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Seneca virus A (SVA) is an emerging novel picornavirus that has recently been identified as the causative agent of many cases of porcine vesicular diseases in multiple countries. In addition to cleavage of viral polyprotein, the viral 3C protease (3Cpro) plays an important role in the regulation of several physiological processes involved in cellular antiviral responses by cleaving critical cellular proteins. Through a combination of crystallography, untargeted lipidomics, and immunoblotting, we identified the association of SVA 3Cpro with an endogenous phospholipid molecule, which binds to a unique region neighboring the proteolytic site of SVA 3Cpro. Our lipid-binding assays showed that SVA 3Cpro displayed preferred binding to cardiolipin (CL), followed by phosphoinositol-4-phosphate (PI4P) and sulfatide. Importantly, we found that the proteolytic activity of SVA 3Cpro was activated in the presence of the phospholipid, and the enzymatic activity is inhibited when the phospholipid-binding capacity decreased. Interestingly, in the wild-type SVA 3Cpro-substrate peptide structure, the cleavage residue cannot form a covalent binding to the catalytic cysteine residue to form the acyl-enzyme intermediate observed in several picornaviral 3Cpro structures. We observed a decrease in infectivity titers of SVA mutants harboring mutations that impaired the lipid-binding ability of 3Cpro, indicating a positive regulation of SVA infection capacity mediated by phospholipids. Our findings reveal a mutual regulation between the proteolytic activity and phospholipid-binding capacity in SVA 3Cpro, suggesting that endogenous phospholipid may function as an allosteric activator that regulate the enzyme's proteolytic activity during infection.
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Cisteína Endopeptidases , Picornaviridae , Animais , Suínos , Cisteína Endopeptidases/metabolismo , Proteases Virais 3C/metabolismo , Peptídeo Hidrolases/metabolismo , Regulação Alostérica , Fosfolipídeos , Proteínas Virais/metabolismoRESUMO
Despite the synthetic versatility of difluorocarbene, its high reactivity severely regulates widespread applications of difluorocarbene in organic synthesis. Here, we report a copper difluorocarbene-involved catalytic coupling, representing a new mode of the difluoromethylation reaction. This method allows difluoromethylation of a wide range of readily available allyl/propargyl electrophiles with NaBH3CN and low-cost difluorocarbene precursor BrCF2CO2K, featuring high cost-efficiency, high stereo- and regioselectivities, and high functional group tolerance, even with complex drug-like molecules. Applying the method led to the efficient synthesis of deuterated difluoromethylated compounds of medicinal interest. The resulting difluoromethylated allyl and allenyl products can serve as versatile synthons for diverse transformations, rendering the approach attractive for synthesizing complex fluorinated structures. Experimental mechanistic studies and computational calculations reveal that the formation of a difluoromethylcopper(I) intermediate through the nucleophilic attack of boron hydride on the copper(I) difluorocarbene is the key step in the reaction.
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Mounting evidence suggests a strong association between tumor immunity and epigenetic regulation. The histone-lysine N-methyltransferase 2 (KMT2) family plays a crucial role in the methylation of histone H3 at lysine 4. By influencing chromatin structure and DNA accessibility, this modification serves as a key regulator of tumor progression and immune tolerance across various tumors. These findings highlight the potential significance of the KMT2 family in determining response to immune checkpoint inhibitor (ICI) therapy, which warrants further exploration. In this study, we integrated four ICI-treated cohorts (n = 2069) across 10 cancer types and The Cancer Genome Atlas pan-cancer cohort and conducted a comprehensive clinical and bioinformatic analysis. Our study indicated that patients with KMT2 family gene mutations benefited more from ICI therapy in terms of overall survival (P < 0.001, hazard ratio [HR] = 0.733 [95% confidence interval (CI): 0.632-0.850]), progression-free survival (P = 0.002, HR = 0.669 [95% CI: 0.518-0.864]), durable clinical benefit (P < 0.001, 54.1% vs. 32.6%), and objective response rate (P < 0.001, 40.6% vs. 22.0%). Through a comprehensive analysis of the tumor microenvironment across different KMT2 mutation statuses, we observed that tumors harboring the KMT2 mutation exhibited enhanced immunogenicity, increased infiltration of immune cells, and higher levels of immune cell cytotoxicity, suggesting a propensity towards a "hot tumor" phenotype. Therefore, our study indicates a potential association between KMT2 mutations and a more favorable response to ICI therapy and implicates different tumor microenvironments associated with ICI therapy response.
