RESUMEN
Cyclic-oligonucleotide-based anti-phage signaling system (CBASS) is a common immune system that uses cyclic oligonucleotide signals to limit phage replication. In turn, phages encode anti-CBASS (Acb) proteins such as Acb2, which can sequester some cyclic dinucleotides (CDNs) and limit downstream effector activation. Here, we identified that Acb2 sequesters many CDNs produced by CBASS systems and inhibits stimulator of interferon genes (STING) activity in human cells. Surprisingly, the Acb2 hexamer also binds with high affinity to CBASS cyclic trinucleotides (CTNs) 3'3'3'-cyclic AMP-AMP-AMP and 3'3'3'-cAAG at a distinct site from CDNs. One Acb2 hexamer can simultaneously bind two CTNs and three CDNs. Phage-encoded Acb2 provides protection from type III-C CBASS that uses cA3 signaling molecules. Moreover, phylogenetic analysis of >2,000 Acb2 homologs encoded by diverse phages and prophages revealed that most are expected to bind both CTNs and CDNs. Altogether, Acb2 sequesters nearly all known CBASS signaling molecules through two distinct binding pockets and therefore serves as a broad-spectrum inhibitor of cGAS-based immunity.
Asunto(s)
Bacteriófagos , Nucleótidos Cíclicos , Humanos , Nucleótidos Cíclicos/metabolismo , Bacteriófagos/genética , Bacteriófagos/metabolismo , Filogenia , AMP Cíclico , OligonucleótidosRESUMEN
Marine photosynthetic dinoflagellates are a group of successful phytoplankton that can form red tides in the ocean and also symbiosis with corals. These features are closely related to the photosynthetic properties of dinoflagellates. We report here three structures of photosystem I (PSI)-chlorophylls (Chls) a/c-peridinin protein complex (PSI-AcpPCI) from two species of dinoflagellates by single-particle cryoelectron microscopy. The crucial PsaA/B subunits of a red tidal dinoflagellate Amphidinium carterae are remarkably smaller and hence losing over 20 pigment-binding sites, whereas its PsaD/F/I/J/L/M/R subunits are larger and coordinate some additional pigment sites compared to other eukaryotic photosynthetic organisms, which may compensate for the smaller PsaA/B subunits. Similar modifications are observed in a coral symbiotic dinoflagellate Symbiodinium species, where two additional core proteins and fewer AcpPCIs are identified in the PSI-AcpPCI supercomplex. The antenna proteins AcpPCIs in dinoflagellates developed some loops and pigment sites as a result to accommodate the changed PSI core, therefore the structures of PSI-AcpPCI supercomplex of dinoflagellates reveal an unusual protein assembly pattern. A huge pigment network comprising Chls a and c and various carotenoids is revealed from the structural analysis, which provides the basis for our deeper understanding of the energy transfer and dissipation within the PSI-AcpPCI supercomplex, as well as the evolution of photosynthetic organisms.
Asunto(s)
Antozoos , Dinoflagelados , Animales , Antozoos/metabolismo , Complejos de Proteína Captadores de Luz/metabolismo , Dinoflagelados/metabolismo , Floraciones de Algas Nocivas , Simbiosis , Microscopía por Crioelectrón , Complejo de Proteína del Fotosistema I/metabolismo , Clorofila/metabolismoRESUMEN
Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas systems are prokaryotic adaptive immune systems against invading phages and other mobile genetic elements. Notably, some phages, including the Vibrio cholerae-infecting ICP1 (International Center for Diarrheal Disease Research, Bangladesh cholera phage 1), harbor CRISPR-Cas systems to counteract host defenses. Nevertheless, ICP1 Cas8f lacks the helical bundle domain essential for recruitment of helicase-nuclease Cas2/3 during target DNA cleavage and how this system accomplishes the interference stage remains unknown. Here, we found that Cas1, a highly conserved component known to exclusively work in the adaptation stage, also mediates the interference stage through connecting Cas2/3 to the DNA-bound CRISPR-associated complex for antiviral defense (Cascade; CRISPR system yersinia, Csy) of the ICP1 CRISPR-Cas system. A series of structures of Csy, Csy-dsDNA (double-stranded DNA), Cas1-Cas2/3 and Csy-dsDNA-Cas1-Cas2/3 complexes reveal the whole process of Cas1-mediated target DNA cleavage by the ICP1 CRISPR-Cas system. Together, these data support an unprecedented model in which Cas1 mediates the interference stage in a phage-encoded CRISPR-Cas system and the study also sheds light on a unique model of primed adaptation.
