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Piezoelectric composite ceramics, as the key components of ultrasonic transducers, have their vibration modes, electromechanical coupling performance, and acoustic impedance closely related to the volume fraction of ceramics. This study employed a novel digital light processing 3D printing technique (DLP) to fabricate 0.5Ba(Zr0.2Ti0.8)O3-0.5(Ba0.7Ca0.3)TiO3 (BCZT)-based 1-3 piezoelectric composite ceramics with different ceramic volume fractions (15.6 %, 23.5 %, 36.2 %, 48.4 %, 59.5 %). It demonstrates the suitability of the DLP process for the fabrication of 1-3 piezoelectric composite ceramics and investigates the influence of ceramic volume fraction on the performance of these ceramics. When the piezoelectric ceramic volume fraction was 59.5 %, the piezoelectric coefficient effective d33 of the 1-3 piezoelectric composite device reached 315 pC/N, demonstrating excellent piezoelectric performance. The acoustic impedance Z was 16.3 MRayl, and the thickness electromechanical coupling coefficient kt was 0.55, indicating high energy conversion efficiency. The air-coupled ultrasonic transducer prepared from the 1-3 piezoelectric composite ceramics with a ceramic volume fraction of 59.5 % exhibited a round-trip insertion loss (IL) of -70.32 dB and a -6 dB bandwidth (BW-6dB) of 7.42 %. This work provides a more convenient and new method for the preparation of lead-free piezoelectric ceramic ultrasonic transducers.
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Homologous recombination deficiency (HRD) score is a reliable indicator of genomic instability. The significance of HRD in nasopharyngeal carcinoma (NPC), particularly its influence on prognosis and the immune microenvironment, has yet to be adequately explored. Understanding HRD status comprehensively can offer valuable insights for guiding precision treatment. We utilised three cohorts to investigate HRD status in NPC: the Zhujiang cohort from local collection and the Hong Kong (SRA288429) and Singapore (SRP035573) cohorts from public datasets. The GATK (genome analysis toolkit) best practice process was employed to investigate germline and somatic BRCA1/2 mutations and various bioinformatics tools and algorithms to examine the association between HRD status and clinical molecular characteristics. We found that individuals with a negative HRD status (no-HRD) exhibited a higher risk of recurrence [hazard ratio (HR), 1.43; 95% confidence interval (CI), 2.03-333.76; p = 0.012] in the Zhujiang cohort, whereas, in the Singapore cohort, they experienced a higher risk of mortality (HR, 26.04; 95% CI, 1.43-34.21; p = 0.016) compared with those in the HRD group. In vitro experiments demonstrated that NPC cells with BRCA1 knockdown exhibit heightened sensitivity to chemoradiotherapy. Furthermore, the HRD group showed significantly higher tumour mutational burden and tumour neoantigen burden levels than the no-HRD group. Immune infiltration analysis indicated that HRD tissues tend to have a non-inflamed tumour microenvironment. In conclusion, patients with HRD exhibit a comparatively favourable prognosis in NPC, possibly associated with a non-inflammatory immune microenvironment. These findings have positive implications for treatment stratification, enabling the selection of more precise and effective therapeutic approaches and aiding in the prediction of treatment response and prognosis to a certain extent.
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Proteína BRCA1 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Microambiente Tumoral , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/inmunología , Masculino , Femenino , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/inmunología , Pronóstico , Persona de Mediana Edad , Proteína BRCA1/genética , Proteína BRCA2/genética , Mutación , Adulto , Recombinación Homóloga/genética , Biomarcadores de Tumor/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/genética , Inestabilidad GenómicaRESUMEN
The competition among drugs for binding to plasma proteins is regarded as a pharmacokinetic drug interaction. Competition between antitumor agents and other drugs for plasma protein binding can alter the free concentration of the drug, potentially impacting its efficacy and increasing the risk of toxic side effects. Through a range of spectroscopic techniques, this study examined the interaction between limonin and human serum albumin (HSA) in the context of berberine (Ber) and curcumin (Cur) under physiological conditions to clarify the binding mechanisms of binary and ternary systems at the molecular level. As demonstrated by fluorescence quenching experiments, Static quenching was identified as the mechanism of interaction between HSA and limonin. The results of site competition experiments indicated that the binding site between limonin and HSA was site I, a result further supported by molecular docking simulations. Through the use of thermodynamic data calculations, it was determined that limonin forms a stable complex with HSA by establishing hydrogen bonds and van der Waals forces. Circular dichroism (CD) spectroscopy, three-dimensional (3D) fluorescence spectroscopy, and synchronous fluorescence spectroscopy (SFS) employed to validate the notion that limonin perturbed the microenvironment of amino acids and induced conformational changes in HSA. What's more, the presence of Ber or Cur was found to have further modified the alterations observed in the interaction between the original HSA-limonin binary system. In vitro cellular experiments showed that interaction with HSA reduced the antitumor activity of limonin. In contrast, adding Ber or Cur increased the inhibition rate of tumor cells. The coexistence of both Ber and Cur significantly diminished limonin's binding affinity to HSA. The current investigation enhances comprehension regarding the binding characteristics and interaction mechanisms involving limonin, Ber, Cur, and HSA. It explores the potential of HSA as a versatile drug carrier and furnishes theoretical underpinnings for co-administrative strategies.
