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1.
JCI Insight ; 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38814732

RESUMEN

Influenza poses a persistent health burden worldwide. To design equitable vaccines effective across all demographics, it is essential to better understand how host factors such as genetic background and aging affect the single-cell immune landscape of influenza infection. Cytometry by time-of-flight (CyTOF) represents a promising technique in this pursuit, but interpreting its large, high-dimensional data remains difficult. We've developed a new analytical approach iGATE (in-silico gating annotating training elucidating) based on probabilistic support vector machine classification. By rapidly and accurately "gating" tens of millions of cells in silico into user-defined types, iGATE enabled us to track 25 canonical immune cell types in mouse lung over the course of influenza infection. Applying iGATE to study effects of host genetic background, we show that the lower survival of C57BL/6 mice compared to BALB/c is associated with a more rapid accumulation of inflammatory cell types and decreased IL-10 expression. Further, we demonstrate that the most prominent effect of aging is a defective T-cell response, reducing survival of aged mice. Finally, iGATE reveals that the 25 canonical immune cell types exhibit differential influenza infection susceptibility and replication permissiveness in vivo, but neither property varies with host genotype or aging. Software is available at https://github.com/UmichWenLab/iGATE.

2.
Angew Chem Int Ed Engl ; : e202405679, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38771671

RESUMEN

An optimal cancer chemotherapy regimen should effectively address the drug resistance of tumors while eliciting antitumor-immune responses. Research has shown that non-apoptotic cell death, such as pyroptosis and ferroptosis, can enhance the immune response. Despite this, there has been limited investigation and reporting on the mechanisms of oncosis and its correlation with immune response. Herein, we designed and synthesized a Ru(II) complex that targeted the nucleus and mitochondria to induce cell oncosis. Briefly, the Ru(II) complex disrupts the nucleus and mitochondria DNA, which active polyADP-ribose polymerase 1, accompanied by ATP consumption and porimin activation. Concurrently, mitochondrial damage and endoplasmic reticulum stress result in the release of Ca2+ ions and increased expression of Calpain 1. Subsequently, specific pore proteins porimin and Calpain 1 promote cristae destruction or vacuolation, ultimately leading to cell membrane rupture. The analysis of RNA sequencing demonstrates that Ru(II) complex can initiate the oncosis-associated pathway and activate both innate and adaptive immunity. In vivo experiments have confirmed that oncosis facilitates the maturation of dendritic cells and the awakening of adaptive cytotoxic T lymphocytes but also induces the polarization of tumor-associated macrophages (TAMs) towards an M1 phenotype and activates the innate immune response of TAMs.

3.
Nat Genet ; 56(5): 889-899, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38741018

RESUMEN

The extent of cell-to-cell variation in tumor mitochondrial DNA (mtDNA) copy number and genotype, and the phenotypic and evolutionary consequences of such variation, are poorly characterized. Here we use amplification-free single-cell whole-genome sequencing (Direct Library Prep (DLP+)) to simultaneously assay mtDNA copy number and nuclear DNA (nuDNA) in 72,275 single cells derived from immortalized cell lines, patient-derived xenografts and primary human tumors. Cells typically contained thousands of mtDNA copies, but variation in mtDNA copy number was extensive and strongly associated with cell size. Pervasive whole-genome doubling events in nuDNA associated with stoichiometrically balanced adaptations in mtDNA copy number, implying that mtDNA-to-nuDNA ratio, rather than mtDNA copy number itself, mediated downstream phenotypes. Finally, multimodal analysis of DLP+ and single-cell RNA sequencing identified both somatic loss-of-function and germline noncoding variants in mtDNA linked to heteroplasmy-dependent changes in mtDNA copy number and mitochondrial transcription, revealing phenotypic adaptations to disrupted nuclear/mitochondrial balance.