RESUMEN
The long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) is involved in a variety of human cancers. Two overlapping NEAT1 isoforms, NEAT1_1 and NEAT1_2, are produced through mutually exclusive alternative 3' end formation. Previous studies extensively investigated NEAT1 dysregulation in tumors, but often failed to achieve distinct quantification of the two NEAT1 isoforms. Moreover, molecular mechanisms governing the biogenesis of NEAT1 isoforms and the functional impacts of their dysregulation in tumorigenesis remain poorly understood. In this study, we employed an isoform-specific quantification assay and found differential dysregulation of NEAT1 isoforms in patient-derived glioblastoma multiforme cells. We further showed usage of the NEAT1 proximal polyadenylation site (PAS) is a critical mechanism that controls glioma NEAT1 isoform production. CRISPR-Cas9-mediated PAS deletion reduced NEAT1_1 and reciprocally increased NEAT1_2, which enhanced nuclear paraspeckle formation in human glioma cells. Moreover, the utilization of the NEAT1 PAS is facilitated by the RNA-binding protein quaking (QKI), which binds to the proximal QKI recognition elements. Functionally, we identified transcriptomic changes and altered biological pathways caused by NEAT1 isoform imbalance in glioma cells, including the pathway for the regulation of cell migration. Finally, we demonstrated the forced increase of NEAT1_2 upon NEAT1 PAS deletion is responsible for driving glioma cell migration and promoting the expression of genes implicated in the regulation of cell migration. Together, our studies uncovered a novel mechanism that regulates NEAT1 isoforms and their functional impacts on the glioma transcriptome, which affects pathological pathways of glioma, represented by migration.
RESUMEN
BACKGROUND: Jianli pig, a renowned indigenous breed in China, has the characteristics of a two-end black (TEB) coat color, excellent meat quality, strong adaptability and increased prolificacy. However, there is limited information available regarding the genetic diversity, population structure and genomic regions under selection of Jianli pig. On the other hand, the genetic mechanism of TEB coat color has remained largely unknown. RESULTS: In this study, the whole genome resequencing of 30 Jianli pigs within a context of 153 individuals representing 13 diverse breeds was performed. The population structure analysis revealed that Jianli pigs have close genetic relationships with the Tongcheng pig breed, their geographical neighbors. Three methods (observed heterozygosity, expected heterozygosity, and runs of homozygosity) implied a relatively high level of genetic diversity and, a low inbreeding coefficient in Jianli compared with other pigs. We used Fst and XP-EHH to detect the selection signatures in Jianli pigs compared with Asian wild boar. A total of 451 candidate genes influencing meat quality (CREBBP, ADCY9, EEPD1 and HDAC9), reproduction (ESR1 and FANCA), and coat color (EDNRB, MITF and MC1R), were detected by gene annotation analysis. Finally, to fine-map the genomic region for the two-end black (TEB) coat color phenotype in Jianli pigs, we performed three signature selection methods between the TEB coat color and no-TEB coat color pig breeds. The current study, further confirmed that the EDNRB gene is a candidate gene for TEB color phenotype found in Chinese pigs, including Jinhua pigs, and the haplotype harboring 25 SNPs in the EDNRB gene may promote the formation of TEB coat color. Further ATAC-seq and luciferase reporter assays of these regions suggest that the 25-SNPs region was a strong candidate causative mutation that regulates the TEB coat color phenotype by altering enhancer function. CONCLUSION: Our results advanced the understanding of the genetic mechanism behind artificial selection, and provided further resources for the protection and breeding improvement of Jianli pigs.