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Background Sexual transmission accounts for a substantial proportion of HIV infections. Although some countries are experiencing an upward trend in HIV infections, there has been a lack of studies assessing the global burden of HIV/AIDS acquired through sexual transmission. We assessed the global, regional, and national burdens of HIV/AIDS acquired through sexual transmission from 1990 to 2019. Methods Data on deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALY) of HIV/AIDS acquired through sexual transmission in 204 countries and territories from 1990 to 2019 were retrieved from the Global Burden of Disease Study (GBD) 2019. The burdens and trends were evaluated using the age-standardised rates (ASR) and estimated annual percentage change (EAPC). Results Globally, HIV/AIDS acquired through sexual transmission accounted for ~695.8 thousand (95% uncertainty interval 628.0-811.3) deaths, 33.0million (28.7-39.9) YLLs, 3.4million (2.4-4.6) YLDs, and 36.4million (32.2-43.1) DALYs in 2019. In 2019, Southern sub-Saharan Africa (11350.94), Eastern sub-Saharan Africa (3530.91), and Western sub-Saharan Africa (2037.74) had the highest ASR of DALYs of HIV/AIDS acquired through sexual transmission per 100,000. In most regions of the world, the burden of HIV/AIDS acquired through sexual transmission has been increasing from 1990 to 2019, mainly in Oceania (EAPC 17.20, 95% confidence interval 12.82-21.75), South Asia (9.00, 3.94-14.30), and Eastern Europe (7.09, 6.35-7.84). Conclusions HIV/AIDS acquired through sexual transmission results in a major burden globally, regionally, and nationally.
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Carga Global de Enfermedades , Salud Global , Infecciones por VIH , Humanos , Infecciones por VIH/epidemiología , Infecciones por VIH/transmisión , Masculino , Femenino , Salud Global/estadística & datos numéricos , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Síndrome de Inmunodeficiencia Adquirida/transmisión , Adulto , Años de Vida Ajustados por Discapacidad , Persona de Mediana EdadRESUMEN
BACKGROUND: With the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of Zanthoxylum armatum DC. (ZADC), it has been found that ZADC is hepatotoxic. However, the toxic substance basis and mechanism of action have not been fully elucidated. Hydroxy-α-sanshool (HAS) belongs to an amide compound in the fruits of ZADC, which may be hepatotoxic. However, the specific effects of HAS, including liver toxicity, are unclear. PURPOSE: The objectives of this research was to determine how HAS affects hepatic lipid metabolism, identify the mechanism underlying the accumulation of liver lipids by HAS, and offer assurances on the safe administration of HAS. METHODS: An in vivo experiment was performed by gavaging C57 BL/6 J mice with various dosages of HAS (5, 10, and 20 mg/kg). Biochemical indexes were measured, and histological analysis was performed to evaluate HAS hepatotoxicity. Hepatic lipid levels were determined using lipid indices and oil red O (ORO) staining. Intracellular lipid content were determined by biochemical analyses and ORO staining after treating HepG2 cells with different concentrations of HAS in vitro. Mitochondrial membrane potential, respiratory chain complex enzymes, and ATP levels were assessed by fluorescence labeling of mitochondria. The levels of proteins involved in lipogenesis and catabolism were determined using Western blotting. RESULTS: Mice in the HAS group had elevated alanine and aspartate aminotransferase blood levels as well as increased liver index compared with the controls. The pathological findings showed hepatocellular necrosis. Serum and liver levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were increased, whereas high-density lipoprotein cholesterol levels decreased. The ORO staining findings demonstrated elevated liver lipid levels. In vitro experiments demonstrated a notable elevation in triglyceride and total cholesterol levels in the HAS group. ATP, respiratory chain complex enzyme gene expression, mitochondrial membrane potential, and mitochondrial number were reduced in the HAS group. The levels of lipid synthesis-associated proteins (ACC, FASN, and SREBP-1c) were increased, and lipid catabolism-associated protein levels (PPARα and CPT1) and the p-AMPK/AMPK ratio were decreased in vivo and in vitro. CONCLUSION: HAS has hepatotoxic effects, which can induce fatty acid synthesis and mitochondrial function damage by inhibiting the AMPK signaling pathway, resulting in aberrant lipid increases.
