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1.
J Int Med Res ; 52(9): 3000605241258181, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39291425

RESUMO

OBJECTIVE: To analyze the predictive value of the triglyceride-glucose (TyG) index and neutrophil-to-high-density lipoprotein ratio (NHR) for in-hospital major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI), and to establish an associated nomogram model. METHODS: In this retrospective study, we collected data from consecutive STEMI patients who underwent PCI from October 2019 to June 2023 at the Second People's Hospital of Hefei and the Second Affiliated Hospital of Anhui Medical University, as training and validation sets. Stepwise regression and multivariate logistic regression analysis were performed to screen independent risk factors, and a nomogram model was constructed and evaluated for its predictive efficacy. RESULTS: The TyG index, NHR, urea, diastolic blood pressure, hypertension, and left ventricular ejection fraction were independent risk factors for in-hospital MACE after PCI, and were used to construct the nomogram model. The C-index of the training and validation sets were 0.799 and 0.753, respectively, suggesting that the model discriminated well. Calibration and clinical decision curves also demonstrated that the nomogram model had good predictive power. CONCLUSION: In STEMI patients, increased TyG index and NHR were closely related to the occurrence of in-hospital MACE after PCI. Our constructed nomogram model has some value for predicting the occurrence of in-hospital MACE in STEMI patients.


Assuntos
Glicemia , Lipoproteínas HDL , Neutrófilos , Nomogramas , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Triglicerídeos , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Masculino , Feminino , Triglicerídeos/sangue , Pessoa de Meia-Idade , Estudos Retrospectivos , Lipoproteínas HDL/sangue , Idoso , Fatores de Risco , Neutrófilos/patologia , Glicemia/análise , Glicemia/metabolismo , Prognóstico
2.
Plant Commun ; : 101134, 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39277789

RESUMO

Flavonoids, the largest class of polyphenols, exhibit substantial structural and functional diversity, yet their evolutionary diversification and specialized functions remain largely unexplored. The genus Scutellaria is notable for its rich flavonoid diversity, particularly the 6/8-hydroxylated variants biosynthesized by the cytochrome P450 subfamily CYP82D. Our study analyzes metabolic differences between Scutellaria baicalensis and Scutellaria barbata, suggesting that CYP82Ds have acquired a broad range of catalytic functions over their evolution. By integrating analyses of metabolic networks and gene evolution across 22 Scutellaria species, we rapid identified 261 flavonoids and delineated five clades associated with various catalytic functions of CYP82Ds. This approach uncovered a unique catalytic mode for 6/8-hydroxylated function under flavanone substrates and the first instance of 7-O-demethylation of flavonoid substrates catalyzed by cytochrome P450. Ancestral sequence reconstruction and functional validation demonstrated that gradual neofunctionalization of CYP82Ds has driven the chemical diversity of flavonoids in Scutellaria throughout its evolutionary history. Our study enhances the understanding of flavonoid diversity, elucidates the intricate roles of CYP82Ds in Scutellaria plants, and underscores the extensive catalytic versatility of cytochrome P450 members within plant taxa.

3.
Int J Mol Sci ; 25(16)2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39201771

RESUMO

High-altitude diseases, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), are closely related to an individual's ability to adapt to hypoxic environments. However, specific research in this field is relatively limited, and further biomarker research and clinical trials are needed to clarify the exact role and potential therapeutic applications of key genes in high-altitude diseases. This study focuses on the role of the STC1 gene in high-altitude diseases and explores its expression patterns in different types of cancer. By using gene expression data analysis and functional experiments, we identified STC1 as a key gene affecting the development of altitude sickness. In addition, we also conducted expression and mutation analysis on STC1 in various cancer samples and found significant differences in the expression of this gene in 13 types of malignant tumors, which is associated with the hypoxic state in the tumor microenvironment. In addition, STC1 is significantly associated with patient prognosis and influences tumor immunity by mediating six types of immune cells (CD8+T cells, CD4+T cells, neutrophils, macrophages, monocytes, and B cells) in the tumor microenvironment. The expression and diagnostic value of STC1 were confirmed through GEO datasets and qPCR testing, indicating consistency with the results of bioinformatics analysis. These results indicate that STC1 is not only an important factor in the adaptive response to high-altitude diseases but may also play a role in the adaptation of cancer to low-oxygen environments. Our research provides a new perspective and potential targets for the discovery of biomarkers for high-altitude diseases and cancer treatment.