Asunto(s)
Genoma , Receptor de Endotelina B , Selección Genética , Animales , Haplotipos , Homocigoto , Fenotipo , Polimorfismo de Nucleótido Simple , Receptor de Endotelina B/genética , Porcinos/genéticaRESUMEN
The high recurrence rate of cervical cancer is a leading cause of cancer deaths in women. 5-Fluorouracil (5-FU) is an antitumor drug used to treat many types of cancer, but its diminishing effectiveness and side effects limit its use. Norcantharidin (NCTD), a demethylated derivative of cantharidin, exhibits various biological activities. Here, we investigated whether NCTD could potentiate 5-FU to induce cervical cancer cell death. To assess the cell viability and synergistic effects of the drugs, cell counting kit-8 and colony formation assays were performed using HR-HPV-positive cervical cancer cell lines. Annexin V-FITC/PI staining and TUNEL assays were performed to confirm the induction of apoptosis. The synergistic effect of NCTD on the antitumor activity of 5-FU was analyzed using network pharmacology, molecular docking, and molecular dynamics simulations. Apoptosis-related proteins were examined using immunoblotting. The combination of NCTD and 5-FU was synergistic in cervical cancer cell lines. Network pharmacological analysis identified 10 common targets of NCTD and 5-FU for cervical cancer treatment. Molecular docking showed the strong binding affinity of both compounds with CA12, CASP9, and PTGS1. Molecular dynamics simulations showed that the complex system of both drugs with caspase-9 could be in a stable state. NCTD enhanced 5-FU-mediated cytotoxicity by activating apoptosis-related proteins. NCTD acts synergistically with 5-FU to inhibit cervical cancer cell proliferation. NCTD enhances 5-FU-induced apoptosis in cervical cancer cell lines via the caspase-dependent pathway.
RESUMEN
RATIONALE: Early natural menopause (early-M; <45 years of age) increases the risk of lung morbidities and mortalities in smokers. However, it is largely unknown whether early-M due to surgery demonstrates similar effects and whether menopausal hormone therapy (MHT) is protective against lung diseases. OBJECTIVES: To assess the associations of early-M and MHT with lung morbidities and mortalities using the prospective Prostate, Lung, Colorectal and Ovarian (PLCO) trial. METHODS: We estimated the risk among 69 706 postmenopausal women in the PLCO trial, stratified by menopausal types and smoking status. RESULTS: Early-M was associated with an increased risk of most lung disease and mortality outcomes in ever smokers with the highest risk seen for respiratory mortality (HR 1.98, 95% CI 1.34 to 2.92) in those with bilateral oophorectomy (BO). Early-M was positively associated with chronic bronchitis, and all-cause, non-cancer and respiratory mortality in never smokers with natural menopause or BO, with the highest risk seen for BO- respiratory mortality (HR 1.91, 95% CI 1.16 to 3.12). Ever MHT was associated with reduced all-cause, non-cancer and cardiovascular mortality across menopause types regardless of smoking status and was additionally associated with reduced risk of non-ovarian cancer, lung cancer (LC) and respiratory mortality in ever smokers. Among smokers, ever MHT use was associated with a reduction in HR for all-cause, non-cancer and cardiovascular mortality in a duration-dependent manner. CONCLUSIONS: Smokers with early-M should be targeted for smoking cessation and LC screening regardless of menopause types. MHT users had a lower likelihood of dying from LC and respiratory diseases in ever smokers.
RESUMEN
Ovarian cancer is one of the most lethal malignant tumors, characterized by high incidence and poor prognosis. Patients relapse occurred in 65-80% after initial treatment. To date, no effective treatment has been established for these patients. Recently, CD47 has been considered as a promising immunotherapy target. In this paper, we reviewed the biological roles of CD47 in ovarian cancer and summarized the related mechanisms. For most types of cancers, the CD47/Sirpα immune checkpoint has attracted the most attention in immunotherapy. Notably, CD47 monoclonal antibodies and related molecules are promising in the immunotherapy of ovarian cancer, and further research is needed. In the future, new immunotherapy regimens targeting CD47 can be applied to the clinical treatment of ovarian cancer patients.