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BACKGROUND: Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process. METHODS: Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation. RESULTS: We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis. CONCLUSIONS: Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.
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Ferroptosis, an emerging type of programmed cell death, is initiated by iron-dependent and excessive ROS-mediated lipid peroxidation, which eventually leads to plasma membrane rupture and cell death. Many canonical signalling pathways and biological processes are involved in ferroptosis. Furthermore, cancer cells are more susceptible to ferroptosis due to the high load of ROS and unique metabolic characteristics, including iron requirements. Recent investigations have revealed that ferroptosis plays a crucial role in the progression of tumours, especially HCC. Specifically, the induction of ferroptosis can not only inhibit the growth of hepatoma cells, thereby reversing tumorigenesis, but also improves the efficacy of immunotherapy and enhances the antitumour immune response. Therefore, triggering ferroptosis has become a new therapeutic strategy for cancer therapy. In this review, we summarize the characteristics of ferroptosis based on its underlying mechanism and role in HCC and provide possible therapeutic applications.
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Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Especies Reactivas de Oxígeno/metabolismo , Animales , Peroxidación de Lípido , Transducción de Señal , Hierro/metabolismoRESUMEN
Osteocytes are terminally differentiated cells derived from osteoblasts and are deeply embedded within the bone matrix. They play a critical role in bone remodeling by generating a lacuno-canalicular network (LCN) and controlling the transport of nutrients. Due to the absence of blood vessels within the bone matrix, it is widely believed that osteocytes develop in a hypoxic environment. However, the mechanisms of osteocytogenesis and the role of oxygen sensing in this process remain unclear. Hypoxia-inducible factors (HIFs) are major transcriptional factors involved in oxygen sensing. Previous studies have shown that accumulation of HIFs in osteoblasts leads to abnormal bone remodeling, potentially linked with the alterations of the LCN network. Specifically, HIF-1α is hypothesized to play a more significant role in regulating bone remodeling compared to HIF-2α. Therefore, we investigated the functions of HIF-1α in dendrite formation and the establishment of the LCN network during osteocytogenesis. Immunostaining and scanning electron microscopy revealed that the E11 protein aggregates to form a ring structure that defines the site for dendrite initiation. This process is followed by activation of the ERM/RhoA pathway and recruitment of matrix metalloproteinase 14 (MMP14) to facilitate extracellular matrix degradation, enabling dendrite elongation. However, both hypoxic treatment and overexpression of HIF-1α impair ring formation, resulting in reduced ERM/RhoA activity and decreased matrix degradation capability. These findings suggest that abnormal HIF-1α activity in local areas could contribute to impaired LCN network formation and abnormal bone remodeling observed in bone diseases such as osteopenia and aging.
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Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.
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Carcinoma Hepatocelular , Doxorrubicina , Sinergismo Farmacológico , Neoplasias Hepáticas , Naftoquinonas , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Doxorrubicina/química , Naftoquinonas/administración & dosificación , Naftoquinonas/química , Naftoquinonas/farmacología , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Humanos , Polietilenglicoles/química , Polietilenglicoles/administración & dosificación , Ratones Endogámicos BALB C , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Línea Celular Tumoral , Ratones , Nanopartículas/química , Resistencia a Antineoplásicos/efectos de los fármacos , Sistema de Administración de Fármacos con Nanopartículas/química , Ratones Desnudos , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologíaRESUMEN
The dynamics of locally interacting particles that are distributed in space give rise to a multitude of complex behaviours. However the simulation of reaction-diffusion processes which model such systems is highly computationally expensive, the cost increasing rapidly with the size of space. Here, we devise a graph neural network based approach that uses cheap Monte Carlo simulations of reaction-diffusion processes in a small space to cast predictions of the dynamics of the same processes in a much larger and complex space, including spaces modelled by networks with heterogeneous topology. By applying the method to two biological examples, we show that it leads to accurate results in a small fraction of the computation time of standard stochastic simulation methods. The scalability and accuracy of the method suggest it is a promising approach for studying reaction-diffusion processes in complex spatial domains such as those modelling biochemical reactions, population evolution and epidemic spreading.
