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1.
Artigo em Inglês | MEDLINE | ID: mdl-38568400

RESUMO

The delayed titration of guideline-directed drug therapy (GDMT) is a complex event influenced by multiple factors that often result in poor prognosis for patients with heart failure (HF). Individualized adjustments in GDMT titration may be necessary based on patient characteristics, and every clinician is responsible for promptly initiating GDMT and titrating it appropriately within the patient's tolerance range. This review examines the current challenges in GDMT implementation and scrutinizes titration considerations within distinct subsets of HF patients, with the overarching goal of enhancing the adoption and effectiveness of GDMT. The authors also underscore the significance of establishing a novel management strategy that integrates cardiologists, nurse practitioners, pharmacists, and patients as a unified team that can contribute to the improved promotion and implementation of GDMT.

2.
Bioresour Bioprocess ; 11(1): 29, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38647930

RESUMO

Thermophilic endo-chitinases are essential for production of highly polymerized chitooligosaccharides, which are advantageous for plant immunity, animal nutrition and health. However, thermophilic endo-chitinases are scarce and the transformation from exo- to endo-activity of chitinases is still a challenging problem. In this study, to enhance the endo-activity of the thermophilic chitinase Chi304, we proposed two approaches for rational design based on comprehensive structural and evolutionary analyses. Four effective single-point mutants were identified among 28 designed mutations. The ratio of (GlcNAc)3 to (GlcNAc)2 quantity (DP3/2) in the hydrolysates of the four single-point mutants undertaking colloidal chitin degradation were 1.89, 1.65, 1.24, and 1.38 times that of Chi304, respectively. When combining to double-point mutants, the DP3/2 proportions produced by F79A/W140R, F79A/M264L, F79A/W272R, and M264L/W272R were 2.06, 1.67, 1.82, and 1.86 times that of Chi304 and all four double-point mutants exhibited enhanced endo-activity. When applied to produce chitooligosaccharides (DP ≥ 3), F79A/W140R accumulated the most (GlcNAc)4, while M264L/W272R was the best to produce (GlcNAc)3, which was 2.28 times that of Chi304. The two mutants had exposed shallower substrate-binding pockets and stronger binding abilities to shape the substrate. Overall, this research offers a practical approach to altering the cutting pattern of a chitinase to generate functional chitooligosaccharides.

3.
J Transl Med ; 22(1): 259, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461346

RESUMO

BACKGROUND: Amino acids (AAs) are one of the primary metabolic substrates for cardiac work. The correlation between AAs and both atrial fibrillation (AF) and aging has been documented. However, the relationship between AAs and age-related AF remains unclear. METHODS: Initially, the plasma AA levels of persistent AF patients and control subjects were assessed, and the correlations between AA levels, age, and other clinical indicators were explored. Subsequently, the age-related AF mouse model was constructed and the untargeted myocardial metabolomics was conducted to detect the level of AAs and related metabolites. Additionally, the gut microbiota composition associated with age-related AF was detected by a 16S rDNA amplicon sequencing analysis on mouse fecal samples. RESULTS: Higher circulation levels of lysine (Student's t-test, P = 0.001), tyrosine (P = 0.002), glutamic acid (P = 0.008), methionine (P = 0.008), and isoleucine (P = 0.014), while a lower level of glycine (P = 0.003) were observed in persistent AF patients. The feature AAs identified by machine learning algorithms were glutamic acid and methionine. The association between AAs and age differs between AF and control subjects. Distinct patterns of AA metabolic profiles were observed in the myocardial metabolites of aged AF mice. Aged AF mice had lower levels of Betaine, L-histidine, L-alanine, L-arginine, L-Pyroglutamic acid, and L-Citrulline compared with adult AF mice. Aged AF mice also presented a different gut microbiota pattern, and its functional prediction analysis showed AA metabolism alteration. CONCLUSION: This study provided a comprehensive network of AA disturbances in age-related AF from multiple dimensions, including plasma, myocardium, and gut microbiota. Disturbances of AAs may serve as AF biomarkers, and restoring their homeostasis may have potential benefits for the management of age-related AF.


