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6:2 fluorotelomer carboxylic acid (6:2 FTCA) is a perfluorooctanoic acid (PFOA) substitute, which is supposedly less accumulative and toxic than PFOA. However, 6:2 FTCA is structurally similar to PFOA, and there had already been reports about its toxicities comparable to PFOA. The aim of the current study is to assess potential effects of developmental exposure to 6:2 FTCA on the development of kidney in chicken embryo and to investigate underlying mechanism. Fertile chicken eggs were exposed to 1.25â¯mg/kg, 2.5â¯mg/kg or 5â¯mg/kg doses of 6:2 FTCA, or 2â¯mg/kg PFOA, then incubated to hatch. Serum and kidney of hatchling chickens were collected. Blood urea nitrogen (BUN) and creatinine (Cre) levels were measured with commercially available kits. Morphology of kidney was assessed with histopathology. To further reveal molecular mechanism of observed endpoints, IGF signaling molecules were assessed in the kidney samples with qRT-PCR, results indicated that IGFBP3 is a potentially crucial molecule. Lentiviruses overexpressing or silencing IGFBP3 were designed and applied to enhance/suppress the expression of IGFBP3 in developing chicken embryo for further verification of its role in the observed effects. Disrupted nephron formation, in the manifestation of decreased glomeruli number/area and increased serum BUN/Cre levels, was observed in the animals developmentally exposed to 6:2 FTCA. Correspondingly, IGF signaling molecules (IGF1, IGF1R and IGFBP3) were affected by 6:2 FTCA exposure. Meanwhile, overexpression of IGFBP3 effectively alleviated such changes, while silencing of IGFBP3 mimicked observed effects. In conclusion, developmental exposure to 6:2 FTCA is associated with disrupted chicken embryo renal development, in which IGFBP3 seems to be a remarkable contributor, suggesting potential health risks for human and other species. Further risk assessments and mechanistic works are necessary.
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Rim , Transdução de Sinais , Animais , Embrião de Galinha , Rim/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fluorocarbonos/toxicidade , Caprilatos/toxicidade , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Galinhas , Nitrogênio da Ureia Sanguínea , Creatinina/sangueRESUMO
INTRODUCTION: Executive functions (EF), encompassing inhibition, updating, and shifting, are widely acknowledged as cognitive factors that promote resilience. However, prior research examining the association between EF and resilience has been hampered by inconsistent conceptualizations of resilience and an overreliance on cross-sectional designs. We embraced a process-oriented conceptualization of resilience and employed a longitudinal approach to investigate how EF components interplay with the dynamic processes of resilience resources and resilient functioning. METHODS: A total of 144 Chinese preadolescents (aged 10-12, 53.5% male) completed computer-based EF assessments at baseline and self-reported their resilience at three intervals during 2019-2020. The resilience evaluations encompassed resilience resources at individual, familial, and social levels, as measured by the Resilience Scale for Chinese Adolescents, and resilient functioning, operationalized as the residuals of socioemotional difficulties after accounting for stressful life events. RESULTS: The findings emphasized the dynamic nature of resilience, unveiling a developmental cascade from resilience resources to resilient functioning and back to resilience resources. Furthermore, distinct effects of EF components on resilience development were found. Specifically, inhibition was associated with both concurrent and long-term resilience resources and functioning, while updating predicted long-term resilience resources, and shifting predicted long-term resilient functioning. CONCLUSION: These results underscored the pivotal role of EF as a cognitive foundation in comprehending the dynamic resilience processes during preadolescence.