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Epigênese Genética , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Microambiente Tumoral , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
Cuproptosis, a newly characterized form of regulated cell death driven by copper accumulation, has emerged as a significant mechanism underlying various non-cancerous diseases. This review delves into the complex interplay between copper metabolism and the pathogenesis of conditions such as Wilson's disease (WD), neurodegenerative disorders, and cardiovascular pathologies. We examine the molecular mechanisms by which copper dysregulation induces cuproptosis, highlighting the pivotal roles of key copper transporters and enzymes. Additionally, we evaluate the therapeutic potential of copper chelation strategies, which have shown promise in experimental models by mitigating copper-induced cellular damage and restoring physiological homeostasis. Through a comprehensive synthesis of recent advancements and current knowledge, this review underscores the necessity of further research to translate these findings into clinical applications. The ultimate goal is to harness the therapeutic potential of targeting cuproptosis, thereby improving disease management and patient outcomes in non-cancerous conditions associated with copper dysregulation.
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Efficient electrocatalysts capable of operating continuously at industrial ampere-level current densities are crucial for large-scale applications of electrocatalytic water decomposition for hydrogen production. However, long-term industrial overall water splitting using a single electrocatalyst remains a major challenge. Here, bimetallic polyphthalocyanine (FeCoPPc)-anchored Ru nanoclusters, an innovative electrocatalyst comprising the hydrogen evolution reaction (HER) active Ru and the oxygen evolution reaction (OER) active FeCoPPc, engineered for efficient overall water splitting are demonstrated. By density functional theory calculations and systematic experiments, the electrocatalytic coenhancement effect resulting from unique charge redistribution, which synergistically boosts the HER activity of Ru and the OER activity of FeCoPPc by optimizing the adsorption energy of intermediates, is unveiled. As a result, even at a large current density of 2.0 A cm-2 , the catalyst exhibits low overpotentials of 220 and 308 mV, respectively, for HER and OER. It exhibits excellent stability, requiring only 1.88 V of cell voltage to achieve a current density of 2.0 A cm-2 in a 6.0 m KOH electrolyte at 70 °C, with a remarkable operational stability of over 100 h. This work provides a new electrocatalytic coenhancement strategy for the design and synthesis of electrocatalyst, paving the way for industrial-scale overall water splitting applications.
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Copper plays vital roles in numerous cellular processes and its imbalance can lead to oxidative stress and dysfunction. Recent research has unveiled a unique form of copper-induced cell death, termed cuproptosis, which differs from known cell death mechanisms. This process involves the interaction of copper with lipoylated tricarboxylic acid cycle enzymes, causing protein aggregation and cell death. Recently, a growing number of studies have explored the link between cuproptosis and cancer development. This review comprehensively examines the systemic and cellular metabolism of copper, including tumor-related signaling pathways influenced by copper. It delves into the discovery and mechanisms of cuproptosis and its connection to various cancers. Additionally, the review suggests potential cancer treatments using copper ionophores that induce cuproptosis, in combination with small molecule drugs, for precision therapy in specific cancer types.