Assuntos
Doença da Altitude , Biomarcadores Tumorais , Glicoproteínas , Neoplasias , Humanos , Altitude , Doença da Altitude/genética , Biomarcadores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Microambiente Tumoral/genética
4.
Int J Biol Macromol ; 277(Pt 2): 133985, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39033887

RESUMO

Crocins are bioactive natural products that rarely exist in plants. High costs and resource shortage severely limit its development and application. Synthetic biology studies on crocins are of considerable global interest. However, the lack of high-efficiency genetic tools and complex cascade biocatalytic systems have substantially hindered progress in crocin biosynthesis-related research. Based on mutagenesis, a high-efficiency GjCCD4a mutant (N212m) was constructed with a catalytic efficiency that was 25.08-fold higher than that of the wild-type. Solubilized GjCCD4a was expressed via fusion with an MBP tag. Moreover, N212m and ten other genes were introduced into Escherichia coli for the de novo biosynthesis of five crocins. The engineered E57 strain produced crocins III and V with a total yield of 11.50 mg/L, and the E579 strain produced crocins I-V with a total output of 8.43 mg/L at shake-flask level. This study identified a marvelous genetic element (N212m) for crocin biosynthesis and achieved its de novo biosynthesis in E. coli using glucose. This study provides a reference for the large-scale production of five crocins using E. coli cell factories.


Assuntos
Carotenoides , Escherichia coli , Mutação , Carotenoides/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Engenharia Metabólica/métodos
5.
ACS Infect Dis ; 10(8): 2961-2977, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39066703

RESUMO

The primary obstacles in the management of Enterococcus and Streptococcal infections are drug resistance and biofilm formation. Our study revealed that loratadine at a concentration of ≥25 µM exhibited significant inhibitory effects on biofilm formation in 167 clinical strains of Enterococcus faecalis and 15 clinical isolates of Streptococcus agalactiae, Streptococcus pyogenes, and Streptococcus pneumoniae. Additionally, the antibiofilm activity against E. faecalis and Streptococcal was demonstrated by several loratadine derivatives with altered side-chain carbamate moieties. This study investigated the antibacterial activity of the loratadine derivative Lo-7 against clinical strains of S. agalactiae and S. pyogenes, with minimum inhibitory concentrations ranging from 12.5 to 25 µM. The findings revealed that a low concentration of loratadine derivative Lo-7 (3.125 µM) significantly augmented the bactericidal efficacy of vancomycin against multidrug-resistant (MDR) S. agalactiae, both in vitro and in vivo. The loratadine derivative Lo-7, even at low concentrations, demonstrated significant efficacy in eliminating intracellular MDR S. agalactiae within macrophages, potentially indicating a unique advantage over vancomycin, linezolid, and loratadine. Mechanistically, exposure to the loratadine derivative Lo-7 resulted in membrane depolarization without affecting membrane permeability in S. agalactiae. The potential targeting of the SecG subunit of the SecYEG membrane-embedded channel by the loratadine derivative Lo-7 in S. agalactiae was identified through quantitative proteomics, a drug affinity responsive target stability assay, and molecular docking.