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BACKGROUND: The axonemal microtubules of primary cilium undergo a conserved protein posttranslational modification (PTM) - polyglutamylation. This reversible procedure is processed by tubulin tyrosine ligase-like polyglutamylases to form secondary polyglutamate side chains, which are metabolized by the 6-member cytosolic carboxypeptidase (CCP) family. Although polyglutamylation modifying enzymes have been linked to ciliary architecture and motility, it was unknown whether they also play a role in ciliogenesis. RESULTS: In this study, we found that CCP5 expression is transiently downregulated upon the initiation of ciliogenesis, but recovered after cilia are formed. Overexpression of CCP5 inhibited ciliogenesis, suggesting that a transient downregulation of CCP5 expression is required for ciliation initiation. Interestingly, the inhibitory effect of CCP5 on ciliogenesis does not rely on its enzyme activity. Among other 3 CCP members tested, only CCP6 can similarly suppress ciliogenesis. Using CoIP-MS analysis, we identified a protein that potentially interacts with CCP - CP110, a known negative regulator of ciliogenesis, whose degradation at the distal end of mother centriole permits cilia assembly. We found that both CCP5 and CCP6 can modulate CP110 level. Particularly, CCP5 interacts with CP110 through its N-terminus. Loss of CCP5 or CCP6 led to the disappearance of CP110 at the mother centriole and abnormally increased ciliation in cycling RPE-1 cells. Co-depletion of CCP5 and CCP6 synergized this abnormal ciliation, suggesting their partially overlapped function in suppressing cilia formation in cycling cells. In contrast, co-depletion of the two enzymes did not further increase the length of cilia, although CCP5 and CCP6 differentially regulate polyglutamate side-chain length of ciliary axoneme and both contribute to limiting cilia length, suggesting that they may share a common pathway in cilia length control. Through inducing the overexpression of CCP5 or CCP6 at different stages of ciliogenesis, we further demonstrated that CCP5 or CCP6 inhibited cilia formation before ciliogenesis, while shortened the length of cilia after cilia formation. CONCLUSION: These findings reveal the dual role of CCP5 and CCP6. In addition to regulating cilia length, they also retain CP110 level to suppress cilia formation in cycling cells, pointing to a novel regulatory mechanism for ciliogenesis mediated by demodifying enzymes of a conserved ciliary PTM, polyglutamylation.
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Carboxipeptidases , Cílios , Proteínas Associadas aos Microtúbulos , Células HEK293 , Humanos , Carboxipeptidases/fisiologia , Proteínas Associadas aos Microtúbulos/fisiologia , Cílios/fisiologia , MicrotúbulosRESUMO
To improve the selective separation performance of silica nanofibers (SiO2 NFs) for cesium ions (Cs+) and overcome the defects of Prussian blue nanoparticles (PB NPs), PB/SiO2-NH2 NFs were prepared to remove Cs+ from water. Among them, 3-aminopropyltriethoxysilane (APTES) underwent an alkylation reaction with SiO2, resulting in the formation of a dense Si-O-Si network structure that decorated the surface of SiO2 NFs. Meanwhile, the amino functional groups in APTES combined with Fe3+ and then reacted with Fe2+ to form PB NPs, which anchored firmly on the aminoated SiO2 NFs surface. In our experiment, the maximum adsorption capacity of PB/SiO2-NH2 NFs was 111.38 mg/g, which was 31.5 mg/g higher than that of SiO2 NFs. At the same time, after the fifth cycle, the removal rate of Cs+ by PB/SiO2-NH2 NFs adsorbent was 75.36% ± 3.69%. In addition, the adsorption isotherms and adsorption kinetics of PB/SiO2-NH2 NFs were combined with the Freundlich model and the quasi-two-stage fitting model, respectively. Further mechanism analysis showed that the bond between PB/SiO2-NH2 NFs and Cs+ was mainly a synergistic action of ion exchange, electrostatic adsorption and membrane separation.