Asunto(s)
Antígeno CD47 , Progresión de la Enfermedad , Neoplasias Ováricas , Humanos , Antígeno CD47/metabolismo , Antígeno CD47/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Femenino , Inmunoterapia/métodos , AnimalesRESUMEN
Soybean is a major source of protein and edible oil worldwide. Originating from the Huang-Huai-Hai region, which has a temperate climate, soybean has adapted to a wide latitudinal gradient across China. However, the genetic mechanisms responsible for the widespread latitudinal adaptation in soybean, as well as the genetic basis, adaptive differentiation, and evolutionary implications of theses natural alleles, are currently lacking in comprehensive understanding. In this study, we examined the genetic variations of fourteen major gene loci controlling flowering and maturity in 103 wild species, 1048 landraces, and 1747 cultivated species. We found that E1, E3, FT2a, J, Tof11, Tof16, and Tof18 were favoured during soybean improvement and selection, which explained 75.5% of the flowering time phenotypic variation. These genetic variation was significantly associated with differences in latitude via the LFMM algorithm. Haplotype network and geographic distribution analysis suggested that gene combinations were associated with flowering time diversity contributed to the expansion of soybean, with more HapA clustering together when soybean moved to latitudes beyond 35°N. The geographical evolution model was developed to accurately predict the suitable planting zone for soybean varieties. Collectively, by integrating knowledge from genomics and haplotype classification, it was revealed that distinct gene combinations improve the adaptation of cultivated soybeans to different latitudes. This study provides insight into the genetic basis underlying the environmental adaptation of soybean accessions, which could contribute to a better understanding of the domestication history of soybean and facilitate soybean climate-smart molecular breeding for various environments.
Asunto(s)
Domesticación , Variación Genética , Glycine max , Glycine max/genética , Glycine max/fisiología , Glycine max/crecimiento & desarrollo , Genes de Plantas , Adaptación Fisiológica/genética , China , Haplotipos , Flores/genética , Flores/crecimiento & desarrollo , Flores/fisiologíaRESUMEN
Chikungunya fever is an acute infectious disease caused by chikungunya virus (CHIKV), which is transmitted by Aedes mosquitoes. Simple, rapid, and sensitive detection of CHIKV is critical for its prevention and spread. To address this issue, we combined one-tube, reverse transcription semi-nested, multi-enzyme isothermal rapid amplification, and lateral flow dipstick strips assay to detect CHIKV RNA. The study used a 318-bp gene fragment of CHIKV NSP4 as the target of the assay. This method of amplification takes 30 min for two-step amplification at 39°C. The dilution of amplification products was added to the LFD strip with results visible to the naked eye after 10 min. The method has a sensitivity of 1 copy/µL for the detection of CHIKV RNA, which is 100-fold higher than the conventional reverse transcription-multi-enzyme isothermal rapid amplification and 10-fold higher than the reverse transcription quantitative PCR (RT-qPCR) method. In addition, the method demonstrated good specificity and a better detection rate (85.7%, 18 of 21) than RT-qPCR (80.9%, 17 of 21) in clinically confirmed patient plasma samples. Thus, the rapid CHIKV RNA assay developed in this study will be an important tool for the rapid and accurate screening of patients for chikungunya fever. IMPORTANCE: This study presents a new one-tube, reverse transcription semi-nested, multi-enzyme isothermal rapid amplification assay combined with lateral flow dipstick strips for the detection of CHIKV. This technique significantly improves sensitivity and outperforms RT-qPCR for the detection of CHIKV, especially in samples with low viral loads. It is also significantly faster than conventional RT-qPCR and does not require special equipment or a standard PCR laboratory. The combination of the isothermal amplification technology developed in this study with point-of-care molecular testing offers the potential for rapid, on-site, low-cost molecular diagnosis of CHIKV.
RESUMEN
The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (ptrend = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection.