Assuntos
Antibacterianos , Biofilmes , Loratadina , Testes de Sensibilidade Microbiana , Infecções Estreptocócicas , Loratadina/farmacologia , Loratadina/química , Antibacterianos/farmacologia , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/tratamento farmacológico , Humanos , Streptococcus agalactiae/efeitos dos fármacos , Animais , Enterococcus/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Camundongos , Vancomicina/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos
6.
Opt Express ; 32(9): 15295-15314, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38859184

RESUMO

The accuracy of phase demodulation has significant impact on the accuracy of fringe projection 3D measurement. Currently, researches based on deep learning methods for extracting wrapped phase mostly use U-Net as the subject of network. The connection method between its hierarchies has certain shortcomings in global information transmission, which hinders the improvement of wrapped phase prediction accuracy. We propose a single-shot phase demodulation method for fringe projection based on a novel full-scale connection network SE-FSCNet. The encoder and decoder of the SE-FSCNet have the same number of hierarchies but are not completely symmetrical. At the decoder a full-scale connection method and feature fusion module are designed so that SE-FSCNet has better abilities of feature transmission and utilization compared with U-Net. A channel attention module based on squeeze and excitation is also introduced to assign appropriate weights to features with different scales, which has been proved by the ablation study. The experiments conducted on the test set have demonstrated that the SE-FSCNet can achieve higher precision than the traditional Fourier transform method and the U-Net in phase demodulation.

7.
bioRxiv ; 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38746374

RESUMO

Meta-analysis is used to aggregate the effects of interest across multiple studies, while its methodology is largely underexplored in mediation analysis, particularly in estimating the total mediation effect of high-dimensional omics mediators. Large-scale genomic consortia, such as the Trans-Omics for Precision Medicine (TOPMed) program, comprise multiple cohorts with diverse technologies to elucidate the genetic architecture and biological mechanisms underlying complex human traits and diseases. Leveraging the recent established asymptotic standard error of the R-squared R2-based mediation effect estimation for high-dimensional omics mediators, we have developed a novel meta-analysis framework requiring only summary statistics and allowing inter-study heterogeneity. Whereas the proposed meta-analysis can uniquely evaluate and account for potential effect heterogeneity across studies due to, for example, varying genomic profiling platforms, our extensive simulations showed that the developed method was more computationally efficient and yielded satisfactory operating characteristics comparable to analysis of the pooled individual-level data when there was no inter-study heterogeneity. We applied the developed method to 8 TOPMed studies with over 5800 participants to estimate the mediation effects of gene expression on age-related variation in systolic blood pressure and sex-related variation in high-density lipoprotein (HDL) cholesterol. The proposed method is available in R package MetaR2M on GitHub.

8.
J Med Chem ; 67(11): 8791-8816, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38775356

RESUMO

The spread of the influenza virus has caused devastating pandemics and huge economic losses worldwide. Antiviral drugs with diverse action modes are urgently required to overcome the challenges of viral mutation and drug resistance, and targeted protein degradation strategies constitute excellent candidates for this purpose. Herein, the first degradation of the influenza virus polymerase acidic (PA) protein using small-molecule degraders developed by hydrophobic tagging (HyT) technology to effectively combat the influenza virus was reported. The SAR results revealed that compound 19b with Boc2-(L)-Lys demonstrated excellent inhibitory activity against A/WSN/33/H1N1 (EC50 = 0.015 µM) and amantadine-resistant strain (A/PR/8/H1N1), low cytotoxicity, high selectivity, substantial degradation ability, and good drug-like properties. Mechanistic studies demonstrated that the proteasome system and autophagic lysosome pathway were the potential drivers of these HyT degraders. Thus, this study provides a powerful tool for investigating the targeted degradation of influenza virus proteins and for antiviral drug development.