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Césio , Ferrocianetos , Nanofibras , Nanopartículas , Poluentes Químicos da Água , Purificação da Água , Ferrocianetos/química , Nanofibras/química , Poluentes Químicos da Água/química , Césio/química , Adsorção , Purificação da Água/métodos , Nanopartículas/química , Dióxido de Silício/química , Cinética , Propilaminas/química , SilanosRESUMO
OBJECTIVES: For a conventional indirect restoration, temporary cementation inevitably contaminated collapsed dentin collagen. The purpose of this review was to evaluate the optimal strategy for minimizing its negative effects. MATERIAL AND METHODS: Databases such as PubMed, Web of Science, EMBASE, and the Cochrane Library were searched for in vitro studies, involving the influence of immediate dentin sealing (IDS), different temporary cements, and their removal strategies on dentin bond strength. The meta-analysis used the inverse variance method with effect method of the standardized mean difference and statistical significance at p ≤ 0.05. The I2 value and the Q-test were used to assess the heterogeneity. RESULTS: A total of 14 in vitro trials were subjected to the meta-analysis. Within the study's limitations, we assumed that IDS eliminated the negative effects of temporary bonding, achieving the comparable immediate bond strength with the control (p = 0.46). In contrast, under delayed dentin sealing (DDS), temporary cementation statistically decreased bond strength (p = 0.002). Compared with resin-based and non-eugenol zinc oxide cements, polycarboxylate and calcium hydroxide cements performed better on bond strength with no statistical difference from the control group (p > 0.05). Among the removal methods of temporary cements, the Al2O3 abrasion restored the decreased bond strength (p = 0.07) and performed better than hand instruments alone (p = 0.04), while pumice removal slightly reduced the bond strength in contrast with the control group (p = 0.05, 95% CI = - 1.62 to 0). CONCLUSIONS: The choices of IDS, polycarboxylate and calcium hydroxide temporary cements, Al2O3 abrasion removal method were feasible and efficient to enhance the bond strength. CLINICAL RELEVANCE: It is worthwhile applying IDS technique, polycarboxylate and calcium hydroxide temporary cements during indirect restoration. The Al2O3 abrasion of cleaning dentin can minimize the negative effects of temporary cement.
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Colagem Dentária , Cimentos de Resina , Cimentos de Resina/química , Colagem Dentária/métodos , Adesivos Dentinários/química , Hidróxido de Cálcio , Cimentos Dentários/química , Teste de Materiais , Dentina , Resistência à Tração , Análise do Estresse DentárioRESUMO
The ocean is one of the most extensive ecosystems on Earth and can absorb large amounts of carbon dioxide. Changes in seawater carbon dioxide concentrations are one of the most important factors affecting marine ecosystems. Excess carbon dioxide can lead to ocean acidification, threatening the stability of marine ecosystems and species diversity. Dissolved carbon dioxide detection in seawater has great scientific significance. Conducting online monitoring of seawater carbon dioxide can help to understand the health status of marine ecosystems and to protect marine ecosystems. Current seawater detection equipment is large and costly. This study designed a low-cost infrared carbon dioxide detection system based on molecular theory. Using the HITRAN database, the absorption spectra and coefficients of carbon dioxide molecules under different conditions were calculated and derived, and a wavelength of 2361 cm-1 was selected as the measurement channel for carbon dioxide. In addition, considering the interference effect of direct light, an infrared post-splitting method was proposed to eliminate the interference of light and improve the detection accuracy of the system. The system was designed for the online monitoring of carbon dioxide in seawater, including a peristaltic pump to accelerate gas-liquid separation, an optical path structure, and carbon dioxide concentration inversion. The experimental results showed that the standard deviation of the gas test is 3.05, the standard deviation of the seawater test is 6.04, and the error range is within 20 ppm. The system can be flexibly deployed and has good stability and portability, which can meet the needs of the online monitoring of seawater carbon dioxide concentration.
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With the development of artificial intelligence technology, virtual reality technology has been widely used in the medical and entertainment fields, as well as other fields. This study is supported by the 3D modeling platform in UE4 platform technology and designs a 3D pose model based on inertial sensors through blueprint language and C++ programming. It can vividly display changes in gait, as well as changes in angles and displacements of 12 parts such as the big and small legs and arms. It can be used to combine with the module of capturing motion which is based on inertial sensors to display the 3D posture of the human body in real-time and analyze the motion data. Each part of the model contains an independent coordinate system, which can analyze the angle and displacement changes of any part of the model. All joints of the model are interrelated, the motion data can be automatically calibrated and corrected, and errors measured by an inertial sensor can be compensated, so that each joint of the model will not separate from the whole model and there will not occur actions that against the human body's structures, improving the accuracy of the data. The 3D pose model designed in this study can correct motion data in real time and display the human body's motion posture, which has great application prospects in the field of gait analysis.