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Cobre , Neoplasias , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Cobre/metabolismo , Animais , Transdução de Sinais , Morte CelularRESUMO
BACKGROUND: Nosocomial infections caused by Serratia marcescens mostly occurred in pediatrics and it was very rarely reported after adult surgery. Here, an intracranial abscess caused by Serratia marcescens was reported. We report a rare case of a postoperative intracranial abscess caused by Serratia marcescens in a 63-year-old male patient with a left parietal mass. The patient underwent resection of the mass on June 1, 2022, and the postoperative pathology revealed an angiomatous meningioma, WHO I. He then experienced recurrent worsening of right limb movements, and repeated cranial CT scans showed oozing blood and obvious low-density shadows around the operation area. Delayed wound healing was considered. Subsequently, a large amount of pus was extracted from the wound. The etiological test showed that Serratia marcescens infection occurred before the removal of the artificial titanium mesh. Antibiotics were initiated based on the results of drug susceptibility tests. At present, the patient is recovering well and is still closely monitored during follow-up. CONCLUSION: It is rare for Serratia marcescens to cause brain abscesses without any obvious signs of infection. This report provided in detail our experience of a warning postoperative asymptomatic brain abscess caused by an uncommon pathogen.
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Abscesso Encefálico , Infecção Hospitalar , Adulto , Masculino , Humanos , Criança , Pessoa de Meia-Idade , Serratia marcescens , Antibacterianos/uso terapêutico , Abscesso Encefálico/diagnóstico , Período Pós-OperatórioRESUMO
Contamination of small-sized plastics is recognized as a factor of global change. Nanoplastics (NPs) can readily enter organisms and pose significant ecological risks. Arbuscular mycorrhizal (AM) fungi are the most ubiquitous and impactful plant symbiotic fungi, regulating essential ecological functions. Here, we first found that an AM fungus, Rhizophagus irregularis, increased lettuce shoot biomass by 25-100% when exposed to positively and negatively charged NPs vs control, although it did not increase that grown without NPs. The stress alleviation was attributed to the upregulation of gene expressions involving phytohormone signaling, cell wall metabolism, and oxidant scavenging. Using a root organ-fungus axenic growth system treated with fluorescence-labeled NPs, we subsequently revealed that the hyphae captured NPs and further delivered them to roots. NPs were observed at the hyphal cell walls, membranes, and spore walls. NPs mediated by the hyphae were localized at the root epidermis, cortex, and stele. Hyphal exudates aggregated positively charged NPs, thereby reducing their uptake due to NP aggregate formation (up to 5000 nm). This work demonstrates the critical roles of AM fungus in regulating NP behaviors and provides a potential strategy for NP risk mitigation in terrestrial ecosystems. Consequent NP-induced ecological impacts due to the affected AM fungi require further attention.
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Micorrizas , Micorrizas/metabolismo , Microplásticos , Raízes de Plantas/metabolismo , Raízes de Plantas/microbiologia , Hifas , Ecossistema , Expressão GênicaRESUMO
Acute oral toxicity is currently not available for most polycyclic aromatic hydrocarbons (PAHs), especially their derivatives, because it is cost-prohibitive to experimentally determine all of them. Here, quantitative structure-activity relationship (QSAR) models using machine learning (ML) for predicting the toxicity of PAH derivatives were developed, based on oral toxicity data points of 788 individual substances of rats. Both the individual ML algorithm gradient boosting regression trees (GBRT) and the stacking ML algorithm (extreme gradient boosting + GBRT + random forest regression) provided the best prediction results with satisfactory determination coefficients for both cross-validation and the test set. It was found that those PAH derivatives with fewer polar hydrogens, more large-sized atoms, more branches, and lower polarizability have higher toxicity. Software based on the optimal ML-QSAR model was successfully developed to expand the application potential of the developed model, obtaining reliable prediction of pLD50 values and reference doses for 6893 external PAH derivatives. Among these chemicals, 472 were identified as moderately or highly toxic; 10 out of them had clear environment detection or use records. The findings provide valuable insights into the toxicity of PAHs and their derivatives, offering a standard platform for effectively evaluating chemical toxicity using ML-QSAR models.