Assuntos
Antivirais , Interações Hidrofóbicas e Hidrofílicas , Tioureia , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Cães , Animais , Tioureia/farmacologia , Tioureia/análogos & derivados , Tioureia/química , Relação Estrutura-Atividade , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Células Madin Darby de Rim Canino , Proteólise/efeitos dos fármacos , Proteínas Virais/metabolismo , Proteínas Virais/química , Proteínas Virais/antagonistas & inibidores , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Farmacorresistência Viral/efeitos dos fármacos
9.
J Virol ; 98(5): e0031724, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38624231

RESUMO

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a newly discovered swine coronavirus with potential cross-species transmission risk. Although SADS-CoV-induced host cell apoptosis and innate immunity antagonization has been revealed, underlying signaling pathways remain obscure. Here, we demonstrated that infection of SADS-CoV induced apoptosis in vivo and in vitro, and that viral protein NS7a is mainly responsible for SADS-CoV-induced apoptosis in host cells. Furthermore, we found that NS7a interacted with apoptosis-inducing factor mitochondria associated 1 (AIFM1) to activate caspase-3 via caspase-6 in SADS-CoV-infected cells, and enhanced SADS-CoV replication. Importantly, NS7a suppressed poly(I:C)-induced expression of type III interferon (IFN-λ) via activating caspase-3 to cleave interferon regulatory factor 3 (IRF3), and caspase-3 inhibitor protects piglets against SADS-CoV infection in vivo. These findings reveal how SADS-CoV induced apoptosis to inhibit innate immunity and provide a valuable clue to the development of effective drugs for the clinical control of SADS-CoV infection.IMPORTANCEOver the last 20 years, multiple animal-originated coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2, have caused millions of deaths, seriously jeopardized human health, and hindered social development, indicating that the study of animal-originated coronaviruses with potential for cross-species transmission is particularly important. Bat-originated swine acute diarrhea syndrome coronavirus (SADS-CoV), discovered in 2017, can not only cause fatal diarrhea in piglets, but also infect multiple human cells, with a potential risk of cross-species transmission, but its pathogenesis is unclear. In this study, we demonstrated that NS7a of SADS-CoV suppresses IFN-λ production via apoptosis-inducing factor mitochondria associated 1 (AIFM1)-caspase-6-caspase-3-interferon regulatory factor 3 (IRF3) pathway, and caspase-3 inhibitor (Z-DEVD-FMK) can effectively inhibit SADS-CoV replication and protect infected piglets. Our findings in this study contribute to a better understanding of SADS-CoV-host interactions as a part of the coronaviruses pathogenesis and using apoptosis-inhibitor as a drug as potential therapeutic approaches for prevention and control of SADS-CoV infection.


Assuntos
Apoptose , Imunidade Inata , Fator Regulador 3 de Interferon , Interferons , Proteínas não Estruturais Virais , Animais , Suínos , Humanos , Interferons/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Proteínas não Estruturais Virais/metabolismo , Replicação Viral , Interferon lambda , Infecções por Coronavirus/virologia , Infecções por Coronavirus/metabolismo , Alphacoronavirus/metabolismo , Caspase 3/metabolismo , Doenças dos Suínos/virologia , Doenças dos Suínos/metabolismo , Células Vero , Transdução de Sinais , Chlorocebus aethiops , Células HEK293
10.
Stat Med ; 43(13): 2560-2574, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38636557

RESUMO

Massive genetic compendiums such as the UK Biobank have become an invaluable resource for identifying genetic variants that are associated with complex diseases. Due to the difficulties of massive data collection, a common practice of these compendiums is to collect interval-censored data. One challenge in analyzing such data is the lack of methodology available for genetic association studies with interval-censored data. Genetic effects are difficult to detect because of their rare and weak nature, and often the time-to-event outcomes are transformed to binary phenotypes for access to more powerful signal detection approaches. However transforming the data to binary outcomes can result in loss of valuable information. To alleviate such challenges, this work develops methodology to associate genetic variant sets with multiple interval-censored outcomes. Testing sets of variants such as genes or pathways is a common approach in genetic association settings to lower the multiple testing burden, aggregate small effects, and improve interpretations of results. Instead of performing inference with only a single outcome, utilizing multiple outcomes can increase statistical power by aggregating information across multiple correlated phenotypes. Simulations show that the proposed strategy can offer significant power gains over a single outcome approach. We apply the proposed test to the investigation that motivated this study, a search for the genes that perturb risks of bone fractures and falls in the UK Biobank.