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Inteligência Artificial , Análise da Marcha , Humanos , Marcha , Movimento (Física) , Postura , Fenômenos BiomecânicosRESUMO
BACKGROUND AND OBJECTIVES: We aimed to investigate the association of triglyceride-glucose (TyG) index with hypertension and compare the discriminative power of the TyG index, lipid, glycemic parameters for hypertension using the China Health Examination Collaborative study (CHEC Study). METHODS AND STUDY DESIGN: Data were collected at Ningbo Mingzhou Hospital and Beijing physical examination center from the CHEC Study during 2014 and 2021. Participants with ≥2 medical check-up times were included. The TyG index is the logarithmized product of fasting triglyceride and glucose. Generalised estimation equation (GEE) model was used to evaluate the association between the TyG index, lipid parameters, glycemic parameters and hypertension. Receiver operating characteristic (ROC) analysis was performed to explore the predictive ability of TyG index on hypertension at different years of medical check-up. RESULTS: 112,902 participants with an average age of 42.8 years were recruited in the study, 36,839 participants developed hypertension over the 8-year period. GEE model analysis showed that the ORs with 95% CI of hypertension were 3.35 (3.15-3.57), 1.86 (1.76-1.95), 1.67 (1.58-1.78), 1.45 (1.33-1.58), 1.24 (1.19-1.29), 0.92 (0.86-0.99), and 1.90 (1.83-1.97) in the highest versus lowest quintiles of TyG index, TG/HDL-C ratio, TG, TC, LDL-C, HDL-C and FPG in model 2. The area under the ROC curve of the overall years of medical check-up was signifi-cantly higher than a particular year in predicting hypertension (AUC: 0.883, p < 0.05). CONCLUSIONS: TyG index is associated with hypertension and shows the superior discriminative ability for hypertension compared with lipid and glycemic parameters.
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Hipertensão , Resistência à Insulina , Humanos , Adulto , Triglicerídeos , Glucose , Glicemia , População do Leste Asiático , China/epidemiologia , Hipertensão/epidemiologia , BiomarcadoresRESUMO
Advanced nitrogen removal faces the challenges of high operational cost resulted from the additional carbon source and secondary pollution caused by inaccurate carbon source dosage in municipal wastewater. To address these problems, a novel carbon source was developed, which was the oxidation products of refractory organic matters in the secondary effluent of municipal wastewater treatment plant (MWWTP) by in-situ generated biogenic manganese oxides (BMOs) in the denitrifying filter. In the steady phase, the effluent chemical oxygen demand (CODcr), NO3--N and total nitrogen (TN) in the denitrifying filter 2# with BMOs was 11.27, 9.03 and 10.36 mg/L, and the corresponding removal efficiency was 54.79%, 51.85% and 48.03%, respectively, which was significantly higher than those in the control denitrifying filter 1# that the removal efficiency of CODcr, NO3--N and TN was only 32.30%, 28.58% and 29.36%, respectively. Kinds of denitrifying bacteria (Candidatus Competibacter, Defluviicoccus, Dechloromonas, Candidatus Competibacter, Dechloromonas, Pseudomonas, Thauera, Acinetobacter, Denitratisoma, Anaerolineae and Denitratisoma) and anammox bacteria (Pirellula, Gemmata, Anammoximicrobium and Brocadia) were identified in the denitrifying filters 1# and 2#, which explained why the actual CODcr consumption (1.55 and 1.44 mg) of reducing 1 mg NO3--N was much lower than the theoretical CODcr consumption. While manganese oxidizing bacteria (MnOB, Bacillus, Crenothrix and Pedomicrobium) was only identified in the denitrifying filter 2#. This novel technology presented the advantages of no additional carbon source, low operational cost and no secondary pollution. Therefore, the novel technology has superlative application value and broad application prospect.
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Manganês , Microbiota , Desnitrificação , Nitrogênio , Óxidos , Oxirredução , Bactérias , Carbono , Reatores Biológicos/microbiologia , EsgotosRESUMO
The regulation of fibrotic activities is key to improving pathological remodelling post-myocardial infarction (MI). Currently, in the clinic, safe and curative therapies for cardiac fibrosis and improvement of the pathological fibrotic environment, scar formation and pathological remodelling post-MI are lacking. Previous studies have shown that miR-486 is involved in the regulation of fibrosis. However, it is still unclear how miR-486 functions in post-MI regeneration. Here, we first demonstrated that miR-486 targeting SRSF3/p21 mediates the senescence of cardiac myofibroblasts to improve their fibrotic activity, which benefits the regeneration of MI by limiting scar size and post-MI remodelling. miR-486-targeted silencing has high potential as a novel target to improve fibrotic activity, cardiac fibrosis and pathological remodelling.