Assuntos
Aminoácidos , Fibrilação Atrial , Adulto , Humanos , Animais , Camundongos , Idoso , Aminoácidos/metabolismo , Fibrilação Atrial/metabolismo , Metabolômica/métodos , Metionina , Glutamatos
4.
Microb Biotechnol ; 17(3): e14447, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38478376

RESUMO

Chicken coccidiosis is an intestinal disease caused by the parasite Eimeria, which severely damages the growth of chickens and causes significant economic losses in the poultry industry. Improvement of the immune protective effect of antigens to develop high efficiency subunit vaccines is one of the hotspots in coccidiosis research. Sporozoite-specific surface antigen 1 (SAG1) of Eimeria tenella (E. tenella) is a well-known protective antigen and is one of the main target antigens for the development of subunit, DNA and vector vaccines. However, the production and immunoprotective effects of SAG1 need to be further improved. Here, we report that both SAG1 from E. tenella and its fusion protein with the xylanase XynCDBFV-SAG1 are recombinant expressed and produced in Pichia pastoris (P. pastoris). The substantial expression quantity of fusion protein XynCDBFV-SAG1 is achieved through fermentation in a 15-L bioreactor, reaching up to about 2 g/L. Moreover, chickens immunized with the fusion protein induced higher protective immunity as evidenced by a significant reduction in the shedding of oocysts after E. tenella challenge infection compared with immunized with recombinant SAG1. Our results indicate that the xylanase enhances the immunogenicity of subunit antigens and has the potential for developing novel molecular adjuvants. The high expression level of fusion protein XynCDBFV-SAG1 in P. pastoris holds promise for the development of effective recombinant anti-coccidial subunit vaccine.


Assuntos
Coccidiose , Eimeria tenella , Saccharomycetales , Animais , Eimeria tenella/genética , Galinhas , Antígenos de Superfície , Antígenos de Protozoários/genética , Coccidiose/prevenção & controle , Coccidiose/veterinária , Proteínas Recombinantes/genética , Vacinas Sintéticas/genética
5.
Int J Cardiol ; : 131985, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38513736

RESUMO

Radiofrequency ablation (RFA) has been a central therapeutic strategy for ventricular tachycardia (VT). However, concerns about its long-term effectiveness and complications have arisen. Pulsed field ablation (PFA), characterized by its nonthermal, highly tissue-selective ablation technique, has emerged as a promising alternative. This comprehensive review delves into the potential advantages and opportunities presented by PFA in the realm of VT, drawing insights from both animal experimentation and clinical case studies. PFA shows promise in generating superior lesions within scarred myocardial tissue, and its inherent repetition dependency holds the potential to enhance therapeutic outcomes. Clinical cases underscore the promise of PFA for VT ablation. Despite its promising applications, challenges such as catheter maneuverability and proarrhythmic effects require further investigation. Large-scale, long-term studies are essential to establish the suitability of PFA for VT treatment.

6.
Bioresour Technol ; 398: 130538, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38452952

RESUMO

Advancement in commodity chemical production from carbon dioxide (CO2) offers a promising path towards sustainable development goal. Cupriavidus necator is an ideal host to convert CO2 into high-value chemicals, thereby achieving this target. Here, C. necator was engineered for heterotrophic and autotrophic production of L-isoleucine and L-valine. Citramalate synthase was introduced to simplify isoleucine synthesis pathway. Blocking poly-hydroxybutyrate biosynthesis resulted in significant accumulation of isoleucine and valine. Besides, strategies like key enzymes screening and overexpressing, reducing power balancing and feedback inhibition removing were applied in strain modification. Finally, the maximum isoleucine and valine titers of the best isoleucine-producing and valine-producing strains reached 857 and 972 mg/L, respectively, in fed-batch fermentation using glucose as substrate, and 105 and 319 mg/L, respectively, in autotrophic fermentation using CO2 as substrate. This study provides a feasible solution for developing C. necator as a microbial factory to produce amino acids from CO2.