Assuntos
Simulação por Computador , Humanos , Estudos de Associação Genética/métodos , Modelos Estatísticos , Fenótipo , Variação Genética , Fraturas Ósseas/genética , Feminino
11.
Acta Pharm Sin B ; 14(4): 1878-1891, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572115

RESUMO

Crocus sativus (saffron) is a globally autumn-flowering plant, and its stigmas are the most expensive spice and valuable herb medicine. Crocus specialized metabolites, crocins, are biosynthesized in distant species, Gardenia (eudicot) and Crocus (monocot), and the evolution of crocin biosynthesis remains poorly understood. With the chromosome-level Crocus genome assembly, we revealed that two rounds of lineage-specific whole genome triplication occurred, contributing important roles in the production of carotenoids and apocarotenoids. According to the kingdom-wide identification, phylogenetic analysis, and functional assays of carotenoid cleavage dioxygenases (CCDs), we deduced that the duplication, site positive selection, and neofunctionalization of Crocus-specific CCD2 from CCD1 members are responsible for the crocin biosynthesis. In addition, site mutation of CsCCD2 revealed the key amino acids, including I143, L146, R161, E181, T259, and S292 related to the catalytic activity of zeaxanthin cleavage. Our study provides important insights into the origin and evolution of plant specialized metabolites, which are derived by duplication events of biosynthetic genes.

12.
Vet Res ; 55(1): 45, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589958

RESUMO

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel porcine enteric coronavirus that causes acute watery diarrhea, vomiting, and dehydration in newborn piglets. The type III interferon (IFN-λ) response serves as the primary defense against viruses that replicate in intestinal epithelial cells. However, there is currently no information available on how SADS-CoV modulates the production of IFN-λ. In this study, we utilized IPI-FX cells (a cell line of porcine ileum epithelium) as an in vitro model to investigate the potential immune evasion strategies employed by SADS-CoV against the IFN-λ response. Our results showed that SADS-CoV infection suppressed the production of IFN-λ1 induced by poly(I:C). Through screening SADS-CoV-encoded proteins, nsp1, nsp5, nsp10, nsp12, nsp16, E, S1, and S2 were identified as antagonists of IFN-λ1 production. Specifically, SADS-CoV nsp1 impeded the activation of the IFN-λ1 promoter mediated by MAVS, TBK1, IKKε, and IRF1. Both SADS-CoV and nsp1 obstructed poly(I:C)-induced nuclear translocation of IRF1. Moreover, SADS-CoV nsp1 degraded IRF1 via the ubiquitin-mediated proteasome pathway without interacting with it. Overall, our study provides the first evidence that SADS-CoV inhibits the type III IFN response, shedding light on the molecular mechanisms employed by SADS-CoV to evade the host immune response.


Assuntos
Alphacoronavirus , Infecções por Coronavirus , Doenças dos Suínos , Animais , Suínos , Complexo de Endopeptidases do Proteassoma , Interferon lambda , Alphacoronavirus/fisiologia , Ubiquitinas , Infecções por Coronavirus/veterinária
13.
Materials (Basel) ; 17(8)2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38673168

RESUMO

Pb plays an important role in determining the morphologies and mechanical properties of the Mg2Si phase in Mg-2.5Si-xPb alloys. As the amount of Pb increases from 0.4 wt.% to 1 wt.%, the primary Mg2Si phase is refined during solidification. Its morphologies transform from equiaxed-dendrite to polygonal and finally to roughly circular. The key reason for morphology evolution is the preferential adsorption of Pb atoms on Mg2Si {100} surfaces to suppress the growth rate along the ⟨100⟩ directions, which is demonstrated by the adsorption model based on first principles. In addition, the hardness of the Mg2Si phase decreases with the increasing solution content of Pb according to the results of the nanoindentation. With the addition of Pb at 1 wt.%, Pb content in the primary Mg2Si phase reaches a maximum of 0.4 wt.%, and the hardness of the primary Mg2Si phase reaches a minimum of 3.64 GPa. This reduction in hardness is attributed to the augmented ionic bond ratio resulting from the solution of Pb, which concurrently enhances the toughness of the Mg2Si phase.