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OBJECTIVES: Patients with hemifacial spasm (HFS) often resort to botulinum toxin injections or microvascular decompression surgery when medication exhibits limited effectiveness. This study aimed to identify MRI and demographic factors associated with poor drug response at an early stage in patients with HFS. METHODS: We retrospectively included patients with HFS who underwent pre-therapeutic MRI examination. The presence, location, severity, and the offending vessels of neurovascular compression were blindly evaluated using MRI. Drug responses and clinical data were obtained from the medical notes or phone follow-ups. Logistic regression analysis was performed to identify potential factors. RESULTS: A total of 116 patients were included, with an average age at the time of first examination of 50.4 years and a median duration of onset of 18 months. Forty-nine (42.2%) patients reported no symptom relief. Thirty-seven (31.9%) patients reported poor symptom relief. Twenty-two (19.0%) patients reported partial symptom relief. Eight (6.9%) patients achieved complete symptom relief. The factors that were statistically significant associated with poor drug responses were contact in the attach segment of the facial nerve and aged 70 and above, with an odds ratio of 7.772 (p = 0.002) and 0.160 (p = 0.028), respectively. CONCLUSIONS: This study revealed that mild compression in the attach segment of the facial nerve in pre-therapeutic MRI increases the risk of poor drug responses in patients with HFS, while patients aged 70 and above showed a decreased risk. These findings may assist clinician to choose optimal treatment at an early stage.
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Espasmo Hemifacial , Imageamento por Ressonância Magnética , Humanos , Espasmo Hemifacial/tratamento farmacológico , Espasmo Hemifacial/diagnóstico por imagem , Espasmo Hemifacial/cirurgia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Adulto , Fármacos Neuromusculares/administração & dosagem , Fármacos Neuromusculares/uso terapêutico , Resultado do Tratamento , Nervo Facial/diagnóstico por imagem , Nervo Facial/fisiopatologiaRESUMO
Long noncoding RNAs (lncRNAs) are important regulators of bone metabolism. In this study, lncRNA microarray analysis was used to identify differentially expressed lncRNAs in differentiated osteoclasts. lncRNA-Gm5532 is highly expressed during osteoclast differentiation. lncRNA-Gm5532 knockdown impairs osteoclast formation and bone resorption. Mechanistic experiments show that lncRNA-Gm5532 functions as a competing endogenous RNA (ceRNA) and acts as a sponge for miR-125a-3p, which promotes TNF receptor-associated factor 6 (TRAF6) expression. miR-125a-3p mimics suppress osteoclast differentiation and TAK1/NF-κB/MAPK signaling. The miR-125a-3p inhibitor reverses the negative effects of siGm5532 on osteoclast differentiation. In summary, our study reveals that lncRNA-Gm5532 functions as an activator in osteoclast differentiation by targeting the miR-125a-3p/TRAF6 axis, making it a novel biomarker and potential therapeutic target for osteoporosis.
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Reabsorção Óssea , MicroRNAs , RNA Longo não Codificante , Humanos , MicroRNAs/metabolismo , Osteoclastos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismoRESUMO
Triazine herbicides are common contaminants in coastal waters, and they are recognized as inhibitors of photosystem II, causing significant hinderance to the growth and reproduction of phytoplankton. However, the influence of these herbicides on microalgal toxin production remains unclear. This study aimed to examine this relationship by conducting a comprehensive physiological and 4D label-free quantitative proteomic analysis on the harmful dinoflagellate Karenia mikimotoi in the presence of the triazine herbicide dipropetryn. The findings demonstrated a significant decrease in photosynthetic activity and pigment content, as well as reduced levels of unsaturated fatty acids, reactive oxygen species (ROS), and hemolytic toxins in K. mikimotoi when exposed to dipropetryn. The proteomic analysis revealed a down-regulation in proteins associated with photosynthesis, ROS response, and energy metabolism, such as fatty acid biosynthesis, chlorophyll metabolism, and nitrogen metabolism. In contrast, an up-regulation of proteins related to energy-producing processes, such as fatty acid ß-oxidation, glycolysis, and the tricarboxylic acid cycle, was observed. This study demonstrated that dipropetryn disrupts the photosynthetic systems of K. mikimotoi, resulting in a notable decrease in algal toxin production. These findings provide valuable insights into the underlying mechanisms of toxin production in toxigenic microalgae and explore the potential effect of herbicide pollution on harmful algal blooms in coastal environments.