Assuntos
Dióxido de Carbono , Cupriavidus necator , Dióxido de Carbono/metabolismo , Isoleucina , Cupriavidus necator/genética , Valina , Processos Autotróficos
7.
Heliyon ; 10(5): e27083, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38439838

RESUMO

Background: Observational studies have linked exposure to fine (PM2.5) and coarse (PM10) particulate matter air pollution with adverse COVID-19 outcomes, including higher incidence and mortality. However, some studies questioned the effect of air pollution on COVID-19 susceptibility, raising questions about the causal nature of these associations. To address this, a less biased method like Mendelian randomization (MR) is utilized, which employs genetic variants as instrumental variables to infer causal relationships in observational data. Method: We performed two-sample MR analysis using public genome-wide association studies data. Instrumental variables correlated with PM2.5 concentration, PM2.5 absorbance, PM2.5-10 concentration and PM10 concentration were identified. The inverse variance weighted (IVW), robust adjusted profile score (RAPS) and generalized summary data-based Mendelian randomization (GSMR) methods were used for analysis. Results: IVW MR analysis showed PM2.5 concentration [odd ratio (OR) = 3.29, 95% confidence interval (CI) 1.48-7.35, P-value = 0.0036], PM2.5 absorbance (OR = 5.62, 95%CI 1.98-15.94, P-value = 0.0012), and PM10 concentration (OR = 3.74, 95%CI 1.52-9.20, P-value = 0.0041) increased the risk of COVID-19 severity after Bonferroni correction. Further validation confirmed PM2.5 absorbance was associated with heightened COVID-19 severity (OR = 6.05, 95%CI 1.99-18.38, P-value = 0.0015 for RAPS method; OR = 4.91, 95%CI 1.65-14.59, P-value = 0.0042 for GSMR method) and hospitalization (OR = 3.15, 95%CI 1.54-6.47, P-value = 0.0018 for RAPS method). No causal links were observed between particulate matter exposure and COVID-19 susceptibility. Conclusions: Our study established a causal relationship between smaller particle pollution, specifically PM2.5, and increased risk of COVID-19 severity and hospitalization. These findings highlight the importance of improving air quality to mitigate respiratory disease progression.

8.
Ecotoxicol Environ Saf ; 273: 116130, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38394761

RESUMO

The manganese peroxidase (MnP) can degrade multiple mycotoxins including deoxynivalenol (DON) efficiently; however, the lignin components abundant in foods and feeds were discovered to interfere with DON catalysis. Herein, using MnP from Ceriporiopsis subvermispora (CsMnP) as a model, it was demonstrated that desired catalysis of DON, but not futile reactions with lignin, in the reaction systems containing feeds could be achieved by engineering MnP and supplementing with a boosting reactant. Specifically, two successive strategies (including the fusion of CsMnP to a DON-recognizing ScFv and identification of glutathione as a specific targeting enhancer) were combined to overcome the lignin competition, which together resulted into elevation of the degradation rate from 2.5% to as high as 82.7% in the feeds. The method to construct a targeting MnP and fortify it with an additional enhancer could be similarly applied to catalyze the many other mycotoxins with yet unknown responsive biocatalysts.


Assuntos
Lignina , Micotoxinas , Tricotecenos , Lignina/metabolismo , Peroxidases/metabolismo
9.
Angew Chem Int Ed Engl ; 63(13): e202318763, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38300154

RESUMO

The synthesis of mono-N-methylated aliphatic primary amines has traditionally been challenging, requiring noble metal catalysts and high-pressure H2 for achieving satisfactory yields and selectivity. Herein, we developed an approach for the selective coupling of methanol and aliphatic primary amines, without high-pressure hydrogen, using a manganese-based catalyst. Remarkably, up to 98 % yields with broad substrate scope were achieved at low catalyst loadings. Notably, due to the weak base-catalyzed alcoholysis of formamide intermediates, our novel protocol not only obviates the addition of high-pressure H2 but also prevents side secondary N-methylation, supported by control experiments and density functional theory calculations.

