfermedad del Hígado Graso no Alcohólico , Ensayos Clínicos Controlados Aleatorios como Asunto , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Humanos , Hígado/metabolismo , Masculino , Alanina Transaminasa/metabolismo , Femenino , Triglicéridos/metabolismo , Adulto

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Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/diagnóstico por imagen , Fluoroscopía , Constricción Patológica , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/diagnóstico por imagen , Masculino , Radiografía Intervencional , Persona de Mediana Edad , Carcinoma/radioterapia , Carcinoma/terapia , Dilatación/métodos , Traumatismos por Radiación/terapia , Traumatismos por Radiación/etiología , Traumatismos por Radiación/diagnóstico por imagen

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The pharmacological mechanism of Phellodendri Chinensis cortex (PCC) against diseases, especially bladder cancer (BC), has never been reported systematically. This study was designed to explore potential mechanism of PCC in treatment of BC. First, we used network pharmacology to discover the potential mechanism of Phellodendri Chinensis cortex and phellodendrine against bladder cancer. Then, we used bioinformatics analysis to verify the correlation between gene expression analysis, survival analysis and common targets. Finally, molecular docking was used to calculate the binding energies of phellodendrine and common targets.A total of 264 targets for PCC were predicted, and 391 BC-related targets were obtained from 4 databases. There were 54 potential targets, 315 biological processes, and 120 signaling pathways involved for PCC against BC. The CDKN2A expression increased and the ESR1, JUN, IL6, AR, and PTGS2 levels decreased in BC according to Gene Expression Profiling Interactive Analysis version 2. The high expression of JUN, MYC, EGFR, and EGF and low expression of VEGFA and PPARG were associated with short overall survival (OS). The high expression of AKT1, EGFR, and EGF and low expression of IL1ß were associated with poor disease-free survival (DFS). The search of the intersection of phellodendrine and BC targets yielded 11 common targets, 50 biological processes, and 13 signaling pathways involved. High AURKA and FASN and low ESR1, JUN, ABCB1, and PTGS1 were expressed in BC. The high expression of FASN, ABCC1, PTGS1, JUN, and PIK3CA was associated with short OS, the high expression of PIK3CA and ABCC1 was associated with poor DFS prognosis. Phellodendrine showed a better binding affinity for PTGS2 protein with a docking score of -7.183 and a MM-GBSA result of -46.47 kcal/mol. This study revealed potential mechanism of PCC and phellodendrine against BC through network pharmacology and bioinformatics.

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Establishing an accurate and robust feature fusion mechanism is key to enhancing the tracking performance of single-object trackers based on a Siamese network. However, the output features of the depth-wise cross-correlation feature fusion module in fully convolutional trackers based on Siamese networks cannot establish global dependencies on the feature maps of a search area. This paper proposes a dynamic cascade feature fusion (DCFF) module by introducing a local feature guidance (LFG) module and dynamic attention modules (DAMs) after the depth-wise cross-correlation module to enhance the global dependency modeling capability during the feature fusion process. In this paper, a set of verification experiments is designed to investigate whether establishing global dependencies for the features output by the depth-wise cross-correlation operation can significantly improve the performance of fully convolutional trackers based on a Siamese network, providing experimental support for rational design of the structure of a dynamic cascade feature fusion module. Secondly, we integrate the dynamic cascade feature fusion module into the tracking framework based on a Siamese network, propose SiamDCFF, and evaluate it using public datasets. Compared with the baseline model, SiamDCFF demonstrated significant improvements.