14.
Artigo em Inglês | MEDLINE | ID: mdl-38584561

RESUMO

BACKGROUND: The enhancer of rudimentary homolog (ERH) has been shown to play significant roles in tumorigenesis and progression. However, few systematic pan-cancer analyses about ERH have been described. METHODS: From the tumor immune estimation resource web server2.0 (TIMER2.0), the Genotype-Tissue Expression database (GTEx) and the Gene Expression Profile Interactive Analysis version 2 (GEPIA2) databases, we explored the expression profiles and prognostic significance of ERH in 33 cancers. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas (HPA) databases were further used to examine the differential expression of ERH at the protein level. The genetic alteration profile was obtained from the cBioPortal. The correlation between ERH expression and the quantities of immune infiltrating cells was examined by the TIMER tool. Spearman's correlation test was conducted to analyze the association between ERH expression status and a number of prognostic indicators, including immune checkpoints, TMB, MSI, immune neoantigen, MMR genes, and DNA methyltransferases. ProteinProtein Interaction analyses were performed in the String and GeneMANIA databases, and enrichment analysis and predicted signaling pathways were identified through GO and KEGG. To make our results convincing, we validated them in six datasets in the Gene Expression Omnibus (GEO) database. In addition, we verified the expression of ERH between gastric cancer tissues and adjacent normal tissues by RT-qPCR. RESULTS: ERH expression was elevated in numerous tumors, and it was not associated with the patient's prognosis. Furthermore, the quantities of immune infiltrating cells and immune checkpoint genes were remarkably associated with ERH. TMB and MSI were related to ERH expression in 14 and 15 cancer types, respectively. Moreover, the expression of ERH was strongly associated with MMR defects in multiple cancer types, and almost all tumors showed coexpression of ERH and four DNA methyltransferases. The results of GO and KEGG analysis confirmed that ERH potentially impacts several important signaling pathways. Both the GEO datasets and the RT-qPCR experiment validated our previous analysis. CONCLUSION: Our pan-cancer analysis demonstrated the characterization of ERH in multiple tumors. ERH may be a valuable novel biological indicator for assessing immunotherapy efficacy and prognosis in various malignancies.

15.
Cancer Res ; 84(10): 1719-1732, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38451249

RESUMO

Longitudinal monitoring of patients with advanced cancers is crucial to evaluate both disease burden and treatment response. Current liquid biopsy approaches mostly rely on the detection of DNA-based biomarkers. However, plasma RNA analysis can unleash tremendous opportunities for tumor state interrogation and molecular subtyping. Through the application of deep learning algorithms to the deconvolved transcriptomes of RNA within plasma extracellular vesicles (evRNA), we successfully predicted consensus molecular subtypes in patients with metastatic colorectal cancer. Analysis of plasma evRNA also enabled monitoring of changes in transcriptomic subtype under treatment selection pressure and identification of molecular pathways associated with recurrence. This approach also revealed expressed gene fusions and neoepitopes from evRNA. These results demonstrate the feasibility of using transcriptomic-based liquid biopsy platforms for precision oncology approaches, spanning from the longitudinal monitoring of tumor subtype changes to the identification of expressed fusions and neoantigens as cancer-specific therapeutic targets, sans the need for tissue-based sampling. SIGNIFICANCE: The development of an approach to interrogate molecular subtypes, cancer-associated pathways, and differentially expressed genes through RNA sequencing of plasma extracellular vesicles lays the foundation for liquid biopsy-based longitudinal monitoring of patient tumor transcriptomes.


