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2.
Front Genet ; 12: 762160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34795697

RESUMO

Colon adenocarcinoma (COAD) is one of the diseases with the highest morbidity and mortality in the world. At present, immunotherapy has become a valuable method for the treatment of COAD. Tumor mutational burden (TMB) is considered to be the most common biomarker for predicting immunotherapy. According to reports, the mutation rate of COAD ranks third. However, whether these gene mutations are related to TMB and immune response is still unknown. Here, COAD somatic mutation data were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Bioinformatics methods were used to study the relationships among gene mutations, COAD survival prognosis, and tumor immune response. A total of 22 of the top 40 mutations in TCGA and ICGC databases were the same. Among them, the USH2A mutation was associated with high TMB and poor clinical prognosis. According to Gene Set Enrichment Analysis (GSEA) and the CIBERSORT algorithm, we determined that the USH2A mutation upregulates signaling pathways involved in the immune system and the antitumor immune response. In cases with a USH2A mutation, the immune score and MSI score of TCGA samples increased, the expression of immune checkpoint genes decreased significantly, and the TIDE score decreased significantly. Dependent on the presence or absence of a USH2A mutation, TCGA COAD samples were analyzed for differentially expressed genes, 522 of which were identified. Using a univariate Cox analysis and LASSO COX analysis of these differential genes, a prediction model was established, which established significant differences in the infiltration of immune cells, immune checkpoint gene expression, immune score, MSI score, TMB, and TIDE in patients in high- and low-risk groups. In conclusion, mutation of USH2A is frequent in COAD and is related to an increase in TMB and the antitumor immunity. The differential genes screened by USH2A mutation allowed the construction of a risk model for predicting the survival and prognosis of cancer patients, in addition to providing new ideas for COAD immunotherapy.

3.
Org Lett ; 23(21): 8291-8295, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34670091

RESUMO

Herein, we report the arylation, alkylation, and alkenylation of aryl ketones via a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The use of the pyridine-oxazoline ligand is the key to the cleavage of the unstrained C-C bond. The late-stage arylation of aryl ketones derived from drugs and natural products demonstrated the synthetic utility of this protocol.

4.
Cell Rep ; 37(1): 109777, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34610306

RESUMO

Non-degradative ubiquitin chains and phosphorylation events govern signaling responses by innate immune receptors. The deubiquitinase CYLD in complex with SPATA2 is recruited to receptor signaling complexes by the ubiquitin ligase LUBAC and regulates Met1- and Lys63-linked polyubiquitin and receptor signaling outcomes. Here, we investigate the molecular determinants of CYLD activity. We reveal that two CAP-Gly domains in CYLD are ubiquitin-binding domains and demonstrate a requirement of CAP-Gly3 for CYLD activity and regulation of immune receptor signaling. Moreover, we identify a phosphorylation switch outside of the catalytic USP domain, which activates CYLD toward Lys63-linked polyubiquitin. The phosphorylated residue Ser568 is a novel tumor necrosis factor (TNF)-regulated phosphorylation site in CYLD and works in concert with Ser418 to enable CYLD-mediated deubiquitination and immune receptor signaling. We propose that phosphorylated CYLD, together with SPATA2 and LUBAC, functions as a ubiquitin-editing complex that balances Lys63- and Met1-linked polyubiquitin at receptor signaling complexes to promote LUBAC signaling.

5.
Sci Rep ; 11(1): 20863, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675301

RESUMO

Long non-coding RNA (lncRNA) is a prognostic biomarker for many types of cancer. Here, we aimed to study the prognostic value of lncRNA in Breast Invasive Carcinoma (BRCA). We downloaded expression profiles from The Cancer Genome Atlas (TCGA) datasets. Subsequently, we screened the differentially expressed genes between normal tissues and tumor tissues. Univariate Cox, LASSO regression, and multivariate Cox regression analysis were used to construct a lncRNA prognostic model. Finally, a nomogram based on the lncRNAs model was developed, and weighted gene co-expression network analysis (WGCNA) was used to predict mRNAs related to the model, and to perform function and pathway enrichment. We constructed a 6-lncRNA prognostic model. Univariate and multivariate Cox regression analysis showed that the 6-lncRNA model could be used as an independent prognostic factor for BRCA patients. We developed a nomogram based on the lncRNAs model and age, and showed good performance in predicting the survival rates of BRCA patients. Also, functional pathway enrichment analysis showed that genes related to the model were enriched in cell cycle-related pathways. Tumor immune infiltration analysis showed that the types of immune cells and their expression levels in the high-risk group were significantly different from those in the low-risk group. In general, the 6-lncRNA prognostic model and nomogram could be used as a practical and reliable prognostic tool for invasive breast cancer.