Asunto(s)
Núcleo Celular , Variaciones en el Número de Copia de ADN , ADN Mitocondrial , Genoma Mitocondrial , Neoplasias , Análisis de la Célula Individual , Humanos , ADN Mitocondrial/genética , Análisis de la Célula Individual/métodos , Variaciones en el Número de Copia de ADN/genética , Núcleo Celular/genética , Neoplasias/genética , Neoplasias/patología , Línea Celular Tumoral , Animales , Mitocondrias/genética , Secuenciación Completa del Genoma/métodos , Ratones , Heteroplasmia/genética
4.
Artículo en Inglés | MEDLINE | ID: mdl-38755472

RESUMEN

The large-scale integration of renewable power poses great challenges to grid stability. Among flexible resources, demand response (DR) stands out for its advantages in cost and efficiency. To identify key factors influencing DR, this study adopted the modified theory of planned behavior (TPB) to establish the conceptual model. Social norms were included as a front-end variable, and institutional factors and electricity consumption habits served as moderating variables. The model was subsequently tested and modified using the structural equation modelling (SEM). Results indicated that social norms can exert a substantial indirect effect on DR behavior. However, due to the deficiency of such norms, the formation of the positive attitude towards DR was hindered, resulting in a low standard coefficient of 0.16. Moreover, the influence of subjective norm on response intention was rejected due to limited perceived external pressure. Perceived behavior control exhibited the most significant direct influence on response intention (0.76). Additionally, the positive effects of situational factors and personal habits on the conversion from response intention to behavior were supported. Based on these findings, several policy suggestions including enhancing publicity and incentive policies were proposed.

5.
Curr Med Sci ; 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38748368

RESUMEN

OBJECTIVE: Ferritin, initially acting as an iron-storage protein, was found to be associated with metabolic diseases. Our study was designed to investigate the association between serum ferritin and metabolic-associated fatty liver disease (MAFLD) using data from the National Health and Nutrition Examination Survey (NHANES) of the United State of America. METHODS: A cross-sectional study was conducted, enrolling a total of 2145 participants from the NHANES in the 2017-2018 cycles. Hepatic steatosis and liver fibrosis were assessed by ultrasound images and several non-invasive indexes. Multiple regression analysis was conducted to determine the associations between serum ferritin concentration and MAFLD and liver fibrosis. RESULTS: The analysis revealed that participants with higher serum ferritin levels (Q3 and Q4 groups) had a higher prevalence of MAFLD than those with the lowest serum ferritin levels [Q3 vs. Q1: OR=2.17 (1.33, 3.53), P<0.05 in fatty liver index (FLI); Q4 vs. Q1: OR=3.13 (1.91, 5.13), P<0.05 in FLI]. Additionally, participants with the highest serum ferritin levels (Q4 group) displayed a higher prevalence of liver fibrosis [Q4 vs. Q1: OR=2.59 (1.19, 5.62), P<0.05 in liver stiffness measurement; OR=5.06 (1.12, 22.94), P<0.05 in fibrosis-4 index], with significantly increased risk observed in participants with concomitant diabetes [OR=7.45 (1.55, 35.72), P=0.012]. CONCLUSION: Our study revealed that elevated serum ferritin levels are associated with a higher prevalence of MAFLD and advanced liver fibrosis in patients. Elevated serum ferritin levels combined with diabetes are important risk factors for liver fibrosis.

6.
bioRxiv ; 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38798558

RESUMEN

Microbiome differential abundance analysis remains a challenging problem despite multiple methods proposed in the literature. The excessive zeros and compositionality of metagenomics data are two main challenges for differential abundance analysis. We propose a novel method called "analysis of differential abundance by pooling Tobit models" (ADAPT) to overcome these two challenges. ADAPT uniquely treats zero counts as left-censored observations to facilitate computation and enhance interpretation. ADAPT also encompasses a theoretically justified way of selecting non-differentially abundant microbiome taxa as a reference for hypothesis testing. We generate synthetic data using independent simulation frameworks to show that ADAPT has more consistent false discovery rate control and higher statistical power than competitors. We use ADAPT to analyze 16S rRNA sequencing of saliva samples and shotgun metagenomics sequencing of plaque samples collected from infants in the COHRA2 study. The results provide novel insights into the association between the oral microbiome and early childhood dental caries.