Assuntos
Biomarcadores Tumorais , Vesículas Extracelulares , Perfilação da Expressão Gênica , Transcriptoma , Humanos , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Perfilação da Expressão Gênica/métodos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Biópsia Líquida/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neoplasias/sangue , Neoplasias/patologia
16.
Adv Sci (Weinh) ; 11(19): e2309990, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38477432

RESUMO

Menispermaceae species, as early-diverging eudicots, can synthesize valuable benzylisoquinoline alkaloids (BIAs) like bisbenzylisoquinoline alkaloids (bisBIAs) and sinomenines with a wide range of structural diversity. However, the evolutionary mechanisms responsible for their chemo-diversity are not well understood. Here, a chromosome-level genome assembly of Menispermum dauricum is presented and demonstrated the occurrence of two whole genome duplication (WGD) events that are shared by Ranunculales and specific to Menispermum, providing a model for understanding chromosomal evolution in early-diverging eudicots. The biosynthetic pathway for diverse BIAs in M. dauricum is reconstructed by analyzing the transcriptome and metabolome. Additionally, five catalytic enzymes - one norcoclaurine synthase (NCS) and four cytochrome P450 monooxygenases (CYP450s) - from M. dauricum are responsible for the formation of the skeleton, hydroxylated modification, and C-O/C-C phenol coupling of BIAs. Notably, a novel leaf-specific MdCYP80G10 enzyme that catalyzes C2'-C4a phenol coupling of (S)-reticuline into sinoacutine, the enantiomer of morphinan compounds, with predictable stereospecificity is discovered. Moreover, it is found that Menispermum-specific CYP80 gene expansion, as well as tissue-specific expression, has driven BIA diversity in Menispermaceae as compared to other Ranunculales species. This study sheds light on WGD occurrences in early-diverging eudicots and the evolution of diverse BIA biosynthesis.


Assuntos
Benzilisoquinolinas , Sistema Enzimático do Citocromo P-450 , Menispermaceae , Benzilisoquinolinas/metabolismo , Benzilisoquinolinas/química , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Menispermaceae/genética , Menispermaceae/metabolismo , Menispermaceae/química , Alcaloides/metabolismo , Filogenia , Evolução Molecular , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
17.
Microorganisms ; 12(3)2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38543614

RESUMO

African swine fever virus (ASFV) and porcine reproductive and respiratory syndrome virus (PRRSV) infections lead to severe respiratory diseases in pigs, resulting in significant economic losses for the global swine industry. While numerous studies have focused on specific gene functions or pathway activities during infection, an investigation of shared immune responses in porcine alveolar macrophages (PAMs) after ASFV and PRRSV infections was lacking. In this study, we conducted a comparison using two single-cell transcriptomic datasets generated from PAMs under ASFV and PRRSV infection. Pattern recognition receptors (PRRs) RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58) were identified as particularly recognizing ASFV and PRRSV, triggering cellular defense responses, including the upregulation of four cytokine families (CCL, CXCL, IL, and TNF) and the induction of pyroptosis. Through weighted gene co-expression network analysis and protein-protein interaction analysis, we identified thirteen gene and protein interactions shared by both scRNA-seq analyses, suggesting the ability to inhibit both ASFV and PRRSV viral replication. We discovered six proteins (PARP12, PARP14, HERC5, DDX60, RSAD2, and MNDA) in PAMs as inhibitors of ASFV and PRRSV replication. Collectively, our findings showed detailed characterizations of the immune responses in PAMs during ASFV and PRRSV infections, which may facilitate the treatments of these viral diseases.