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MicroRNAs , Infarto do Miocárdio , Cicatriz/patologia , Fibrose , Humanos , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Miocárdio/patologia , Miofibroblastos/patologia , Fatores de Processamento de Serina-Arginina/genéticaRESUMO
The long noncoding RNA GUARDIN functions to protect genome stability. Inhibiting GUARDIN expression can alter cell fate decisions toward senescence or apoptosis, but the underlying molecular signals are unknown. Here, we show that GUARDIN is an essential component of a transcriptional repressor complex involving LRP130 and PGC1α. GUARDIN acts as a scaffold to stabilize LRP130/PGC1α heterodimers and their occupancy at the FOXO4 promotor. Destabilizing this complex by silencing of GUARDIN, LRP130, or PGC1α leads to increased expression of FOXO4 and upregulation of its target gene p21, thereby driving cells into senescence. We also found that GUARDIN expression was induced by rapamycin, an agent that suppresses cell senescence. FOS-like antigen 2 (FOSL2) acts as a transcriptional repressor of GUARDIN, and lower FOSL2 levels in response to rapamycin correlate with increased levels of GUARDIN. Together, these results demonstrate that GUARDIN inhibits p21-dependent senescence through a LRP130-PGC1α-FOXO4 signaling axis, and moreover, GUARDIN contributes to the anti-aging activities of rapamycin.
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Senescência Celular , RNA Longo não Codificante , Transdução de Sinais , Apoptose , Proteínas de Ciclo Celular , Senescência Celular/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fatores de Transcrição Forkhead , Humanos , Proteínas de Neoplasias , Coativador 1-alfa do Receptor gama Ativado por Proliferador de PeroxissomoRESUMO
In order to understand how Wuhan curbed the COVID-19 outbreak in 2020, we build a network transmission model of 123 dimensions incorporating the impact of quarantine and medical resources as well as household transmission. Using our new model, the final infection size of Wuhan is predicted to be 50,662 (95%CI: 46,234, 55,493), and the epidemic would last until April 25 (95%CI: April 23, April 29), which are consistent with the actual situation. It is shown that quarantining close contacts greatly reduces the final size and shorten the epidemic duration. The opening of Fangcang shelter hospitals reduces the final size by about 17,000. Had the number of hospital beds been sufficient when the lockdown started, the number of deaths would have been reduced by at least 54.26%. We also investigate the distribution of infectious individuals in unquarantined households of different sizes. The high-risk households are those with size from two to four before the peak time, while the households with only one member have the highest risk after the peak time. Our findings provide a reference for the prevention, mitigation and control of COVID-19 in other cities of the world.
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COVID-19 , Modelos Epidemiológicos , Quarentena , COVID-19/epidemiologia , COVID-19/prevenção & controle , China/epidemiologia , Cidades , Controle de Doenças Transmissíveis , Humanos , SARS-CoV-2RESUMO
Hypertension, diabetes mellitus, and coronary artery disease are common comorbidities and dangerous factors for infection and serious COVID-19. Polymorphisms in genes associated with comorbidities may help observe susceptibility and disease severity variation. However, specific genetic factors and the extent to which they can explain variation in susceptibility of severity are unclear. Therefore, we evaluated candidate genes associated with COVID-19 and hypertension, diabetes mellitus, and coronary artery disease. In particular, we performed searches against OMIM, NCBI, and other databases, protein-protein interaction network construction, and GO and KEGG pathway enrichment analyses. Results showed that the associated overlapping genes were TLR4, NLRP3, MBL2, IL6, IL1RN, IL1B, CX3CR1, CCR5, AGT, ACE, and F2. GO and KEGG analyses yielded 302 GO terms (q < 0.05) and 29 signaling pathways (q < 0.05), respectively, mainly including coronavirus disease-COVID-19 and cytokine-cytokine receptor interaction. IL6 and AGT were central in the PPI, with 8 and 5 connections, respectively. In this study, we identified 11 genes associated with both COVID-19 and three comorbidities that may contribute to infection and disease severity. The key genes IL6 and AGT are involved in regulating immune response, cytokine activity, and viral infection. Therefore, RAAS inhibitors, AGT antisense nucleotides, cytokine inhibitors, vitamin D, fenofibrate, and vaccines regulating non-immune and immune factors could be potential strategies to prevent and cure COVID-19. The study provides a basis for further investigation of genes and pathways with predictive value for the risk of infection and prognosis and could help guide drug and vaccine development to improve treatment efficacy and the development of personalised treatments, especially for COVID-19 individuals with common comorbidities.