Asunto(s)
Predisposición Genética a la Enfermedad , Genotipo , Hepatitis C , Polimorfismo de Nucleótido Simple , Humanos , Masculino , Femenino , Estudios de Casos y Controles , Hepatitis C/genética , Hepatitis C/virología , Hepatitis C/inmunología , Persona de Mediana Edad , Adulto , Antígenos HLA-A/genética , Hepacivirus/genética , Hepacivirus/inmunología , Receptores KIR/genética , Anciano , Receptores KIR3DL2/genéticaRESUMEN
BACKGROUND: Though (1S, 3R)-RSL3 has been used widely in basic research as a small molecular inducer of ferroptosis, the toxicity on normal cells and poor pharmacokinetic properties of RSL3 limited its clinical application. Here, we investigated the synergism of non-thermal plasma (NTP) and low-concentration RSL3 and attempted to rise the sensitivity of NSCLC cells on RSL3. METHODS: CCK-8 assay was employed to detect the change of cell viability. Microscopy and flowcytometry were applied to identify lipid peroxidation, cell death and reactive oxygen species (ROS) level respectively. The molecular mechanism was inspected with western blot and RT-qPCR. A xenograft mice model was adopted to investigate the effect of NTP and RSL3. RESULTS: We found the synergism of NTP and low-concentration RSL3 triggered severe mitochondria damage, more cell death and rapid ferroptosis occurrence in vitro and in vivo. NTP and RSL3 synergistically induced xCT lysosomal degradation through ROS/AMPK/mTOR signaling. Furthermore, we revealed mitochondrial ROS was the main executor for ferroptosis induced by the combined treatment. CONCLUSION: Our research shows NTP treatment promoted the toxic effect of RSL3 by inducing more ferroptosis rapidly and provided possibility of RSL3 clinical application.
Asunto(s)
Ferroptosis , Neoplasias Pulmonares , Animales , Humanos , Ratones , Proteínas Quinasas Activadas por AMP , Lisosomas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina-Treonina Quinasas TOR , Carbolinas/efectos adversos , Carbolinas/toxicidadRESUMEN
The adsorption behaviors and electronic properties of five gas molecules (CO, H2O, NH3, NO, and C2H6O) on the intrinsic Ti2CO2 and Fe-doped Ti2CO2 were calculated and studied based on first principles. The adsorption height, bond length change, adsorption energy, charge transfer, band structure, differential charge, work function, and recovery time of the two gas adsorption systems were discussed, and their sensing performance was evaluated. The results show that the CO gas molecules have the best adsorption energy and charge transfer on Ti2CO2 modified by the Fe atom (Ti2CO2-Fe). The electrical conductivity obviously increases with the decrease of the band gap, which changes from semiconductor to conductor behavior. The reduction of the work function in the Ti2CO2-Fe system weakens the binding of the electron, which improves the electron flow between the substrate and the gas molecules. In addition, the Ti2CO2-Fe system with H2O molecule participation remained the best adsorption effect on CO gas, and the fast recovery time was 625 s at 398 K. Therefore, Ti2CO2-Fe is a prospective material for the advancement of CO gas-sensitive sensors.
RESUMEN
A metal-free and atom-economic route for the synthesis of naphtho[1,2-b]furan-3-ones has been realized via p-TsOH·H2O-catalyzed intramolecular tandem double cyclization of γ-hydroxy acetylenic ketones with alkynes in formic acid. The benzene-linked furanonyl-ynes are the key intermediates obtained by the scission/recombination of C-O double bonds. Further, the structural modifications of the representative product were implemented by reduction, demethylation, substitution, and [5 + 2]-cycloaddition.
RESUMEN
Cadmium poisoning is a chronic accumulation process, and long-term drinking of even low cadmium content water will cause kidney damage, so an ultra-low detection limit is particularly important. However, at the present stage, the traditional detection method cannot reach a sufficiently low detection limit, the response time is too long, and the cost of detection is very high, so that real-time measurement cannot be realized. Therefore, the traditional cadmium ion detection method has a slow response and an insufficient detection limit. This paper presents a fiber optic cadmium ion sensor functionalized based on an Fe3O4@SiO2@CS magnetic ion imprinting polymer (M-IIP). The sensor is based on the coupling characteristics of the optical microfiber coupler (OMC) cone region to achieve a highly sensitive response to the change in the cadmium ion concentration. M-IIP materials were prepared by surface imprinting polymerization to achieve low cross-sensitivity and thus improve the detection limit of the sensor. The results show that the developed fiber sensor has high specificity and a rapid response to cadmium ions. The experimental limit of detection (LOD) reached 0.051 nM within 0-1 µM with a response time of less than 50 s. Moreover, the proposed fiber cadmium ion sensor exhibits excellent performance in terms of sensitivity, stability, repeatability and biocompatibility.