8.
ISME J ; 18(1)2024 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-38691444

RESUMEN

Plant-associated microbiomes play important roles in plant health and productivity. However, despite fruits being directly linked to plant productivity, little is known about the microbiomes of fruits and their potential association with fruit health. Here, by integrating 16S rRNA gene, ITS high-throughput sequencing data, and microbiological culturable approaches, we reported that roots and fruits (pods) of peanut, a typical plant that bears fruits underground, recruit different bacterial and fungal communities independently of cropping conditions and that the incidence of pod disease under monocropping conditions is attributed to the depletion of Bacillus genus and enrichment of Aspergillus genus in geocarposphere. On this basis, we constructed a synthetic community (SynCom) consisting of three Bacillus strains from geocarposphere soil under rotation conditions with high culturable abundance. Comparative transcriptome, microbiome profiling, and plant phytohormone signaling analysis reveal that the SynCom exhibited more effective Aspergillus growth inhibition and pod disease control than individual strain, which was underpinned by a combination of molecular mechanisms related to fungal cell proliferation interference, mycotoxins biosynthesis impairment, and jasmonic acid-mediated plant immunity activation. Overall, our results reveal the filter effect of plant organs on the microbiome and that depletion of key protective microbial community promotes the fruit disease incidence.


Asunto(s)
Arachis , Frutas , Microbiota , Enfermedades de las Plantas , Raíces de Plantas , ARN Ribosómico 16S , Microbiología del Suelo , Frutas/microbiología , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , ARN Ribosómico 16S/genética , Raíces de Plantas/microbiología , Arachis/microbiología , Aspergillus/genética , Aspergillus/aislamiento & purificación , Bacillus/genética , Bacillus/aislamiento & purificación , Reguladores del Crecimiento de las Plantas/metabolismo , Hongos/genética , Hongos/clasificación , Hongos/aislamiento & purificación , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación
9.
Food Res Int ; 187: 114345, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38763637

RESUMEN

Long-term consumption of Western-style diet (WSD) can lead to metabolic disorders and dysbiosis of gut microbiota, presenting a critical risk factor for various chronic conditions such as fatty liver disease. In the present study, we investigated the beneficial role of co-fermented whole grain quinoa and black barley with Lactobacillus kisonensis on rats fed a WSD. Male Sprague-Dawley (SD) rats, aged six weeks and weighing 180 ± 10 g, were randomly assigned to one of three groups: the normal control group (NC, n = 7), the WSD group (HF, n = 7), and the WSD supplemented with a co-fermented whole grain quinoa with black barley (FQB) intervention group (HFF, n = 7). The findings indicated that FQB was effective in suppressing body weight gain, mitigating hepatic steatosis, reducing perirenal fat accumulation, and ameliorating pathological damage in the livers and testicular tissues of rats. Additionally, FQB intervention led to decreased levels of serum uric acid (UA), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). These advantageous effects can be ascribed to the regulation of FQB on gut microbiota dysbiosis, which includes the restoration of intestinal flora diversity, reduction of the F/B ratio, and promotion of probiotics abundance, such as Akkermansia and [Ruminococcus] at the genus level. The study employed the UPLC-Q-TOF-MSE technique to analyze metabolites in fecal and hepatic samples. The findings revealed that FQB intervention led to a regression in the levels of specific metabolites in feces, including oxoadipic acid and 20a, 22b-dihydroxycholesterol, as well as in the liver, such as pyridoxamine, xanthine and xanthosine. The transcriptome sequencing of liver tissues revealed that FQB intervention modulated the mRNA expression of specific genes, including Cxcl12, Cidea, and Gck, known for their roles in anti-inflammatory and anti-insulin resistance mechanisms in the context of WSD. Our findings indicate that co-fermented whole-grain quinoa with black barley has the potential to alleviate metabolic disorders and chronic inflammation resulting from the consumption of WSD.


Asunto(s)
Chenopodium quinoa , Dieta Occidental , Fermentación , Microbioma Gastrointestinal , Hordeum , Lactobacillus , Ratas Sprague-Dawley , Animales , Hordeum/química , Masculino , Lactobacillus/metabolismo , Chenopodium quinoa/química , Ratas , Hígado/metabolismo , Disbiosis , Metabolómica , Alimentos Fermentados , Multiómica
10.
Pancreatology ; 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38763786