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Dinoflagellida , Herbicidas , Microalgas , Espécies Reativas de Oxigênio/metabolismo , Proteômica , Dinoflagellida/metabolismo , Proliferação Nociva de Algas , Fotossíntese , Herbicidas/metabolismo , Ácidos Graxos/metabolismo , Triazinas/toxicidade , Triazinas/metabolismoRESUMO
Three novel diterpenoid alkaloids, comprising two C19 -diterpenoid alkaloids (1 and 2) and one C20 -diterpenoid alkaloid (3), were isolated from Delphinium ajacis, alongside the six known compoundsâ (4-9). Their structures were elucidated by spectroscopic methods (MS, UV, IR, 1D and 2D NMR) and chemical properties. Simultaneously, the anti-inflammatory properties of all compoundsâ (1-9) was conducted, focusing on nitric oxide (NO) production in LPS-induced BV-2 cells. The results indicated compoundsâ 1-3, 7, and 8 have potential anti-inflammatory activity.
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Alcaloides , Delphinium , Diterpenos , Delphinium/química , Espectroscopia de Ressonância Magnética , Alcaloides/farmacologia , Alcaloides/química , Diterpenos/farmacologia , Diterpenos/química , Anti-Inflamatórios/farmacologia , Estrutura MolecularRESUMO
This study explored the biosynthesis of bufadienolides(BDs) in Bufo bufo gargarizans to solve the dilemma of the decreasing resources of B. bufo gargarizans and provide a theoretical basis for the sustainable utilization of the resources. Ultra-high performance liquid chromatography-Orbitrap-mass spectrometry(UHPLC-Orbitrap-MS) was employed to detect the synthesis sites of BDs in B. bufo gargarizans, and the results were verified by desorption electrospray ionization-mass spectrometry imaging(DESI-MSI) and homogenate incubation experiments. BDs in B. bufo gargarizans had the highest content in the liver and the highest concentration in the gallbladder, in addition to the parotid gland and skin, which suggested that the liver could synthesize BDs. The results of DESI-MSI also showed that BDs were mainly enriched in the liver rather than the immature parotid gland. The incubation experiment of liver homogenates demonstrated the liver of B. bufo gargarizans had the ability to synthesize BDs. This study showed that the liver was a major organ for the synthesis of BDs in B. bufo gargarizans during metamorphosis, development, and growth, which provided strong theoretical support for the biosynthesis of BDs and the sustainable utilization of B. bufo gargarizans resources.
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Bufanolídeos , Animais , Bufo bufo , Distribuição Tecidual , Bufonidae , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Wurfbainia villosa is a well-known medicinal and edible plant that is widely cultivated in the Lingnan region of China. Its dried fruits (called Fructus Amomi) are broadly used in traditional Chinese medicine for curing gastrointestinal diseases and are rich in volatile terpenoids. Here, we report a high-quality chromosome-level genome assembly of W. villosa with a total size of approximately 2.80 Gb, 42 588 protein-coding genes, and a very high percentage of repetitive sequences (87.23%). Genome analysis showed that W. villosa likely experienced a recent whole-genome duplication event prior to the W. villosa-Zingiber officinale divergence (approximately 11 million years ago), and a recent burst of long terminal repeat insertions afterward. The W. villosa genome enabled the identification of 17 genes involved in the terpenoid skeleton biosynthesis pathway and 66 terpene synthase (TPS) genes. We found that tandem duplication events have an important contribution to the expansion of WvTPSs, which likely drove the production of volatile terpenoids. In addition, functional characterization of 18 WvTPSs, focusing on the TPS-a and TPS-b subfamilies, showed that most of these WvTPSs are multi-product TPS and are predominantly expressed in seeds. The present study provides insights into the genome evolution and the molecular basis of the volatile terpenoids diversity in W. villosa. The genome sequence also represents valuable resources for the functional gene research and molecular breeding of W. villosa.