18.
Front Plant Sci ; 15: 1363063, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38450408

RESUMO

Phellodendron amurense is the essential source of bisbenzylisoquinoline alkaloids (BIAs), making it a highly valued raw material in traditional Chinese medicine. The plant's root secondary metabolism is intricately linked to the microbial communities that surround it. However, the root-associated microbiomes of P. amurense, as well as the potential correlation between its bioactive compounds and these microbiomes, remain poorly understood. Here, the metabolic profiles of root, rhizosphere, and bulk soils of P. amurense revealed the dramatic differences in the relative content of plant-specialized metabolites. A total of 31, 21, and 0 specialized metabolites in P. amurense were identified in the root, rhizosphere soil, and bulk soil, respectively, with higher content of the seven major BIAs observed in the rhizosphere compared with that in the bulk soils. The composition of the bulk and rhizosphere microbiomes was noticeably distinct from that of the endospheric microbiome. The phylum Cyanobacteria accounted for over 60% of the root endosphere communities, and the α-diversity in root was the lowest. Targeted seven BIAs, namely, berberine, palmatine, magnocurarine, phellodendrine, jatrorrhizine, tetrahydropalmatine, and magnoflorine, were significantly positively correlated with Nectriaceae and Sphingobacteriaceae. This study has illuminated the intricate interaction networks between P. amurense root-associated microorganisms and their key chemical compounds, providing the theoretical foundation for discovering biological fertilizers and laying the groundwork for cultivating high-quality medicinal plants.

19.
Sensors (Basel) ; 24(6)2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38544249

RESUMO

Binocular structured light systems are widely used in 3D measurements. In the condition of complex and local highly reflective scenes, to obtain more 3D information, binocular systems are usually divided into two pairs of devices, each having a Single Camera and a Projector (SCP). In this case, the binocular system can be seen as Dual Cameras-Projector (DCP) system. In the DCP calibration, the Left-SCP and Right-SCP need to be calibrated separately, which leads to inconsistent parameters for the same projector, thus reducing the measurement accuracy. To solve this problem and improve manoeuvrability, a coupled calibration method using an orthogonal phase target is proposed. The 3D coordinates on a phase target are uniquely determined by the binocular camera in DCP, rather than being calculated separately in each SCP. This ensures the consistency of the projector parameters. The coordinates of the projector image plane are calculated through the unwrapped phase, while the parameters are calibrated by the plane calibration method. In order to extract sub-pixel accuracy feature points, a method based on polynomial fitting using an orthogonal phase target is exploited. The experimental results show that the reprojection error of our method is less than 0.033 pixels, which improves the calibration accuracy.

20.
Comput Struct Biotechnol J ; 23: 1106-1116, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38495554

RESUMO

Flavonoid glycosides are widespread in plants, and are of great interest owing to their diverse biological activities and effectiveness in preventing chronic diseases. Periploca forrestii, a renowned medicinal plant of the Apocynaceae family, contains diverse flavonoid glycosides and is clinically used to treat rheumatoid arthritis and traumatic injuries. However, the mechanisms underlying the biosynthesis of these flavonoid glycosides have not yet been elucidated. In this study, we used widely targeted metabolomics and full-length transcriptome sequencing to identify flavonoid diversity and biosynthetic genes in P. forrestii. A total of 120 flavonoid glycosides, including 21 C-, 96 O-, and 3 C/O-glycosides, were identified and annotated. Based on 24,123 full-length coding sequences, 99 uridine diphosphate sugar-utilizing glycosyltransferases (UGTs) were identified and classified into 14 groups. Biochemical assays revealed that four UGTs exhibited O-glycosyltransferase activity toward apigenin and luteolin. Among them, PfUGT74B4 and PfUGT92A8 were highly promiscuous and exhibited multisite O-glycosylation or consecutive glycosylation activities toward various flavonoid aglycones. These four glycosyltransferases may significantly contribute to the diversity of flavonoid glycosides in P. forrestii. Our findings provide a valuable genetic resource for further studies on P. forrestii and insights into the metabolic engineering of bioactive flavonoid glycosides.

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