6.
J Healthc Eng ; 2021: 2481686, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34567479

RESUMO

Motion capture is a cross-cutting application field developed in recent years, which comprises electronics, communications, control, computer graphics, ergonomics, navigation, and other disciplines. The accurate application of basketball technical movements in the basketball game is very important. Therefore, it is of great significance to capture and standardize athletes' movements and improve their training. Unfortunately, there are numerous issues in traditional classroom teaching that largely helps to train the athletes. To solve the issues of traditional basketball classroom teaching, a virtual simulation system for students' sports training is designed in this paper. Firstly, the information of basketball dribbling movement is captured and simulated in three dimensions. Secondly, we compare it with the standard database to judge the irregularities of athletes' movements, and carry out digital processing on athletes' movements and skill improvements statistics in combination with system functions. Thirdly, we set up a gradual training cycle. Finally, the Kinect-based capture technology is adopted to obtain the activity information of different joints of the human body. Through processing the motion data, relevant motion analysis data are fed to the established motion model, to realize the comparative analysis of motion pictures. In our experiments, we observed better training of the physical education.


Assuntos
Desempenho Atlético , Basquetebol , Atletas , Humanos , Movimento , Tecnologia
8.
Front Physiol ; 12: 716654, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489732

RESUMO

There is increasing appreciation for the roles of the gut-liver axis in liver and gall diseases. Specific gut microbes are associated with susceptibility to gallstone diseases, while the relationship between intestinal flora and liver metabolism in the formation of gallstones remains unclear. In this study, an experimental group of model mice was given a lithogenic diet, and a control group was given a normal diet. Both groups were fed for 8 weeks. Integrating 16S rRNA gene sequencing and non-targeted metabolomics to explore the impact of the lithogenic diet on intestinal flora and liver metabolism, Spearman correlation analysis reveals the network of relationships between the intestine and liver. Our findings showed that the gut microbiome and liver metabolome compositions of the test group were significantly changed compared with those of the normal group. Through our research, biomarkers of gallstones were identified at the phylum (5), class (5), order (5), family (7), and genus levels. We predicted the function of the differential flora. We analyzed the liver metabolism of mice with gallstones paired with their flora, and the results showed that there were 138 different metabolites between the two groups. The metabolic pathways enriched by these differential metabolites are highly consistent with the functions of the disordered flora. We focused on an analysis of the relationship between deoxycholic acid, asymmetric dimethylarginine, glucosamine, tauroursodeoxycholic acid, and the disordered flora. This provides a basis for the establishment of the intestine-liver axis in gallstone disease. This research provides a theoretical basis for the research and development of probiotics and prebiotics.

9.
Chem Commun (Camb) ; 57(76): 9716-9719, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34473138

RESUMO

C3-Arylation of indoles with aryl ketones is accomplished via palladium-catalyzed ligand-promoted Ar-C(O) cleavage and subsequent C-H arylation of indole. Various (hetero)aryl ketones are compatible in this reaction, affording the corresponding 3-arylindoles in moderate to good yields. Further introduction of an indole moiety into the natural products desoxyestrone and evodiamine demonstrate the synthetic utility of this protocol.

10.
Biochim Biophys Acta Biomembr ; 1864(1): 183777, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34537214

RESUMO

TMEM16A, the calcium-activated chloride channel, is broadly expressed and plays pivotal roles in diverse physiological processes. To understand the structural and functional relationships of TMEM16A, it is necessary to fully clarify the structural basis of the gating of the TMEM16A channel. Herein, we performed the protein electrostatic analysis and molecular dynamics simulation on the TMEM16A in the presence and absence of Ca2+. Data showed that the separation of TM4 and TM6 causes pore expansion, and Q646 may be a key residue for the formation of π-helix in the middle segment of TM6. Moreover, E705 was found to form a group of H-bond interactions with D554/K588/K645 below the hydrophobic gate to stabilize the closed conformation of the pore in the Ca2+-free state. Interestingly, in the Ca2+ bound state, the E705 side chain swings 100o to serve as Ca2+-binding coordination and released K645. K645 is closer to the hydrophobic gate in the calcium-bound state, which facilitates the provision of electrostatic forces for chloride ions as the ions pass through the hydrophobic gate. Our findings provide the structural-based insights to understanding the mechanisms of gating of TMEM16A.