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Alquil e Aril Transferases , Alquil e Aril Transferases/genética , Terpenos/metabolismo , Plantas/metabolismo , CromossomosRESUMO
Rational design and facile synthesis of efficient environmentally friendly all-inorganic lead-free halide perovskite catalysts are of great significance in photocatalytic CO2 reduction. Aiming at photogenerated charge carrier separation and CO2 reaction dynamics, in this paper, a CsCuCl3 /Cu nanocrystals (NCs) heterojunction catalyst is designed and synthesized via a simple acid-etching solution process by using Cu2 O as the sacrificed template. Due to the disproportionation reaction of Cu2 O induced by concentrated hydrochloric acid, Cu NCs can be deposited onto the surface of CsCuCl3 microcrystals directly and tightly. As revealed by photoelectrochemical analysis, in situ Fourier transform infrared spectra, etc., the Cu NCs contribute a lot to extracting photoelectrons of CsCuCl3 to improve the charge separation efficiency, regulating the CO2 adsorption and activation, and also stabilizing the reaction intermediates. Therefore, CsCuCl3 /Cu heterojunction exhibits a total electron consumption rate of 58.77 µmol g-1 h-1 , which is 2.9-fold of that of single CsCuCl3 . Moreover, high CH4 selectivity of up to 92.7% is achieved, which is much higher than that of CsCuCl3 (50.4%) and most lead-free halide perovskite-based catalysts. This work provides an ingenious but simple strategy to rationally design cocatalysts in situ decorated perovskite catalysts for manipulating both the catalytic activity and the product selectivity.
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Ultrathin 2D porous carbon-based materials offer numerous fascinating electrical, catalytic, and mechanical properties, which hold great promise in various applications. However, it remains a formidable challenge to fabricate these materials with tunable morphology and composition by a simple synthesis strategy. Here, a facile one-step self-flowering method without purification and harsh conditions is reported for large-scale fabrication of high-quality ultrathin (≈1.5 nm) N-doped porous carbon nanosheets (NPC) and their composites. It is demonstrated that the layered tannic/oxamide (TA/oxamide) hybrid is spontaneously blown, exfoliated, bloomed, in situ pore-formed, and aromatized during pyrolysis to form flower-like aggregated NPC. This universal one-step self-flowering system is compatible with various precursors to construct multiscale NPC-based composites (Ru@NPC, ZnO@NPC, MoS2 @NPC, Co@NPC, rGO@NPC, etc.). Notably, the programmable architecture enables NPC-based materials with excellent multifunctional performances, such as microwave absorption and hydrogen evolution. This work provides a facile, universal, scalable, and eco-friendly avenue to fabricate functional ultrathin porous carbon-based materials with programmability.