RESUMEN

BACKGROUND & AIMS: Mutations in genes, including serine protease inhibitor Kazal-type 1 (SPINK1), influence disease progression following sentinel acute pancreatitis event (SAPE) attacks. SPINK1 c.194+2T > C intron mutation is one of the main mutants of SPINK1,which leads to the impairment of SPINK1 function by causing skipping of exon 3. Research on the pathogenesis of SAPE attacks would contribute to the understanding of the outcomes of acute pancreatitis. Therefore, the aim of the study was to clarify the role of SPINK1 c.194+2T > C mutation in the CP progression after an AP attack. METHODS: SAPE attacks were induced in wildtype and SPINK mutant (Spink1 c.194+2T > C) mice by cerulein injection. The mice were sacrificed at 24 h, 14 d, 28 d, and 42 d post-SAPE. Data-independent acquisition (DIA) proteomic analysis was performed for the identification of differentially expressed protein in the pancreatic tissues. Functional analyses were performed using THP-1 and HPSCs. RESULTS: Following SAPE attack, the Spink1 c.194+2T > C mutant mice exhibited a more severe acute pancreatitis phenotype within 24 h. In the chronic phase, the chronic pancreatitis phenotype was more severe in the Spink1 c.194+2T > C mutant mice after SAPE. Proteomic analysis revealed elevated IL-33 level in Spink1 c.194+2T > C mutant mice. Further in vitro analyses revealed that IL-33 induced M2 polarization of macrophages and activation of pancreatic stellate cells. CONCLUSION: Spink1 c.194+2T > C mutation plays an important role in the prognosis of patients following SAPE. Heterozygous Spink1 c.194+2T > C mutation promotes the development of chronic pancreatitis after an acute attack in mice through elevated IL-33 level and the induction of M2 polarization in coordination with pancreatic stellate cell activation.

11.
Sex Med ; 12(2): qfae025, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38715577

RESUMEN

Background: The monocyte-to-high-density lipoprotein cholesterol ratio (MHR) has become a novel inflammation marker with a possible association with erectile dysfunction (ED); however, there are fewer studies exploring the association between MHR and ED. Aim: This study sought to explore the association between MHR and ED. Methods: This study population was drawn from participants in two 2-year cycles of the National Health and Nutrition Examination Survey (2001-2002 and 2003-2004). MHR was calculated as the ratio of monocyte count (103 cells/µL) to high-density lipoprotein cholesterol (mg/dL). The relationship between MHR and ED was explored using survey-weighted logistic regression models with MHR as a continuous variable and divided into tertiles (tertile 1 [T1]: <0.01; T2: 0.01-0.014; T3: >0.014). We also used a smooth curve fit (penalized spline method) to characterize the dose-response relationship between MHR and ED. In addition, subgroup analyses based on age, body mass index, smoking, hypertension, diabetes mellitus, and cardiovascular disease were performed to further analyze the data. Sensitivity analyses were also conducted to further assess the stability of the results. Outcomes: The main outcome measure was the difference in ED prevalence between MHR levels. Results: A total of 1361 participants were enrolled, with 513 (T1), 438 (T2), and 410 (T3) participants in the 3 MHR groups. After adjusting for all potential covariates, survey-weighted logistic regression analyses showed a significant association between MHR and ED (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.26-3.05). When MHR was used as a categorical variable, the adjusted OR for ED prevalence increased significantly with increasing MHR after adjusting for all potential covariates (T3 vs T1: OR, 2.14; 95% CI, 1.29-3.55). The dose-response curves showed that the prevalence of ED increased with increasing MHR. Clinical Implications: Easy to access and low cost, MHR is a convenient clinical tool that helps clinicians in the prevention and treatment of ED. Strengths and Limitations: The present study is the first to examine the association between MHR and ED nationally representative data. However, the study population was derived from a U.S. database, so the findings are limited to the U.S. population. Conclusion: Our study demonstrated that MHR levels were independently associated with ED and that ED patients had higher MHR levels, suggesting that MHR may be a valuable predictor for identifying people at higher risk for ED.