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COVID-19/genética , COVID-19/epidemiologia , Comorbidade , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/genética , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Hipertensão/genética , Mutação , Mapas de Interação de ProteínasRESUMO
Farnesoid X receptor (FXR) plays an indispensable role in liver homeostasis and has been a promising drug target for hepatic diseases. However, the concerns of undesired biological actions limit the clinical applications of FXR agonists. To reveal the intrinsic mechanism of FXR agonist-induce hepatotoxicity, two typical FXR agonists with different structures (obeticholic acid (OCA) and Px-102) were investigated in the present study. By detecting MMP, ROS, and ATP and analyzing the fate of cells, we found that both OCA and Px-102 reduced the mitochondrial function of hepatocytes and promoted cell apoptosis. Gene ablation or inhibition of FXR or SHP ameliorated the cytotoxicities of OCA and Px-102, which indicated the adverse actions of FXR/SHP activation including down-regulation of phosphorylation of PI3K/AKT and functional hepatic genes. The dose-related injurious effects of OCA (10 mg/kg and 30 mg/kg) and Px-102 (5 mg/kg and 15 mg/kg) on the liver were confirmed on a high-fat diet mouse model. The decrease of hepatocyte-specific genes and augmenter of liver regeneration in the liver caused by OCA or Px-102 suggested an imbalance of liver regeneration and a disruption of hepatic functions. Exploration of intestinally biased FXR agonists or combination of FXR agonist with apoptosis inhibitor may be more beneficial strategies for liver diseases.
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Ácido Quenodesoxicólico/análogos & derivados , Neoplasias Hepáticas Experimentais , Oxazóis , Receptores Citoplasmáticos e Nucleares , Animais , Apoptose/efeitos dos fármacos , Ácido Quenodesoxicólico/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Oxazóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: Pituitary adenomas are the most common type of pituitary disorders, which usually occur in young adults and often affect the patient's physical development, labor capacity and fertility. Clinical free texts noted in electronic medical records (EMRs) of pituitary adenomas patients contain abundant diagnosis and treatment information. However, this information has not been well utilized because of the challenge to extract information from unstructured clinical texts. This study aims to enable machines to intelligently process clinical information, and automatically extract clinical named entity for pituitary adenomas from Chinese EMRs. METHODS: The clinical corpus used in this study was from one pituitary adenomas neurosurgery treatment center of a 3A hospital in China. Four types of fine-grained texts of clinical records were selected, which included notes from present illness, past medical history, case characteristics and family history of 500 pituitary adenoma inpatients. The dictionary-based matching, conditional random fields (CRF), bidirectional long short-term memory with CRF (BiLSTM-CRF), and bidirectional encoder representations from transformers with BiLSTM-CRF (BERT-BiLSTM-CRF) were used to extract clinical entities from a Chinese EMRs corpus. A comprehensive dictionary was constructed based on open source vocabularies and a domain dictionary for pituitary adenomas to conduct the dictionary-based matching method. We selected features such as part of speech, radical, document type, and the position of characters to train the CRF-based model. Random character embeddings and the character embeddings pretrained by BERT were used respectively as the input features for the BiLSTM-CRF model and the BERT-BiLSTM-CRF model. Both strict metric and relaxed metric were used to evaluate the performance of these methods. RESULTS: Experimental results demonstrated that the deep learning and other machine learning methods were able to automatically extract clinical named entities, including symptoms, body regions, diseases, family histories, surgeries, medications, and disease courses of pituitary adenomas from Chinese EMRs. With regard to overall performance, BERT-BiLSTM-CRF has the highest strict F1 value of 91.27% and the highest relaxed F1 value of 95.57% respectively. Additional evaluations showed that BERT-BiLSTM-CRF performed best in almost all entity recognition except surgery and disease course. BiLSTM-CRF performed best in disease course entity recognition, and performed as well as the CRF model for part of speech, radical and document type features, with both strict and relaxed F1 value reaching 96.48%. The CRF model with part of speech, radical and document type features performed best in surgery entity recognition with relaxed F1 value of 95.29%. CONCLUSIONS: In this study, we conducted four entity recognition methods for pituitary adenomas based on Chinese EMRs. It demonstrates that the deep learning methods can effectively extract various types of clinical entities with satisfying performance. This study contributed to the clinical named entity extraction from Chinese neurosurgical EMRs. The findings could also assist in information extraction in other Chinese medical texts.