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The development of high-throughput technologies has enhanced our understanding of small non-coding RNAs (sncRNAs) and their crucial roles in various diseases, including atrial fibrillation (AF). This study aimed to systematically delineate sncRNA profiles in AF patients. PANDORA-sequencing was used to examine the sncRNA profiles of atrial appendage tissues from AF and non-AF patients. Differentially expressed sncRNAs were identified using the R package DEGseq 2 with a fold change >2 and p < 0.05. The target genes of the differentially expressed sncRNAs were predicted using MiRanda and RNAhybrid. Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. In AF patients, the most abundant sncRNAs were ribosomal RNA-derived small RNAs (rsRNAs), followed by transfer RNA-derived small RNAs (tsRNAs), and microRNAs (miRNAs). Compared with non-AF patients, 656 rsRNAs, 45 miRNAs, 191 tsRNAs and 51 small nucleolar RNAs (snoRNAs) were differentially expressed in AF patients, whereas no significantly differentially expressed piwi-interacting RNAs were identified. Two out of three tsRNAs were confirmed to be upregulated in AF patients by quantitative reverse transcriptase polymerase chain reaction, and higher plasma levels of tsRNA 5006c-LysCTT were associated with a 2.55-fold increased risk of all-cause death in AF patients (hazard ratio: 2.55; 95% confidence interval, 1.56-4.17; p < 0.001). Combined with our previous transcriptome sequencing results, 32 miRNA, 31 snoRNA, 110 nucleus-encoded tsRNA, and 33 mitochondria-encoded tsRNA target genes were dysregulated in AF patients. GO and KEGG analyses revealed enrichment of differentially expressed sncRNA target genes in AF-related pathways, including the 'calcium signaling pathway' and 'adrenergic signaling in cardiomyocytes.' The dysregulated sncRNA profiles in AF patients suggest their potential regulatory roles in AF pathogenesis. Further research is needed to investigate the specific mechanisms of sncRNAs in the development of AF and to explore potential biomarkers for AF treatment and prognosis.

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Apéndice Atrial , Fibrilación Atrial , Perfilación de la Expresión Génica , ARN Pequeño no Traducido , Humanos , Fibrilación Atrial/genética , ARN Pequeño no Traducido/genética , Apéndice Atrial/metabolismo , Masculino , Femenino , MicroARNs/genética , Ontología de Genes , Anciano , Persona de Mediana Edad , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Regulación de la Expresión Génica , Transcriptoma/genética , Biología Computacional/métodos , Pronóstico

RESUMEN

BACKGROUND: Patients with Parkinson's disease (PD) undergoing long-term levodopa therapy are prone to develop levodopa-induced dyskinesia (LID). Amantadine is the main drug recommended for the treatment of LID by current guidelines, but it is far from meeting clinical needs. Tianqi Pingchan Granule (TPG), a compound Chinese herbal medicine, has been developed to relieve symptom of LID. OBJECTIVE: This randomized controlled trial evaluated the efficacy and safety of the combination of TPG and amantadine for LID. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This is a randomized double-blind placebo-controlled trial, conducted from January 2020 to August 2021 at 6 sites in Jiangsu, Zhejiang and Shanghai, China. One hundred PD patients with ≥ 0.5 h of LID were randomly assigned to either the TPG plus amantadine group (TPG group) or the placebo plus amantadine group (placebo group), and treated for a period of 12 weeks. To ensure unbiased results, all study participants, investigators and sponsors were unaware of group allocations. Additionally, the data analysts remained blinded until the analysis was finalized. MAIN OUTCOME MEASURES: The primary outcome was assessed using the Unified Dyskinesia Rating Scale (UDysRS) (Range 0-104). The key secondary end point was improvement of motor and non-motor symptoms. Safety analyses included all enrolled patients. RESULTS: One hundred patients were enrolled and randomized into the two treatment groups. The changes in UDysRS at week 12 were -11.02 for the TPG group and -4.19 for the placebo group (treatment difference -6.83 [-10.53 to -3.12]; P = 0.0004). Adverse events were reported for 2 of 50 patients (4.0%) in each of the groups. CONCLUSION: This study indicated that a 12-week treatment of amantadine plus TPG effectively reduced UDysRS scores and was well tolerated, demonstrating the efficacy and safety of TPG for the treatment of LID in PD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04173832. PLEASE CITE THIS ARTICLE AS: Zhang Y, Zhu XB, Zhao Y, Cui GY, Li WT, Yuan CX, Huang JP, Wan Y, Wu N, Song L, Zhao JH, Liang Y, Xu CY, Liu MJ, Gao C, Chen XX, Liu ZG. Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson's disease: A randomized double-blind placebo-controlled trial. J Integr Med. 2024; Epub ahead of print.