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Método de Montecarlo , Redes Neurales de la Computación , Procesos Estocásticos , Modelos Biológicos , Simulación por ComputadorRESUMEN
Numerous recent studies have underscored the indispensable roles of long non-coding RNAs (lncRNAs) in various diseases. However, their precise mechanisms in urinary bladder cancer (UBC) remain to be further elucidated. To delve into this inquiry, online databases were analyzed to identify differentially expressed lncRNAs in UBC, followed by the functional experiments in vivo and in vitro functional experiments. GAS6-AS1 exhibited high expression levels in UBC tissues and was shown to regulate the proliferation, migration, invasion, and cell cycle progression of UBC cells in vitro and in vivo. Then, a series of molecular biology experiments, including RNA pull-down, dual-luciferase reporter gene assays, RNA immunoprecipitation (RIP) assays, fluorescent in situ hybridization (FISH), and the triplex-capture assay demonstrated its interaction with miR-367-3p and PRC1. Mechanistically, GAS6-AS1 was found to enhance MMP7 expression by sequestering miR-367-3p. Moreover, GAS6-AS1 inhibited APC transcription by binding with PRC1, thereby activating several oncogenes downstream of the WNT pathway. To sum up, GAS6-AS1 promotes UBC progression through two distinct axes: the GAS6-AS1/miR-367-3p/MMP7 axis and the GAS6-AS1/PRC1/APC/Wnt/MMP7 axis, respectively. As a potential biomarker for UBC, GAS6-AS1 holds promising prospects for the diagnosis, treatment, and prognosis of UBC.
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Due to a high degree of symptom overlap in the early stages, with movement disorders predominating, Parkinson's disease (PD) and multiple system atrophy (MSA) may exhibit a similar decline in motor areas, yet they differ in their spread throughout the brain, ultimately resulting in two distinct diseases. Drawing upon neuroimaging analyses and altered motor cortex excitability, potential diffusion mechanisms were delved into, and comparisons of correlations across distinct disease groups were conducted in a bid to uncover significant pathological disparities. We recruited thirty-five PD, thirty-seven MSA, and twenty-eight matched controls to conduct clinical assessments, electromyographic recording, and magnetic resonance imaging scanning during the "on medication" state. Patients with neurodegeneration displayed a widespread decrease in electrophysiology in bilateral M1. Brain function in early PD was still in the self-compensatory phase and there was no significant change. MSA patients demonstrated an increase in intra-hemispheric function coupled with a decrease in diffusivity, indicating a reduction in the spread of neural signals. The level of resting motor threshold in healthy aged showed broad correlations with both clinical manifestations and brain circuits related to left M1, which was absent in disease states. Besides, ICF exhibited distinct correlations with functional connections between right M1 and left middle temporal gyrus in all groups. The present study identified subtle differences in the functioning of PD and MSA related to bilateral M1. By combining clinical information, cortical excitability, and neuroimaging intuitively, we attempt to bring light on the potential mechanisms that may underlie the development of neurodegenerative disease.