10.
Ecotoxicol Environ Saf ; 272: 116049, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38301584

RESUMO

Global concern exists regarding the contamination of food and animal feed with aflatoxin B1 (AFB1), which poses a threat to the health of both humans and animals. Previously, we found that a laccase from Bacillus subtilis (BsCotA) effectively detoxified AFB1 in a reaction mediated by methyl syringate (MS), although the underlying mechanism has not been determined. Therefore, our primary objective of this study was to explore the detoxification mechanism employed by BsCotA. First, the enzyme and mediator dependence of AFB1 transformation were studied using the BsCotA-MS system, which revealed the importance of MS radical formation during the oxidation process. Aflatoxin Q1 (AFQ1) resulting from the direct oxidation of AFB1 by BsCotA, was identified using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The results of UPLC-MS/MS and density functional theory calculations indicated that the products included AFQ1, AFB1-, and AFD1-MS-coupled products in the BsCotA-MS system. The toxicity evaluations revealed that the substances derived from the transformation of AFB1 through the BsCotA-MS mechanism exhibited markedly reduced toxicity compared to AFB1. Finally, we proposed a set of different AFB1-transformation pathways generated by the BsCotA-MS system based on the identified products. These findings greatly enhance the understanding of the AFB1-transformation mechanism of the laccase-mediator system.


Assuntos
Aflatoxina B1 , Ácido Gálico/análogos & derivados , Lacase , Humanos , Aflatoxina B1/toxicidade , Aflatoxina B1/química , Cromatografia Líquida , Espectrometria de Massas em Tandem
11.
Scand J Med Sci Sports ; 34(2): e14582, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38349064

RESUMO

BACKGROUND: Due to inconclusive evidence from observational studies regarding the impact of physical activity (PA) and sedentary behavior on frailty and falling risk, we conducted a two-sample Mendelian randomization analysis to investigate the causal associations between PA, sedentary behavior, and frailty and falls. METHODS: We extracted summary data from genome-wide association studies conducted among individuals of European ancestry, encompassing PA (n = 90 667-608 595), sedentary behavior (n = 372 609-526 725), frailty index (n = 175 226), and falling risk (n = 451 179). Single nucleotide polymorphisms associated with accelerometer assessed fraction >425 milligravities, self-reported vigorous activity, moderate to vigorous physical acticity (MVPA), leisure screen time (LST), and sedentary behavior at work were taken as instrumental variables. The causal effects were primarily estimated using inverse variance weighted methods, complemented by several sensitivity and validation analyses. RESULTS: Genetically predicted higher levels of PA were significantly associated with a reduction in the frailty index (accelerometer assessed fraction >425 milligravities: ß = -0.25, 95% CI = -0.36 to -0.14, p = 1.27 × 10-5 ; self-reported vigorous activity: ß = -0.13, 95% CI = -0.20 to -0.05, p = 7.9 × 10-4 ; MVPA: ß = -0.28, 95% CI = -0.40 to -0.16, p = 9.9 × 10-6 ). Besides, LST was significantly associated with higher frailty index (ß = 0.18, 95% CI = 0.14-0.22, p = 5.2 × 10-20 ) and higher odds of falling (OR = 1.13, CI = 1.07-1.19, p = 6.9 × 10-6 ). These findings remained consistent throughout sensitivity and validation analyses. CONCLUSIONS: Our study offers evidence supporting a causal relationship between PA and a reduced risk of frailty. Furthermore, it underscores the association between prolonged LST and an elevated risk of frailty and falls. Therefore, promoting PA and reducing sedentary behavior may be an effective strategy in primary frailty and falls prevention.


Assuntos
Fragilidade , Humanos , Fragilidade/genética , Fragilidade/prevenção & controle , Comportamento Sedentário , Análise da Randomização Mendeliana , Estudo de Associação Genômica Ampla , Acidentes por Quedas , Exercício Físico
12.
J Agric Food Chem ; 72(8): 3833-3845, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38285533

RESUMO

The acquisition of a thermostable enzyme is an indispensable prerequisite for its successful implementation in industrial applications and the development of novel functionalities. Various protein engineering approaches, including rational design, semirational design, and directed evolution, have been employed to enhance thermostability. However, all of these approaches require sensitive and reliable high-throughput screening (HTS) technologies to efficiently and rapidly identify variants with improved properties. While numerous reviews focus on modification strategies for enhancing enzyme thermostability, there is a dearth of literature reviewing HTS methods specifically aimed at this objective. Herein, we present a comprehensive overview of various HTS methods utilized for modifying enzyme thermostability across different screening platforms. Additionally, we highlight significant recent examples that demonstrate the successful application of these methods. Furthermore, we address the technical challenges associated with HTS technologies used for screening thermostable enzyme variants and discuss valuable perspectives to promote further advancements in this field. This review serves as an authoritative reference source offering theoretical support for selecting appropriate screening strategies tailored to specific enzymes with the aim of improving their thermostability.