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Registros Eletrônicos de Saúde , Neoplasias Hipofisárias , Humanos , Armazenamento e Recuperação da Informação , Idioma , Processamento de Linguagem Natural , Neoplasias Hipofisárias/diagnósticoRESUMO
Riboswitches are regulatory noncoding RNAs found in bacteria, fungi and plants, that modulate gene expressions through structural changes in response to ligand binding. Understanding how ligands interact with riboswitches in solution can shed light on the molecular mechanisms of this ancient regulators. Previous studies showed that riboswitches undergo global conformation changes in response to ligand binding to relay information. Here, we report conformation switching models of the recently discovered tetrahydrofolic acid-responsive second class of tetrahydrofolate (THF-II) riboswitches in response to ligand binding. Using a combination of selective 2'-hydroxyl acylation, analyzed by primer extension (SHAPE) assay, 3D modeling and small-angle X-ray scattering (SAXS), we found that the ligand specifically recognizes and reshapes the THF-II riboswitch loop regions, but does not affect the stability of the P3 helix. Our results show that the THF-II riboswitch undergoes only local conformation changes in response to ligand binding, rearranging the Loop1-P3-Loop2 region and rotating Loop1 from a ~120° angle to a ~75° angle. This distinct conformation changes suggest a unique regulatory mechanism of the THF-II riboswitch, previously unseen in other riboswitches. Our findings may contribute to the fields of RNA sensors and drug design.
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Riboswitch , Ligantes , Conformação de Ácido Nucleico , Espalhamento a Baixo Ângulo , Tetra-Hidrofolatos/química , Tetra-Hidrofolatos/genética , Tetra-Hidrofolatos/metabolismo , Difração de Raios XRESUMO
Heavy metals are non-biodegradable and carcinogenic pollutants with great bio-accumulation potential. Their ubiquitous occurrence in water and soils has caused serious environmental concerns. Effective strategies that can eliminate the heavy metal pollution are urgently needed. Here the adsorption potential of seven heavy metal cations (Cd2+, Cu2+, Fe3+, Hg2+, Mn2+, Ni2+ and Zn2+) with 20 amino acids was systematically investigated with Density Functional Theory method. The binding energies calculated at B3LYP-D3/def2TZVP level showed that the contribution order of amino acid side chains to the binding affinity was carboxyl > benzene ring > hydroxyl > sulfhydryl > amino group. The affinity order was inversely proportional to the radius and charge transfer of heavy metal cations, approximately following the order of: Ni2+ > Fe3+ > Cu2+ > Hg2+ > Zn2+ > Cd2+ > Mn2+. Compared to the gas-phase in other researches, the water environment has a significant influence on structures and binding energies of the heavy metal and amino acid binary complexes. Collectively, the present results will provide a basis for the design of a chelating agent (e.g., adding carboxyl or a benzene ring) to effectively remove heavy metals from the environment.