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Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Humanos , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Atrofia de Múltiples Sistemas/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/fisiopatología , Anciano , Imagen por Resonancia Magnética/métodos , Corteza Motora/diagnóstico por imagen , Corteza Motora/fisiopatología , Electromiografía , Neuroimagen/métodosRESUMEN
Recent research has reevaluated the traditional view of cancer's linear progression and recurrence by introducing cellular reprogramming a process in which cancer cells can their state under certain conditions. This change is driven by a combination of genetic and epigenetic factors, with pivotal roles played by key genes, and pathways, notably Wnt and Notch. The complexity of cancer's behavior is further influenced by factors such as the epithelial-mesenchymal transition (EMT) and therapy-induced stress, both of which are significant contributors to cancer recurrence. In this context bibliometric analysis emerges as a crucial tool for evaluating the impacts and trends within scientific literature. Our study utilized bibliometrics to analysis the role of cellular reprogramming oncology over the past two decades, highlighting its potential to improve cancer treatment outcomes. In conducting this analysis, we searched for literature search on cellular reprogramming (CR) in the Web of Science database, covering the years 2002-2022. We employed visualization tools like Citespace, VOSviewer, and Bibliometrix to analyze the collected data resulting in a dataset of 3102 articles. The United States and China emerged as leading contributors to this field, with the University of Texas MD Anderson Cancer Center being the most prolific institution. Menendez was the most influential scholar in this research domain. Cancers was the journal with the most publications on this subject. The most local-cited document was the article titled "Hallmarks of Cancer: The Next Generation". A comprehensive analysis has been conducted based on keywords and cited references. In recent years, the research emphasis has shifted to "extracellular vesicles," "cancer therapy," and "cellular plasticity". Therefore, this analysis uses bibliometrics to chart cutting-edge progress in cancer's cellular reprogramming, aiding experts to quickly understand and innovate in this crucial area.
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Diffuse large B-cell lymphoma (DLBCL) represents the most common tumor in non-Hodgkin's lymphoma. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor highly expressed in healthy tissues but downregulated in many cancers. Although cell proliferation-related metabolism rewiring has been well characterized, less is known about the mechanism of metabolic changes with DLBCL. Herein, we investigated the expressions of NDRG2, MYC and Myc-interacting zinc finger protein 1 (MIZ-1) in seven human lymphoma (mostly DLBCLs) cell lines. NDRG2 expression was inversely correlated with the expressions of MYC and MIZ-1. Further, we explored the regulatory mechanism and biological functions underlying the lymphomagenesis involving NDRG2, MYC and MIZ-1. MYC and MIZ-1 promoted DLBCL cell proliferation, while NDRG2 induced apoptosis in LY8 cells. Moreover, NDRG2 methylation was reversed by the 5-Aza-2'-deoxycytidine (5-Aza-CDR) treatment, triggering the downregulation of MYC and inhibiting DLBCL cell survival. MYC interacts with NDRG2 to regulate energy metabolism associated with mTOR. Remarkably, supporting the biological significance, the converse correlation between NDRG2 and MYC was observed in human DLBCL tumor tissues (R = -0.557). Bioinformatics analysis further validated the association among NDRG2, MYC, MIZ-1, mTOR, and related metabolism genes. Additionally, NDRG2 (P = 0.001) and MYC (P < 0.001) were identified as promising prognostic biomarkers in DLBCL patients through survival analysis. Together, our data demonstrate that the MYC/MIZ-1 complex interplays with NDRG2 to influence the proliferation and apoptosis of DLBCL cells and show the characterizations of NDRG2, MYC and MIZ-1 for metabolism features and prediction prognosis in DLBCL.
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Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-myc , Proteínas Supresoras de Tumor , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Masculino , Pronóstico , Línea Celular Tumoral , Femenino , Persona de Mediana Edad , Metilación de ADN , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Anciano , Proliferación Celular , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: It is essential to assess the risk stratification of patients with aortic stenosis (AS). OBJECTIVE: To clarify the predictive value of red blood cell distribution width (RDW) in AS patients using a large cohort from the MIMIC-IV database. METHODS: Restricted cubic spline, the Kaplan-Meier method, and logistic and Cox regression analyses were used to explore the association between RDW and all-cause mortality in AS patients. Multivariate adjustments, propensity score matching and weighting, and subgroup analysis were conducted to exclude confounding factors. Receiver operating characteristic (ROC) and decision curve analysis (DCA) curves were drawn to evaluate the predictive performance of RDW. RESULTS: 1,148 patients with AS were included. Their death risks gradually increased with the elevation of RDW. Multivariate-adjusted 90-day (OR: 2.12; HR: 1.90; p = 0.001) and 1-year (OR: 2.07; HR: 1.97; p < 0.001) all-cause mortalities were significantly higher in patients with RDW≥14.7 %, which remained robust after propensity score matching and subgroup analysis. For AS patients with high RDW, those < 75 years old had higher death risks than those ≥ 75 years old. The area under the ROC curve of RDW were 0.741 and 0.75 at 90-day and 1-year follow-ups, respectively, exhibiting comparable performance to acute physiology score III and outperforming other critical illness scores in predicting the prognosis of AS patients. DCA curves also illustrated that RDW had a wide range of net benefits. CONCLUSIONS: High RDW was independently associated with increased 90-day and 1-year all-cause mortalities of AS patients, with strong predictive capability of prognosis.