12.
Clin Epigenetics ; 16(1): 63, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38725010

RESUMEN

BACKGROUND: Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy in children. Accordingly, we conducted a study which involved a priming regimen consisting of DAC with cladribine, cytarabine, and granulocyte-stimulating factor (DAC-CLAG) and compared the efficacy and safety of this regimen with CLAG alone. METHODS: A total of 39 R/R AML children who received the CLAG or DAC-CLAG regimen in Shanghai Children's Hospital were retrospectively enrolled in this non-randomized study. These regimens were studied sequentially over time. Twenty-two patients received CLAG from 2015, while 17 patients were administered epigenetic priming with DAC before CLAG from 2020. Patients were subsequently bridged to stem cell transplantation (SCT) or consolidation chemotherapy. Complete remission (CR) and adverse effects were analyzed by Fisher's exact test, and survival was analyzed by the Kaplan-Meier method. RESULTS: DAC-CLAG conferred a numerically higher CR compared to CLAG (70.59% vs 63.64%; P = 0.740). High CR rates occurred in patients with good cytogenetics (P = 0.029) and prior induction without cladribine (P = 0.099). The 1-year event-free survival (EFS) was 64.71% ± 11.59% and 63.31% ± 10.35% in the DAC-CLAG and CLAG group (P = 0.595), and 1-year overall survival (OS) was 81.45% ± 9.72% and 77.01% ± 9.04%, respectively (P = 0.265). The 1-year OS and EFS after SCT were higher in the DAC-CLAG than in the CLAG cohort (100% vs 92.31% ± 7.39%, P = 0.072; 92.31% ± 7.39% vs 85.71% ± 9.35%, P = 0.158). Univariate analysis revealed that a good prognosis included good cytogenetics (P = 0.002), non-complex karyotype (P = 0.056), CR on reinduction (P < 0.0001), and bridging to SCT (P = 0.0007). Use of a hypomethylating agent (P = 0.049) and bridging to SCT (P = 0.011) were independent prognostic factors. Grade 3/4 hematologic toxicity and infection were the main adverse events. CONCLUSIONS: DAC prior to the CLAG regimen improved remission in pediatric R/R AML, and was feasible and well tolerated. CLAG ± DAC as a salvage therapy prior to SCT induced improved survival.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Cladribina , Citarabina , Decitabina , Epigénesis Genética , Leucemia Mieloide Aguda , Humanos , Decitabina/uso terapéutico , Decitabina/administración & dosificación , Decitabina/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Femenino , Niño , Preescolar , Cladribina/uso terapéutico , Cladribina/administración & dosificación , Estudios Retrospectivos , Citarabina/uso terapéutico , Citarabina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adolescente , Epigénesis Genética/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Lactante , Resultado del Tratamiento , Inducción de Remisión/métodos
13.
Reprod Toxicol ; 126: 108602, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38723698

RESUMEN

Reproduction is a functional outcome that relies on complex cellular, tissue, and organ interactions that span the developmental period to adulthood. Thus, the assessment of its disruption by environmental chemicals would benefit significantly from scalable and innovative approaches to testing using functionally comparable reproductive models such as the nematode C. elegans. We adapted a previously described low-throughput in vivo chromosome segregation assay using C. elegans predictive of reproductive toxicity and leveraged available public data sources (ToxCast, ICE) to screen and characterize 133 physiologically-relevant chemicals in a high-throughput manner. The screening outcome was further validated in a second, independent in vivo assay assessing embryonic viability. In total, 13 chemicals were classified as reproductive toxicants with the two most active chemicals belonging to the large family of Quaternary Ammonium Compounds (QACs) commonly used as disinfectants but with limited available reproductive toxicity data. We compared the results from the C. elegans assay with ToxCast in vitro data compiled from 700+ cell response assays and 300+ signaling pathways-based assays. We did not observe a difference in the bioactivity or in the average potency (AC50) between the top and bottom chemicals. However, the intended target categories were significantly different between the classified chemicals with, in particular, an over-representation of steroid hormone targets for the high Z-score chemicals. Taken together, these results point to the value of in vivo models that scale to high-throughput level for reproductive toxicity assessment and to the need to prioritize the assessment of QACs impacts on reproduction.


Asunto(s)
Caenorhabditis elegans , Contaminantes Ambientales , Reproducción , Caenorhabditis elegans/efectos de los fármacos , Animales , Reproducción/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Pruebas de Toxicidad/métodos , Ensayos Analíticos de Alto Rendimiento
14.
J Environ Manage ; 360: 121154, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38744203

RESUMEN

Carbon label is acknowledged as an effective way to combat the problem of global warming. As a powerful way to encourage individuals to adjust their consumption patterns and to promote the development of green consumption, carbon-labeled products are widely developed in China. To reveal the production and consumption process of carbon-labeled products, the present study constructs a tripartite game model consisting of the government, carbon-labeled products manufacturers and consumers based on a media monitoring perspective. The evolutionary stability strategy (ESS) is firstly determined by solving the replication dynamic equations and stability analysis of the equilibrium point, followed by the strategy analysis and sensitivity analysis through numerical simulation. The results show that media supervision can effectively complement and constrain government supervision. In addition, it can promote enterprises to standardize production and enhance consumers' trust and willingness to buy carbon-labeled products. The introduction of media supervision can well realize the ideal equilibrium of "effective government supervision, enterprise compliance and consumer support for purchase".