RESUMEN
Hippocampal neurons maintain the ability of proliferation throughout life to support neurogenesis. Deoxynivalenol (DON) is a mycotoxin that exhibits brain toxicity, yet whether and how DON affects hippocampal neurogenesis remains unknown. Here, we use mouse hippocampal neuron cells (HT-22) as a model to illustrate the effects of DON on neuron proliferation and to explore underlying mechanisms. DON exposure significantly inhibits the proliferation of HT-22 cells, which is associated with an up-regulation of cell cycle inhibitor p21 at both mRNA and protein levels. Global and site-specific m6A methylation levels on the 3'UTR of p21 mRNA are significantly increased in response to DON treatment, whereas inhibition of m6A hypermethylation significantly alleviates DON-induced cell cycle arrest. Further mechanistic studies indicate that the m6A readers YTHDF1 and IGF2BP1 are responsible for m6A-mediated increase in p21 mRNA stability. Meanwhile, 3'UTR of E3 ubiquitin ligase TRIM21 mRNA is also m6A hypermethylated, and another m6A reader YTHDF2 binds to the m6A sites, leading to decreased TRIM21 mRNA stability. Consequently, TRIM21 suppression impairs ubiquitin-mediated p21 protein degradation. Taken together, m6A-mediated upregulation of p21, at both post-transcriptional and post-translational levels, contributes to DON-induced inhibition of hippocampal neuron proliferation. These results may provide new insights for epigenetic therapy of neurodegenerative diseases.
Asunto(s)
Proliferación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Hipocampo , Neuronas , Tricotecenos , Regulación hacia Arriba , Animales , Tricotecenos/toxicidad , Tricotecenos/farmacología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/citología , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Regulación hacia Arriba/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Línea Celular , Regiones no Traducidas 3'/genética , Neurogénesis/efectos de los fármacos , ARN Mensajero/metabolismo , ARN Mensajero/genética , Estabilidad del ARN/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Metilación/efectos de los fármacosRESUMEN
Silicone-based passive samplers, commonly paired with gas chromatography-mass spectrometry (GC-MS) analysis, are increasingly utilized for personal exposure assessments. However, its compatibility with the biotic exposome remains underexplored. In this study, we introduce the wearable silicone-based AirPie passive sampler, coupled with nontargeted liquid chromatography with high-resolution tandem mass spectrometry (LC-HRMS/MS), GC-HRMS, and metagenomic shotgun sequencing methods, offering a comprehensive view of personalized airborne biotic and abiotic exposomes. We applied the AirPie samplers to 19 participants in a unique deep underwater confined environment, annotating 4,390 chemical and 2,955 microbial exposures, integrated with corresponding transcriptomic data. We observed significant shifts in environmental exposure and gene expression upon entering this unique environment. We noted increased exposure to pollutants, such as benzenoids, polycyclic aromatic hydrocarbons (PAHs), opportunistic pathogens, and associated antibiotic-resistance genes (ARGs). Transcriptomic analyses revealed the activation of neurodegenerative disease-related pathways, mostly related to chemical exposure, and the repression of immune-related pathways, linked to both biological and chemical exposures. In summary, we provided a comprehensive, longitudinal exposome map of the unique environment and underscored the intricate linkages between external exposures and human health. We believe that the AirPie sampler and associated analytical methods will have broad applications in exposome and precision medicine.
Asunto(s)
Exposoma , Enfermedades Neurodegenerativas , Hidrocarburos Policíclicos Aromáticos , Dispositivos Electrónicos Vestibles , Humanos , Espacios Confinados , Transcriptoma , Monitoreo del Ambiente/métodos , SiliconasRESUMEN
BACKGROUND AND AIM: The study aims to introduce a novel indicator, effective withdrawal time (WTS), which measures the time spent actively searching for suspicious lesions during colonoscopy and to compare WTS and the conventional withdrawal time (WT). METHODS: Colonoscopy video data from 472 patients across two hospitals were retrospectively analyzed. WTS was computed through a combination of artificial intelligence (AI) and manual verification. The results obtained through WTS were compared with those generated by the AI system. Patients were categorized into four groups based on the presence of polyps and whether resections or biopsies were performed. Bland Altman plots were utilized to compare AI-computed WTS with manually verified WTS. Scatterplots were used to illustrate WTS within the four groups, among different hospitals, and across various physicians. A parallel box plot was employed to depict the proportions of WTS relative to WT within each of the four groups. RESULTS: The study included 472 patients, with a median age of 55 years, and 57.8% were male. A significant correlation with manually verified WTS (r = 0.918) was observed in AI-computed WTS. Significant differences in WTS/WT among the four groups were revealed by the parallel box plot (P < 0.001). The group with no detected polyps had the highest WTS/WT, with a median of 0.69 (interquartile range: 0.40, 0.97). WTS patterns were found to be varied between the two hospitals and among senior and junior physicians. CONCLUSIONS: A promising alternative to traditional WT for quality control and training assessment in colonoscopy is offered by AI-assisted computation of WTS.