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Estenosis de la Válvula Aórtica , Índices de Eritrocitos , Curva ROC , Humanos , Femenino , Masculino , Estenosis de la Válvula Aórtica/sangre , Estenosis de la Válvula Aórtica/mortalidad , Estudios Retrospectivos , Anciano , Medición de Riesgo/métodos , Causas de Muerte/tendencias , Pronóstico , Persona de Mediana Edad , Anciano de 80 o más Años , Valor Predictivo de las Pruebas , Factores de Riesgo , Puntaje de Propensión , Tasa de Supervivencia/tendenciasRESUMEN
The CRISPR system is an adaptive immune system found in prokaryotes that defends host cells against the invasion of foreign DNA1. As part of the ongoing struggle between phages and the bacterial immune system, the CRISPR system has evolved into various types, each with distinct functionalities2. Type II Cas9 is the most extensively studied of these systems and has diverse subtypes. It remains uncertain whether members of this family can evolve additional mechanisms to counter viral invasions3,4. Here we identify 2,062 complete Cas9 loci, predict the structures of their associated proteins and reveal three structural growth trajectories for type II-C Cas9. We found that novel associated genes (NAGs) tended to be present within the loci of larger II-C Cas9s. Further investigation revealed that CbCas9 from Chryseobacterium species contains a novel ß-REC2 domain, and forms a heterotetrameric complex with an NAG-encoded CRISPR-Cas-system-promoting (pro-CRISPR) protein of II-C Cas9 (PcrIIC1). The CbCas9-PcrIIC1 complex exhibits enhanced DNA binding and cleavage activity, broader compatibility for protospacer adjacent motif sequences, increased tolerance for mismatches and improved anti-phage immunity, compared with stand-alone CbCas9. Overall, our work sheds light on the diversity and 'growth evolutionary' trajectories of II-C Cas9 proteins at the structural level, and identifies many NAGs-such as PcrIIC1, which serves as a pro-CRISPR factor to enhance CRISPR-mediated immunity.
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Bacterias , Bacteriófagos , Proteína 9 Asociada a CRISPR , Sistemas CRISPR-Cas , Bacterias/virología , Bacterias/genética , Bacterias/inmunología , Bacteriófagos/genética , Bacteriófagos/inmunología , Chryseobacterium/genética , Chryseobacterium/inmunología , Chryseobacterium/virología , Proteína 9 Asociada a CRISPR/química , Proteína 9 Asociada a CRISPR/genética , Proteína 9 Asociada a CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/inmunología , División del ADN , Sitios Genéticos/genética , Modelos Moleculares , Dominios ProteicosRESUMEN
N6-methyladenosine (m6A) modification, installed by METTL3-METTL14 complex, is abundant and critical in eukaryotic mRNA. However, its role in oral mucosal immunity remains ambiguous. Periodontitis is a special but prevalent infectious disease characterized as hyperinflammation of oral mucosa and bone resorption. Here, it is reported that genetic deletion of Mettl3 alleviates periodontal destruction via suppressing NLRP3 inflammasome activation. Mechanistically, the stability of TNFAIP3 (also known as A20) transcript is significantly attenuated upon m6A modification. When silencing METTL3, accumulated TNFAIP3 functioning as a ubiquitin-editing enzyme facilitates the ubiquitination of NEK7 [NIMA (never in mitosis gene a)-related kinase 7], and subsequently impairs NLRP3 inflammasome assembly. Furtherly, Coptisine chloride, a natural small-molecule, is discovered as a novel METTL3 inhibitor and performs therapeutic effect on periodontitis. The study unveils a previously unknown pathogenic mechanism of METTL3-mediated m6A modifications in periodontitis and indicates METTL3 as a potential therapeutic target.