15.
Polymers (Basel) ; 16(10)2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38794557

RESUMEN

This research focuses on modifying discarded feathers by grafting glycidyl methacrylate (GMA) onto their surface through thiolation, followed by an epoxy ring-opening reaction with N-methyl-D-glucamine (NMDG) to synthesize feather-based boron adsorbents. Optimization of the adsorbent preparation conditions was achieved through single-factor experiments, varying temperature, time, GMA concentration, and initiator dosage. The synthesized adsorbent (F-g-GMA-NMDG) underwent characterization using Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The adsorption behavior of the adsorbent was studied, and its boron adsorption capacity at different temperatures was determined through static adsorption kinetic curves. Analysis of adsorption isotherms, kinetics, and thermodynamics was conducted. Results indicate that the boron adsorption process by F-g-GMA-NMDG follows a pseudo-second-order model. The adsorption process is endothermic, with higher temperatures promoting adsorption efficiency. Gibbs free energy (ΔG) confirms the spontaneity of the adsorption process. Enhanced adsorption efficacy was observed under neutral and acidic pH conditions. After four cycles, the adsorbent maintained its adsorption efficiency, demonstrating its stability and potential for reuse. This study provides novel insights into both the treatment of discarded feathers and the development of boron adsorbents.

16.
Gene ; 920: 148497, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-38677350

RESUMEN

BACKGROUND: Circular RNA (circRNA) is a novel functional non-coding RNA(ncRNA) that plays a role in the occurrence and development of multiple human liver diseases, including liver fibrosis (LF). LF is a reversible repair response after liver injury, and the activation of hepatic stellate cells (HSCs) is the core event. However, the regulatory mechanisms by which circRNAs induce the activation of HSCs in LF are still poorly understood. The circAno6/miR-296-3p/toll-like receptor 4 (TLR4) signaling axis that mediates the inflammatory response and causes the activation of HSCs was investigated in this study. METHODS: First, a circAno6 overexpression plasmid and small interfering RNA were transfected into cells to determine whether circAno6 can affect the function of HSCs. Second, real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), western blotting (WB) and immunofluorescence (IF) were used to detect the effects of circAno6 plasmid/siRNA transfection on HSC activation indices, inflammatory markers and the circAno6/miR-296-3p/TLR4 signaling axis. The subcellular position of circAno6 was then examined by nucleo-cytoplasmic separation and fluorescence in situ hybridization (FISH). Finally, a luciferase reporter gene assay was used to identify the relationship between circAno6 and miR-296-3p as well as the relationship between miR-296-3p and TLR4. RESULTS: CircAno6 was considerably upregulated in HSCs and positively correlated with cell proliferation and alpha-smooth muscle actin (α-SMA), collagen I, NOD-likereceptorthermalproteindomainassociatedprotein 3 (NLRP3), interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) expression. Overexpression of circAno6 increased the inflammatory response and induced HSC activation, whereas interference resulted in the opposite effects. FISH experiments revealed the localization of circAno6 in the cytoplasm. Then, a double luciferase reporter assay confirmed that miR-296-3p significantly inhibited luciferase activity in the circAno6-WT and TLR4-WT groups. CONCLUSION: This study suggests that circAno6 and miR-296-3p/TLR4 may form a regulatory axis and regulate the inflammatory response, which in turn induces HSC activation. Targeting circAno6 may be a potential therapeutic strategy to treat LF.