Assuntos
Ensaios de Triagem em Larga Escala , Engenharia de Proteínas , Ensaios de Triagem em Larga Escala/métodos , Engenharia de Proteínas/métodos , Enzimas , Estabilidade Enzimática
13.
Bioresour Technol ; 394: 130177, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38072076

RESUMO

Utilizing thermostable enzymes in biomass conversion processes presents a promising approach to bypass pretreatment, garnering significant attention from the biorefinery industry. A novel discovered α-l-arabinofuranosidase, Abf4980, exhibits exceptional thermostability by maintaining full activity after 24 h of incubation at 70 °C. It effectively acts on polyarabinosides, cleaving α-1,2- and α-1,3-linked arabinofuranose side chains from water-soluble wheat arabinoxylan while releasing xylose. When synergistically combined with the thermostable bifunctional xylanase/ß-glucanase CbXyn10C from Caldicellulosiruptor bescii at an enzyme-activity ratio of 6:1, Abf4980 achieves the highest degradation efficiency for wheat arabinoxylan. Furthermore, Abf4980 and CbXyn10C demonstrated remarkable efficacy in hydrolyzing unmodified wheat bran and corn cob to generate arabinose and xylooligosaccharides. This discovery holds promising opportunities for improving the efficiency of lignocellulosic biomass conversion into fermentable sugars.


Assuntos
Glicosídeo Hidrolases , Xilanos , Hidrólise , Biomassa , Glicosídeo Hidrolases/metabolismo , Xilanos/metabolismo , Clostridiales/metabolismo
14.
Enzyme Microb Technol ; 174: 110379, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38103484

RESUMO

γ-Aminobutyric acid (GABA) has been widely used in the food, feed, pharmaceutical, and chemical industry fields. Previously, we developed a whole-cell catalyst capable of converting L-glutamate (L-Glu) into GABA by overexpressing the glutamate decarboxylase gene (gadz11) from Bacillus sp. Z11 in Escherichia coli BL21(DE3). However, to enhance cell permeability, a freeze-thaw treatment is required, and to enhance GADZ11 activity, pyridoxal 5'-phosphate (PLP) must be added to the reaction system. The aim of this study is to provide a more efficient approach for GABA production by engineering the recombinant E. coli above. First, the inducible expression conditions of the gadz11 in E. coli were optimized to 37 °C for 6 h. Next, an ideal engineered strain was produced via increasing cell permeability by overexpressing sulA and eliminating PLP dependence by constructing a self-sufficient system. Furthermore, an efficient whole-cell biocatalytic process was optimized. The optimal substrate concentration, cell density, and reaction temperature were 1.0 mol/L (the molecular ratio of L-Glu to L-monosodium glutamate (L-MSG) was 4:1), 15 and 37 °C, respectively. Finally, a whole-cell bioconversion procedure was performed in a 3-L bioreactor under optimal conditions. The strain could be reused for at least two cycles with GABA yield, productivity and conversion ratio of 206.2 g/L, 117.8 g/L/h and 100.0%, respectively. This is currently the highest GABA productivity from a mixture of L-Glu and L-MSG reported without the addition of cofactors or additional treatment of cells. This work demonstrates that the novel engineered E. coli strain has the potential for application in large-scale industrial GABA production.


Assuntos
Escherichia coli , Glutamato de Sódio , Escherichia coli/genética , Escherichia coli/metabolismo , Glutamato de Sódio/metabolismo , Fosfato de Piridoxal/metabolismo , Ácido gama-Aminobutírico , Glutamato Descarboxilase/genética
15.
PLoS One ; 18(11): e0294282, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37956134