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Mercúrio , Metais Pesados , Poluentes do Solo , Aminoácidos , Benzeno , Cádmio , Cátions , China , Monitoramento Ambiental/métodos , Metais Pesados/química , Modelos Teóricos , Poluentes do Solo/análise , Água , ZincoRESUMO
Bortezomib-based chemotherapy represents the most prevalent regimens for multiple myeloma (MM), whereas acquired drug resistance remains a major obstacle. Myeloma cells often produce excessive amount of dickkopf-1 (DKK1), giving rise to myeloma bone disease. However, it remains obscure about the effects and mechanisms of DKK1 in the progression and bortezomib responsiveness of MM cells. In the current study, we found WWP2, an E3 ubiquitin-protein ligase, was downregulated in the bortezomib-resistant cells along with high expression of DKK1. Further investigation revealed that WWP2 was a direct target of Wnt/ß-catenin signaling pathway, and DKK1 suppressed the expression of WWP2 via canonical Wnt signaling. We further identified that WWP2 mediated the ubiquitination and degradation of GLI2, a main transcriptional factor of the Hedgehog (Hh) pathway. Therefore, DKK1-induced WWP2 downregulation improved GLI2 stability and activation of Hh signaling pathway, contributing to the resistance to bortezomib of MM cells. Clinical data also validated that WWP2 expression was associated with the treatment response and clinic outcomes of MM patients. WWP2 overexpression restricted MM progression and enhanced cell sensitivity to bortezomib treatment in vitro and in vivo. Taken together, our findings demonstrate that DKK1 facilitates the generation of bortezomib resistance in MM via downregulating WWP2 and activating Hh pathway. Thus, the manipulation of DKK1-WWP2-GLI2 axis might sensitize myeloma cells to proteasome inhibitors.
Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Mieloma Múltiplo/tratamento farmacológico , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteína Gli2 com Dedos de Zinco/metabolismo , Linhagem Celular Tumoral , Células HEK293 , Humanos , Mieloma Múltiplo/metabolismo , Resultado do Tratamento , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitinação , Via de Sinalização WntRESUMO
Primary cilia are microtubule-based organelles that are involved in sensing micro-environmental cues and regulating cellular homeostasis via triggering signaling cascades. Hypoxia is one of the most common environmental stresses that organ and tissue cells may often encounter during embryogenesis, cell differentiation, infection, inflammation, injury, cerebral and cardiac ischemia, or tumorigenesis. Although hypoxia has been reported to promote or inhibit primary ciliogenesis in different tissues or cultured cell lines, the role of hypoxia in ciliogenesis is controversial and still unclear. Here we investigated the primary cilia change under cobalt chloride (CoCl2)-simulated hypoxia in immortalized human retina pigment epithelial-1 (hTERT RPE-1) cells. We found CoCl2 treatment elongated primary cilia in a time- and dose-dependent manner. The prolonged cilia recovered back to near normal length when CoCl2 was washed out from the cell culture medium. Under CoCl2-simulated hypoxia, the protein expression levels of HIF-1/2α and acetylated-α-tubulin (cilia marker) were increased, while the protein expression level of Rabaptin-5 is decreased during hypoxia. Taken together, our results suggest that hypoxia may elongate primary cilia by downregulating Rabaptin-5 involved endocytosis. The coordination between endocytosis and ciliogenesis may be utilized by cells to adapt to hypoxia.
Assuntos
Hipóxia Celular/efeitos dos fármacos , Cílios/efeitos dos fármacos , Cobalto/toxicidade , Epitélio Pigmentado da Retina/citologia , Hipóxia Celular/fisiologia , Linhagem Celular Transformada , Cobalto/administração & dosagem , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Humanos , Prolil Hidroxilases/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Telomerase/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
BACKGROUND: This study aimed to establish and validate an easy-to-operate novel scoring system based on simple and readily available clinical indices for predicting the progression of chronic kidney disease (CKD). METHODS: We retrospectively evaluated 1045 eligible CKD patients from a publicly available database. Factors included in the model were determined by univariate and multiple Cox proportional hazard analyses based on the training set. RESULTS: Independent prognostic factors including etiology, hemoglobin level, creatinine level, proteinuria, and urinary protein/creatinine ratio were determined and contained in the model. The model showed good calibration and discrimination. The area under the curve (AUC) values generated to predict 1-, 2-, and 3-year progression-free survival in the training set were 0.947, 0.931, and 0.939, respectively. In the validation set, the model still revealed excellent calibration and discrimination, and the AUC values generated to predict 1-, 2-, and 3-year progression-free survival were 0.948, 0.933, and 0.915, respectively. In addition, decision curve analysis demonstrated that the model was clinically beneficial. Moreover, to visualize the prediction results, we established a web-based calculator ( https://ncutool.shinyapps.io/CKDprogression/ ). CONCLUSION: An easy-to-operate model based on five relevant factors was developed and validated as a conventional tool to assist doctors with clinical decision-making and personalized treatment.