Asunto(s)
Células Estrelladas Hepáticas , MicroARNs , ARN Circular , Transducción de Señal , Receptor Toll-Like 4 , Células Estrelladas Hepáticas/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Humanos , Inflamación/genética , Inflamación/metabolismo , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Animales , Proliferación Celular
17.
bioRxiv ; 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38585844

RESUMEN

Reproduction is a functional outcome that relies on complex cellular, tissue, and organ interactions that span the developmental period to adulthood. Thus, the assessment of its disruption by environmental chemicals is remarkably painstaking in conventional toxicological animal models and does not scale up to the number of chemicals present in our environment and requiring testing. We adapted a previously described low-throughput in vivo chromosome segregation assay using C. elegans predictive of reproductive toxicity and leveraged available public data sources (ToxCast, ICE) to screen and characterize 133 physiologically-relevant chemicals in a high-throughput manner. The screening outcome was further validated in a second, independent in vivo assay assessing embryonic viability. In total, 13 chemicals were classified as reproductive toxicants with the two most active chemicals belonging to the large family of Quaternary Ammonium Compounds (QACs) commonly used as disinfectants but with limited available reproductive toxicity data. We compared the results from the C. elegans assay with ToxCast in vitro data compiled from 700+ cell response assays and 300+ signaling pathways-based assays. We did not observe a difference in the bioactivity or in average potency (AC50) between the top and bottom chemicals. However, the intended target categories were significantly different between the classified chemicals with, in particular, an over-representation of steroid hormone targets for the high Z-score chemicals. Taken together, these results point to the value of in vivo models that scale to high-throughput level for reproductive toxicity assessment and to the need to prioritize the assessment of QACs impacts on reproduction.

19.
Food Chem X ; 22: 101322, 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38562183

RESUMEN

Wheat is a vital global cereal crop, but its susceptibility to contamination by mycotoxins can render it unusable. This study explored the integration of two novel non-destructive detection methodologies with convolutional neural network (CNN) for the identification of zearalenone (ZEN) contamination in wheat. Firstly, the colorimetric sensor array composed of six selected porphyrin-based materials was used to capture the olfactory signatures of wheat samples. Subsequently, the colorimetric sensor array, after undergoing a reaction, was characterized by its near-infrared spectral features. Then, the CNN quantitative analysis model was proposed based on the data, alongside the establishment of traditional machine learning models, partial least squares regression (PLSR) and support vector machine regression (SVR), for comparative purposes. The outcomes demonstrated that the CNN model had superior predictive performance, with a root mean square error of prediction (RMSEP) of 40.92 µ g ∙ kg-1 and a coefficient of determination on the prediction (RP2) of 0.91. These results affirmed the potential of integrating colorimetric sensor array with near-infrared spectroscopy in evaluating the safety of wheat and potentially other grains. Moreover, CNN can have the capacity to autonomously learn and distill features from spectral data, enabling further spectral analysis and making it a forward-looking spectroscopic tool.

20.
Cardiology ; 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38565095

RESUMEN

INTRODUCTION: This study aims to evaluate the learning curve associated with the no-touch vein harvesting technique in off-pump coronary artery bypass grafting (CABG), highlighting its impact on surgical proficiency. METHODS: We employed logarithmic curve fitting to analyze the learning curves of 160 patients undergoing no-touch CABG, with a detailed retrospective examination of 89 patients who received three grafts using Cumulative Sum (CUSUM) analysis. Patients were categorized into two phases: the initial learning phase and the subsequent mastery phase, based on the chronological order of surgeries. We then compared perioperative outcomes between these phases. RESULTS: The learning curve for the no-touch vein harvesting technique was quantitatively established at 51 cases via CUSUM analysis, with supporting evidence from logarithmic curve fitting indicating a significant proficiency milestone. In the mastery phase, median operative times, aorta-saphenous vein graft (SVG) anastomosis, and SVG inspection durations were notably reduced (230 vs. 250 minutes, P = 0.002; 11.5 vs. 13.0 minutes, P = 0.025; 9.0 vs. 11.0 minutes, P = 0.002, respectively), alongside decreased initial 48-hour chest tube drainage, shorter postoperative hospital stays, and fewer incidences of delayed leg incision healing compared to the learning phase [312.6 (140.7) ml vs. 401.0 (233.5) ml, P = 0.029; 11.0 d vs. 12.0 d, P = 0.026; 15.7% vs. 2.6%, P = 0.043)]. CONCLUSION: Cardiac surgeons adopting the full-incision SVG harvesting method for no-touch CABG undergo a discernible learning curve before achieving early proficiency. It is crucial, especially during the initial learning phase, to focus on aorta-SVG anastomosis, the meticulous inspection for bleeding, and the management of wound complications to optimize patient outcomes.

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