11.
Chem Commun (Camb) ; 57(69): 8656-8659, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34373875

RESUMO

Herein, we have developed a strategy of sequential C-H activations of indole to construct novel 2-alkynyl aza-spiro[4,5]indole scaffolds, which incorporated both alkyne and spiro-units into indole. Gram-scale synthesis and a one-pot, three-step synthesis demonstrated the utility of this protocol. Hybrid conjugates with an oseltamivir derivative further offered a powerful tool for the construction of a versatile spiroindole-containing library via click chemistry.

12.
Cancers (Basel) ; 13(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34439306

RESUMO

BACKGROUND: CXCs are important genes that regulate inflammation and tumor metastasis. However, the expression level, prognosis value, and immune infiltration of CXCs in cancers are not clear. METHODS: Multiple online datasets were used to analyze the expression, prognosis, and immune regulation of CXCs in this study. Network analysis of the Amadis database and GEO dataset was used to analyze the regulation of intestinal flora on the expression of CXCs. A mouse model was used to verify the fact that intestinal bacterial dysregulation can affect the expression of CXCs. RESULTS: In the three cancers, multiple datasets verified the fact that the mRNA expression of this family was significantly different; the mRNA levels of CXCL3, 8, 9, 10, 14, and 17 were significantly correlated with the prognosis of three cancers. CXCs were correlated with six types of immuno-infiltrating cells in three cancers. Immunohistochemistry of clinical samples confirmed that the expression of CXCL8 and 10 was higher in three cancer tissues. Animal experiments have shown that intestinal flora dysregulation can affect CXCL8 and 10 expressions. CONCLUSION: Our results further elucidate the function of CXCs in cancers and provide new insights into the prognosis and immune infiltration of breast, colon, and pancreatic cancers, and they suggest that intestinal flora may influence disease progression through CXCs.

13.
J Biol Chem ; 297(3): 101016, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34329684

RESUMO

As a calcium-activated chloride channel regulated by the intracellular Ca2+ concentration and membrane potential, TMEM16A has attracted considerable attention and has been proposed as a novel anticancer drug target. We have previously reported that the pocket above the ion conductance pore could be a nonselective inhibitor-binding pocket. However, whether this pocket is druggable remains unexplored. In this study, we performed virtual screening to target the presumed inhibitor-binding pocket and identified a highly effective TMEM16A inhibitor, theaflavin (TF: a tea polyphenol in black tea). Molecular dynamics simulations revealed that theaflavin adopts a "wedge insertion mode" to block the ion conduction pore and induces pore closure. Moreover, the binding mode showed that the TF pedestal plays an important role in pore blockade, and R515, R535, T539, K603, E623, and E633 were determined to be most likely to interact directly with the pedestal. Mutagenesis experiment results corroborated the mechanism through which TF binds to this pocket. Combined with the quantitative calculation results, our data indicated that the three hydroxyl groups on the pedestal may be the most crucial pharmacophores for TMEM16A inhibition by TF. Finally, antitumor experiments revealed that TF could target TMEM16A to inhibit the proliferation and migration of LA795 cells, indicating the potential therapeutic effect of TF on the growth of lung adenocarcinoma with high TMEM16A expression. The successful application of drug screening strategies based on this binding pocket highlights new directions for discovering superior modulators and contributes to the development of novel therapeutics for lung adenocarcinoma.

14.
J Chem Inf Model ; 61(7): 3304-3313, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34242036

RESUMO

Recently, molecular generation models based on deep learning have attracted significant attention in drug discovery. However, most existing molecular generation models have serious limitations in the context of drug design wherein they do not sufficiently consider the effect of the three-dimensional (3D) structure of the target protein in the generation process. In this study, we developed a new deep learning-based molecular generator, SBMolGen, that integrates a recurrent neural network, a Monte Carlo tree search, and docking simulations. The results of an evaluation using four target proteins (two kinases and two G protein-coupled receptors) showed that the generated molecules had a better binding affinity score (docking score) than the known active compounds, and the generated molecules possessed a broader chemical space distribution. SBMolGen not only generates novel binding active molecules but also presents 3D docking poses with target proteins, which will be useful in subsequent drug design. The code is available at https://github.com/clinfo/SBMolGen.