Asunto(s)
Inteligencia Artificial , Colonoscopía , Humanos , Colonoscopía/métodos , Masculino , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Factores de Tiempo , Pólipos del Colon/diagnóstico , Pólipos del Colon/patología , Pólipos del Colon/diagnóstico por imagen , Anciano , Adulto , Grabación en VideoRESUMEN
BACKGROUND: The interrelation between metabolic syndrome (MetS) and Parkinson's disease (PD) likely arises from shared pathological mechanisms. This study thus aims to examine the impact of MetS and its components on PD. METHODS: This study utilized data extracted from the National Health and Nutrition Examination Survey database spanning 1999 to 2020. The random forest algorithm was applied to fill in the missing data. Propensity score optimal full matching was conducted. The data were adjusted by total weights derived from both sampling and matching weights. The weighted data were utilized to create multifactor logistic regression models. Odds ratios (ORs) and average marginal effects, along with their corresponding 95% confidence intervals (CIs), were calculated. RESULTS: MetS did not significantly affect the risk of PD (OR: 1.01; 95% CI: 0.77, 1.34; P = 0.92). Hypertension elevated the risk of PD (OR: 1.33; 95% CI: 1.01, 1.76; P = 0.045), accompanied by a 0.26% increased probability of PD occurrence (95% CI: 0.01%, 0.52%; P = 0.04). Diabetes mellitus (DM) had a 1.38 times greater likelihood of developing PD (OR:1.38; 95% CI: 1.004, 1.89; P = 0.046), corresponding to a 0.32% increased probability of PD occurrence (95% CI: -0.03%, 0.67%; P = 0.07). Nevertheless, no correlation was observed between hyperlipidemia, waist circumference and PD. CONCLUSION: MetS does not affect PD; however, hypertension and DM significantly increase the risk of PD.
Asunto(s)
Síndrome Metabólico , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/complicaciones , Síndrome Metabólico/epidemiología , Síndrome Metabólico/complicaciones , Estudios Transversales , Masculino , Femenino , Persona de Mediana Edad , Factores de Riesgo , Anciano , Encuestas Nutricionales , Hipertensión/epidemiología , Hipertensión/complicaciones , AdultoRESUMEN
BACKGROUND: Helicobacter pylori (H. pylori), according to a number of recent observational studies, is connected to atherosclerosis (AS). However, the link between H. pylori and AS is debatable. METHODS: In order to calculate the causal relationship between H. pylori and AS, we employed a two-sample Mendelian randomization (MR) analysis. The data for H. pylori were obtained from the IEU GWAS database ( https://gwas.mrcieu.ac.uk/datasets/ ) and the data for AS were obtained from the Finngen GWAS database ( https://r5.finngen.fi/ ). We selected single nucleotide polymorphisms with a threshold of 5 × 10-6 from earlier genome-wide association studies. MR was performed mainly using the inverse variance weighted (IVW) method. To ensure the reliability of the findings, We performed a leave-one-out sensitivity analysis to test for sensitivity. F-value was used to test weak instrument. RESULTS: A positive causal relationship between H. pylori OMP antibody levels and peripheral atherosclerosis was shown by our two-sample MR analysis (odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.14-1.54, P = 0.26E-03) using IVW. Additionally, there was a causative link between coronary atherosclerosis and H. pylori VacA antibody levels (IVW OR = 1.06, 95% CI = 1.01-1.10, P = 0.016). All the F-values were above 10. CONCLUSIONS: This MR study discovered a causal link between H. pylori and AS. Different antibodies have different effects, so future researches are needed to figure out the exact mechanisms behind this link.