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BACKGROUND: Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. METHODS: We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. RESULTS: We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. CONCLUSIONS: In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , alfa-Fetoproteínas , Estudos Retrospectivos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de Neoplasia/diagnóstico por imagem , Imunoterapia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND AND AIMS: Magnifying image-enhanced endoscopy (MIEE) is an advanced endoscopy with image enhancement and magnification used in preoperative examination. However, its impact on the detection rate is unknown. METHODS: We conducted an open-label, randomized, parallel (1:1:1), controlled trial in 6 hospitals in China. Patients were recruited between February 14, 2022 and July 30, 2022. Eligible patients were aged ≥18 years and undergoing gastroscopy in outpatient departments. Participants were randomly assigned to the MIEE-only mode (o-MIEE) group, white-light endoscopy-only mode (o-WLE) group, and MIEE when necessary mode (n-MIEE) group (initial WLE followed by switching to another endoscope with MIEE if necessary). Biopsy sampling of suspicious lesions of the lesser curvature of the gastric antrum was performed. Primary and secondary aims were to compare detection rates and positive predictive value (PPV) of early cancer and precancerous lesions in these 3 modes, respectively. RESULTS: A total of 5100 recruited patients were randomly assigned to the o-MIEE (n = 1700), o-WLE (n = 1700), and n-MIEE (n = 1700) groups. In the o-MIEE, o-WLE, and n-MIEE groups, 29 (1.51%; 95% confidence interval [CI], 1.05-2.16), 4 (.21%; 95% CI, .08-.54), and 8 (.43%; 95% CI, .22-.85) early cancers were found, respectively (P < .001). The PPV for early cancer was higher in the o-MIEE group compared with the o-WLE and n-MIEE groups (63.04%, 33.33%, and 38.1%, respectively; P = .062). The same trend was seen for precancerous lesions (36.67%, 10.00%, and 21.74%, respectively). CONCLUSIONS: The o-MIEE mode resulted in a significant improvement in diagnosing early upper GI cancer and precancerous lesions; thus, it could be used for opportunistic screening. (Clinical trial registration number: ChiCTR2200064174.).
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Lesões Pré-Cancerosas , Neoplasias Gástricas , Humanos , Adolescente , Adulto , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Lesões Pré-Cancerosas/diagnóstico por imagem , Lesões Pré-Cancerosas/patologia , Gastroscopia/métodos , Valor Preditivo dos Testes , BiópsiaRESUMO
BACKGROUND: Chinese Nong-favor daqu, the presentative liquor starter of Baijiu, has been enriched with huge amounts of enzymes in degrading various biological macromolecules by openly man-made process for thousand years. According to previous metatranscriptomics analysis, plenty of α-glucosidases were identified to be active in NF daqu and played the key role in degrading starch under solid-state fermentation. However, none of α-glucosidases was characterized from NF daqu, and their actual functions in NF daqu were still unknown. RESULTS: An α-glucosidase (NFAg31A, GH31-1 subfamily), the second highest expressed α-glucosidases in starch degradation of NF daqu, was directly obtained by heterologous expression in Escherichia coli BL21 (DE3). NFAg31A exhibited the highest sequence identities of 65.8% with α-glucosidase II from Chaetomium thermophilum, indicating its origin of fungal species, and it showed some similar features with homologous α-glucosidase IIs, i.e., optimal activity at pH ~ 7.0 and litter higher temperature of 45 â, well stability at 41.3 â and a broad pH range of pH 6.0 to pH 10.0, and preference on hydrolyzing Glc-α1,3-Glc. Besides this preference, NFAg31A showed comparable activities on Glc-α1,2-Glc and Glc-α1,4-Glc, and low activity on Glc-α1,6-Glc, indicating its broad specificities on α-glycosidic substrates. Additionally, its activity was not stimulated by any of those detected metal ions and chemicals, and could be largely inhibited by glucose under solid-state fermentation. Most importantly, it exhibited competent and synergistic effects with two characterized α-amylases of NF daqu on hydrolyzing starch, i.e., all of them could efficiently degrade starch and malto-saccharides, two α-amylases showed advantage in degrading starch and long-chain malto-saccharides, and NFAg31A played the competent role with α-amylases in degrading short-chain malto-saccharides and the irreplaceable contribution in hydrolyzing maltose into glucose, thus alleviating the product inhibitions of α-amylases. CONCLUSIONS: This study provides not only a suitable α-glucosidase in strengthening the quality of daqu, but also an efficient way to reveal roles of the complicated enzyme system in traditional solid-state fermentation. This study would further stimulate more enzyme mining from NF daqu, and promote their actual applications in solid-state fermentation of NF liquor brewing, as well as in other solid-state fermentation of starchy industry in the future.