Assuntos
Inteligência Artificial , Redes Neurais de Computação , Desenho de Fármacos , Descoberta de Drogas , Simulação de Acoplamento Molecular , Proteínas
15.
J Exp Bot ; 72(12): 4298-4318, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33822021

RESUMO

Fatty acyl reductases (FARs) catalyse the reduction of fatty acyl-coenzyme A (CoA) or -acyl carrier protein (ACP) substrates to primary fatty alcohols, which play essential roles in lipid metabolism in plants. However, the mechanism by which FARs are involved in male reproduction is poorly defined. Here, we found that two maize allelic mutants, ms25-6065 and ms25-6057, displayed defective anther cuticles, abnormal Ubisch body formation, impaired pollen exine formation and complete male sterility. Based on map-based cloning and CRISPR/Cas9 mutagenesis, Zm00001d048337 was identified as ZmMs25, encoding a plastid-localized FAR with catalytic activities to multiple acyl-CoA substrates in vitro. Four conserved residues (G101, G104, Y327 and K331) of ZmMs25 were critical for its activity. ZmMs25 was predominantly expressed in anther, and was directly regulated by transcription factor ZmMYB84. Lipidomics analysis revealed that ms25 mutation had significant effects on reducing cutin monomers and internal lipids, and altering the composition of cuticular wax in anthers. Moreover, loss of function of ZmMs25 significantly affected the expression of its four paralogous genes and five cloned lipid metabolic male-sterility genes in maize. These data suggest that ZmMs25 is required for anther development and male fertility, indicating its application potential in maize and other crops.


Assuntos
Regulação da Expressão Gênica de Plantas , Zea mays , Oxirredutases , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plastídeos/metabolismo , Pólen/genética , Pólen/metabolismo , Zea mays/genética , Zea mays/metabolismo
16.
Nucleic Acids Res ; 49(10): 5451-5469, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33836076

RESUMO

Deoxyribonucleic acid (DNA) has evolved to be a naturally selected, robust biomacromolecule for gene information storage, and biological evolution and various diseases can find their origin in uncertainties in DNA-related processes (e.g. replication and expression). Recently, synthetic DNA has emerged as a compelling molecular media for digital data storage, and it is superior to the conventional electronic memory devices in theoretical retention time, power consumption, storage density, and so forth. However, uncertainties in the in vitro DNA synthesis and sequencing, along with its conjugation chemistry and preservation conditions can lead to severe errors and data loss, which limit its practical application. To maintain data integrity, complicated error correction algorithms and substantial data redundancy are usually required, which can significantly limit the efficiency and scale-up of the technology. Herein, we summarize the general procedures of the state-of-the-art DNA-based digital data storage methods (e.g. write, read, and preservation), highlighting the uncertainties involved in each step as well as potential approaches to correct them. We also discuss challenges yet to overcome and research trends in the promising field of DNA-based data storage.


Assuntos
DNA , Genes Sintéticos , Armazenamento e Recuperação da Informação/métodos , DNA/síntese química , DNA/química
17.
Sensors (Basel) ; 21(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919128

RESUMO

Pavement crack detection is essential for safe driving. The traditional manual crack detection method is highly subjective and time-consuming. Hence, an automatic pavement crack detection system is needed to facilitate this progress. However, this is still a challenging task due to the complex topology and large noise interference of crack images. Recently, although deep learning-based technologies have achieved breakthrough progress in crack detection, there are still some challenges, such as large parameters and low detection efficiency. Besides, most deep learning-based crack detection algorithms find it difficult to establish good balance between detection accuracy and detection speed. Inspired by the latest deep learning technology in the field of image processing, this paper proposes a novel crack detection algorithm based on the deep feature aggregation network with the spatial-channel squeeze & excitation (scSE) attention mechanism module, which calls CrackDFANet. Firstly, we cut the collected crack images into 512 × 512 pixel image blocks to establish a crack dataset. Then through iterative optimization on the training and validation sets, we obtained a crack detection model with good robustness. Finally, the CrackDFANet model verified on a total of 3516 images in five datasets with different sizes and containing different noise interferences. Experimental results show that the trained CrackDFANet has strong anti-interference ability, and has better robustness and generalization ability under the interference of light interference, parking line, water stains, plant disturbance, oil stains, and shadow conditions. Furthermore, the CrackDFANet is found to be better than other state-of-the-art algorithms with more accurate detection effect and faster detection speed. Meanwhile, our algorithm model parameters and error rates are significantly reduced.