RESUMO

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the clinic. Aging plays an essential role in the occurrence and development of AF. Herein, we aimed to identify the aging-related genes associated with AF using bioinformatics analysis. Transcriptome profiles of AF were obtained from the GEO database. Differential expression analysis was performed to identify AF-specific aging-related genes. GO and KEGG enrichment analyses were performed. Subsequently, the LASSO, SVM-RFE, and MCC algorithms were applied to screen aging-related genes. The mRNA expression of the screened genes was validated in the left atrial samples of aged rapid atrial pacing-induced AF canine models and their counterparts. The ROC curves of them were drawn to evaluate their diagnostic potential. Moreover, CIBERSORT was used to estimate immune infiltration. A correlation analysis between screened aging-related genes and infiltrating immune cells was performed. A total of 24 aging-related genes were identified, which were found to be mainly involved in the FoxO signaling pathway, PI3K-Akt signaling pathway, longevity regulating pathway, and peroxisome according to functional enrichment analysis. LASSO, SVM-RFE, and MCC algorithms identified three genes (HSPA9, SOD2, TXN). Furthermore, the expression levels of HSPA9 and SOD2 were validated in aged rapid atrial pacing-induced AF canine models. HSPA9 and SOD2 could be potential diagnostic biomarkers for AF, as evidenced by the ROC curves. Immune infiltration and correlation analysis revealed that HSPA9 and SOD2 were related to immune cell infiltrates. Collectively, these findings provide novel insights into the potential aging-related genes associated with AF. HSPA9 and SOD2 may play a significant role in the occurrence and development of AF.


Assuntos
Fibrilação Atrial , Animais , Cães , Fibrilação Atrial/genética , Fosfatidilinositol 3-Quinases , Envelhecimento/genética , Doença do Sistema de Condução Cardíaco , Longevidade
16.
bioRxiv ; 2023 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-37986848

RESUMO

Artificial intelligence (AI) has been used in many areas of medicine, and recently large language models (LLMs) have shown potential utility for clinical applications. However, since we do not know if the use of LLMs can accelerate the pace of genetic discovery, we used data generated from mouse genetic models to investigate this possibility. We examined whether a recently developed specialized LLM (Med-PaLM 2) could analyze sets of candidate genes generated from analysis of murine models of biomedical traits. In response to free-text input, Med-PaLM 2 correctly identified the murine genes that contained experimentally verified causative genetic factors for six biomedical traits, which included susceptibility to diabetes and cataracts. Med-PaLM 2 was also able to analyze a list of genes with high impact alleles, which were identified by comparative analysis of murine genomic sequence data, and it identified a causative murine genetic factor for spontaneous hearing loss. Based upon this Med-PaLM 2 finding, a novel bigenic model for susceptibility to spontaneous hearing loss was developed. These results demonstrate Med-PaLM 2 can analyze gene-phenotype relationships and generate novel hypotheses, which can facilitate genetic discovery.

17.
Brief Bioinform ; 24(6)2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37870286

RESUMO

The advanced language models have enabled us to recognize protein-protein interactions (PPIs) and interaction sites using protein sequences or structures. Here, we trained the MindSpore ProteinBERT (MP-BERT) model, a Bidirectional Encoder Representation from Transformers, using protein pairs as inputs, making it suitable for identifying PPIs and their respective interaction sites. The pretrained model (MP-BERT) was fine-tuned as MPB-PPI (MP-BERT on PPI) and demonstrated its superiority over the state-of-the-art models on diverse benchmark datasets for predicting PPIs. Moreover, the model's capability to recognize PPIs among various organisms was evaluated on multiple organisms. An amalgamated organism model was designed, exhibiting a high level of generalization across the majority of organisms and attaining an accuracy of 92.65%. The model was also customized to predict interaction site propensity by fine-tuning it with PPI site data as MPB-PPISP. Our method facilitates the prediction of both PPIs and their interaction sites, thereby illustrating the potency of transfer learning in dealing with the protein pair task.


Assuntos
Aprendizado de Máquina , Proteínas , Proteínas/química , Sequência de Aminoácidos
18.
Bioresour Technol ; 390: 129883, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37871741

RESUMO

Capsaicinoids are mostly derived from chili peppers and have widespread applications in food, feed, and pharmacology. Compared with plant extraction, the use of microbial cell factories for capsaicinoids production is considered as a more efficient approach. Here, the biotransformation of renewable plant oil and vanillylamine into capsaicinoid nonivamide was investigated. Nonivamide biosynthesis using nonanoic acid and vanillylamine as substrates was achieved in Escherichia coli by heterologous expression of genes encoding amide-forming N-acyltransferase and CoA-ligase. Through increasing nonanoic acid tolerance of chassis cell, screening key enzymes involved in nonivamide biosynthesis and optimizing biotransformation conditions, the nonivamide titer reached 0.5 g/L. By further integrating a route for conversion of oleic acid to nonanoic acid, nonivamide biosynthesis was finally achieved using olive oil and vanillylamine as substrates, yielding a titer of approximately 10.7 mg/L. Results from this study provide valuable information for constructing highly efficient cell factories for the production of capsaicinoid compounds.