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Inflamasomas , Metiltransferasas , Quinasas Relacionadas con NIMA , Ubiquitinación , Quinasas Relacionadas con NIMA/genética , Quinasas Relacionadas con NIMA/metabolismo , Animales , Metiltransferasas/metabolismo , Metiltransferasas/genética , Ratones , Inflamasomas/metabolismo , Inflamasomas/genética , Ubiquitinación/efectos de los fármacos , Ubiquitinación/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Modelos Animales de Enfermedad , Periodontitis/genética , Periodontitis/metabolismo , Periodontitis/tratamiento farmacológico , Ratones Endogámicos C57BL , HumanosRESUMEN
BACKGROUND: Acute-on-chronic liver disease (AoCLD) accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases. AIM: To explore the characterization of AoCLD to provide theoretical guidance for the accurate diagnosis and prognosis of AoCLD. METHODS: Patients with AoCLD from the Chinese Acute-on-Chronic Liver Failure (ACLF) study cohort were included in this study. The clinical characteristics and outcomes, and the 90-d survival rate associated with each clinical type of AoCLD were analyzed, using the Kaplan-Meier method and the log-rank test. RESULTS: A total of 3375 patients with AoCLD were enrolled, including 1679 (49.7%) patients with liver cirrhosis acute decompensation (LC-AD), 850 (25.2%) patients with ACLF, 577 (17.1%) patients with chronic hepatitis acute exacerbation (CHAE), and 269 (8.0%) patients with liver cirrhosis active phase (LC-A). The most common cause of chronic liver disease (CLD) was HBV infection (71.4%). The most common precipitants of AoCLD was bacterial infection (22.8%). The 90-d mortality rates of each clinical subtype of AoCLD were 43.4% (232/535) for type-C ACLF, 36.0% (36/100) for type-B ACLF, 27.0% (58/215) for type-A ACLF, 9.0% (151/1679) for LC-AD, 3.0% (8/269) for LC-A, and 1.2% (7/577) for CHAE. CONCLUSION: HBV infection is the main cause of CLD, and bacterial infection is the main precipitant of AoCLD. The most common clinical type of AoCLD is LC-AD. Early diagnosis and timely intervention are needed to reduce the mortality of patients with LC-AD or ACLF.
RESUMEN
BACKGROUND: Single nuclear polymorphisms (SNPs) have been published to be correlated with multiple diseases. Transcription Factor 21 (TCF21) is a critical transcription factor involved in various types of cancers. However, the association of TCF21 genetic polymorphisms with gastric cancer (GC) susceptibility and prognosis remains unclear. METHODS: A case-control study comprising 890 patients diagnosed with GC and an equal number of cancer-free controls was conducted. After rigorous statistical analysis, molecular experiments were carried out to elucidate the functional significance of the SNPs in the context of GC. RESULTS: TCF21 rs2327430 (OR = 0.78, P = 0.026) provides protection against GC, while rs4896011 (OR = 1.39, P = 0.005) exhibit significant associations with GC risk. Furthermore, patients with the (TC + CC) genotype of rs2327430 demonstrate a relatively favorable prognosis (OR = 0.47, P = 0.012). Mechanistically, chromatin immunoprecipitation assay and luciferase reporter assay revealed that the C allele of rs2327430 disrupts the binding of Transcription Factor AP-2 Alpha (TFAP2A) to the promoter region of TCF21, resulting in increased expression of TCF21 and inhibition of malignant behaviors in GC cells. CONCLUSION: Our findings highlight the significant role of TCF21 SNPs in both the risk and prognosis of GC and provide valuable insights into the underlying molecular mechanisms. Specifically, the disruptive effect of rs2327430 on TCF21 expression and its ability to modulate malignant cell behaviors suggest that rs2327430 may serve as a potential predictive marker for GC risk and prognosis.
RESUMEN
Extensive studies have been conducted on the impact of foreign language reading anxiety on reading, primarily focusing on pedagogy and behavior but lacking electrophysiological evidence. The current study aimed to investigate the influence of foreign language reading anxiety on reading and its underlying mechanisms. The results revealed a negative correlation between foreign language reading anxiety and foreign language reading performance, irrespective of the native language. Adults with low levels of foreign language reading anxiety (LFLRA) demonstrated a significant difference in early lexical component N170 amplitude between foreign and native languages. However, this effect was not observed in adults with high levels of foreign language reading anxiety (HFLRA). In terms of N170 latency, HFLRA showed a longer N170 for the foreign language compared to the native language. Furthermore, the N170 effects were predominantly localized over the left occipitotemporal electrodes. Regarding N400 latency, a significant difference was found in LFLRA individuals between foreign and native language processing, while HFLRA individuals did not exhibit this difference. These findings suggest that HFLRA individuals experience inefficient lexical processing (such as orthography or semantics) during reading in foreign language.