18.
NPJ Precis Oncol ; 5(1): 32, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863983

RESUMO

Approximately 15-30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors. We encountered a case harboring an EGFR-L747P mutation, originally misdiagnosed with EGFR-del19 mutation using a routine diagnostic EGFR mutation test, which was resistant to EGFR-TKI gefitinib. Using this minor mutation and common EGFR-activating mutations, we performed the binding free energy calculations and microsecond-timescale molecular dynamic (MD) simulations, revealing that the L747P mutation considerably stabilizes the active conformation through a salt-bridge formation between K745 and E762. We further revealed why several EGFR inhibitors, including the allosteric inhibitor, were ineffective. Our computational structural analysis strategy would be beneficial for future drug development targeting the EGFR minor mutations.

19.
Artigo em Inglês | MEDLINE | ID: mdl-33925871

RESUMO

Food-borne pathogens have become an important public threat to human health. There are many kinds of pathogenic bacteria in food consumed daily. A rapid and sensitive testing method for multiple food-borne pathogens is essential. Europium nanoparticles (EuNPs) are used as fluorescent probes in lateral flow immunoassays (LFIAs) to improve sensitivity. Here, recombinase polymerase amplification (RPA) combined with fluorescent LFIA was established for the simultaneous and quantitative detection of Listeria monocytogenes, Vibrio parahaemolyticus, and Escherichia coliO157:H7. In this work, the entire experimental process could be completed in 20 min at 37 °C. The limits of detection (LODs) of EuNP-based LFIA-RPA were 9.0 colony-forming units (CFU)/mL for Listeria monocytogenes, 7.0 CFU/mL for Vibrio parahaemolyticus, and 4.0 CFU/mL for Escherichia coliO157:H7. No cross-reaction could be observed in 22 bacterial strains. The fluorescent LFIA-RPA assay exhibits high sensitivity and good specificity. Moreover, the average recovery of the three food-borne pathogens spiked in food samples was 90.9-114.2%. The experiments indicate the accuracy and reliability of the multiple fluorescent test strips. Our developed EuNP-based LFIA-RPA assay is a promising analytical tool for the rapid and simultaneous detection of multiple low concentrations of food-borne pathogens.


Assuntos
Nanopartículas Metálicas , Recombinases , Európio , Microbiologia de Alimentos , Humanos , Imunoensaio , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Foods ; 10(2)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668612

RESUMO

Heavy metals in food packaging materials have been indicated to release into the environment at slow rates. Heavy metal contamination, especially that of cadmium (Cd), is widely acknowledged as a global environment threat that leads to continuous growing pollution levels in the environment. Traditionally, the detection of the concentration of Cd relies on expensive precision instruments, such as inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma-atomic emission spectrometry (ICP-AES). In this study, an indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) based on a specific monoclonal antibody was proposed to rapidly detect Cd. The half-inhibitory concentration and detection sensitivity of the anti-cadmium monoclonal antibody of the ic-ELISA were 5.53 ng mL-1 and 0.35 ng mL-1, respectively. The anti-Cd monoclonal antibody possessed high specificity while diagnosising other heavy metal ions, including Al (III), Ca (II), Cu (II), Fe (III), Hg (II), Mg (II), Mn (II), Pb (II), Zn (II), Cr (III) and Ni (II). The average recovery rates of Cd ranged from 89.03-95.81% in the spiked samples of packing materials, with intra- and inter-board variation coefficients of 7.20% and 6.74%, respectively. The ic-ELISA for Cd detection was applied on 72 food packaging samples that consisted of three material categories-ceramic, glass and paper. Comparison of the detection results with ICP-AES verified the accuracy of the ic-ELISA. The correlation coefficient between the ic-ELISA and the ICP-AES methods was 0.9634, demonstrating that the proposed ic-ELISA approach could be a useful and effective tool for the rapid detection of Cd in food packaging materials.

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