Assuntos
Frutas , Óleos de Plantas , Óleos de Plantas/metabolismo , Biotransformação , Frutas/metabolismo
19.
Sci Rep ; 13(1): 17548, 2023 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-37845390

RESUMO

Atrial fibrillation (AF) and related cardiovascular complications pose a heavy burden to patients and society. Mounting evidence suggests a close association between nonalcoholic fatty liver disease (NAFLD) and AF. NAFLD and AF transcriptomic datasets were obtained from GEO database and analyzed using several bioinformatics approaches. We established a NAFLD-AF associated gene diagnostic signature (NAGDS) using protein-protein interaction analysis and machine learning, which was further quantified through RT-qPCR. Potential miRNA targeting NAGDS were predicted. Gene modules highly correlated with NAFLD liver pathology or AF occurrence were identified by WGCNA. Enrichment analysis of the overlapped genes from key module revealed that T-cell activation plays essential roles in NAFLD and AF, which was further confirmed by immune infiltration. Furthermore, an integrated SVM-RFE and LASSO algorithm was used to identify CCL4, CD48, ITGB2, and RNASE6 as NAGDS, all of which were found to be upregulated in NAFLD and AF mouse tissues. Patients with higher NAGDS showed augmented T cell and macrophage immunity, more advanced liver pathological characteristics, and prolonged AF duration. Additionally, hsa-miR-26a-5p played a central role in the regulation of NAGDS. Our findings highlight the central role of T-cell immune response in linking NAFLD to AF, and established an accurate NAGDS diagnostic model, which could serve as potential targets for immunoregulatory therapy.


Assuntos
Fibrilação Atrial , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Humanos , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/complicações , Fibrilação Atrial/diagnóstico , Transcriptoma , MicroRNAs/genética
20.
J Am Heart Assoc ; 12(20): e029397, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37804190

RESUMO

Background There are limited data on low-density lipoprotein cholesterol (LDL-C) goal achievement per the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidemia management guidelines and its impact on long-term outcomes in patients undergoing coronary artery bypass grafting (CABG). We investigated the association between LDL-C levels attained 1 year after CABG and the long-term outcomes. Methods and Results A total of 2072 patients diagnosed with multivessel coronary artery disease and undergoing CABG between 2011 and 2020 were included. Patients were categorized by lipid levels at 1 year after CABG, and the occurrence of major adverse cardiovascular and cerebrovascular events (MACCEs) was evaluated. The goal of LDL-C <1.40 mmol/L was attained in only 310 patients (14.9%). During a mean follow-up of 4.2 years after the index 1-year assessment, 25.0% of the patients experienced MACCEs. Multivariable-adjusted hazard ratios (95% CIs) for MACCEs, cardiac death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and cardiac rehospitalization were 1.94 (1.41-2.67), 2.27 (1.29-3.99), 2.45 (1.55-3.88), 1.17 (0.63-2.21), 2.47 (1.31-4.66), and 1.87 (1.19-2.95), respectively, in patients with LDL-C ≥2.60 mmol/L, compared with patients with LDL-C <1.40 mmol/L. The LDL-C levels at 1-year post-CABG were independently associated with long-term MACCEs. Conclusions This retrospective analysis demonstrates that lipid goals are not attained in the vast majority of patients at 1 year after CABG, which is independently associated with the increased risk of long-term MACCEs. Further prospective, multicenter studies are warranted to validate if intensive lipid management could improve the outcomes of patients undergoing CABG.


Assuntos
Doença da Artéria Coronariana , Dislipidemias , Intervenção Coronária Percutânea , Humanos , Estudos Retrospectivos , LDL-Colesterol , Resultado do Tratamento , Ponte de Artéria Coronária/efeitos adversos , Doença da Artéria Coronariana/cirurgia , Doença da Artéria Coronariana/etiologia , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia
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