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1.
Talanta ; 236: 122827, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34635217

RESUMO

Cryptococcal meningitis (CM) is a global threat with significant attributable morbidity and mortality. Information on microfluidic detection for CM diagnosis is still limited. We developed a multifunctional microfluidic module that integrated the pathogen enrichment and on-chip nucleic acid extraction. The module adopted a simple filtration membrane to effectively capture Cryptococcus cells and simplify the process, and combined lyticase digestion, alkaline lysis and heating methods to optimize the strategy to achieve nucleic acid extraction. The entire process was operated in the module, which reduced the exposure risk of directly processing cryptococcal samples. A portable one-pot lyophilized LAMP reagent bead with no temperature limit was developed, which improved the flexibility of operation. This module did not require any additional instrument, and is promising to develop a simple, rapid, and efficient approach to realize the "sample in and answer out" detection of real CSF samples. This microfluidic module had practical prospects and is expected to replace LFA for efficacy evaluation and follow-up in the middle and late stages of CM treatment, and could be used as an auxiliary method to confirm cases with questionable LFA results in the early diagnosis of CM.


Assuntos
Meningite Criptocócica , Ácidos Nucleicos , Humanos , Meningite Criptocócica/diagnóstico , Microfluídica , Análise de Sequência com Séries de Oligonucleotídeos
2.
Part Fibre Toxicol ; 18(1): 31, 2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34419099

RESUMO

BACKGROUND: Exposure to indoor air pollution from solid fuel combustion is associated with lung diseases and cancer. This study investigated the cytotoxicity and molecular mechanisms of biomass combustion-derived particles in human pulmonary alveolar epithelial cells (HPAEpiC) using a platform that combines air-liquid interface (ALI) and dynamic culture (DC) systems. METHODS: HPAEpiC were cultured on the surface of polycarbonate (PC) membranes on the ALI-DC platform. The cells were sprayed with an aerosolized solution of biomass combustion soluble constituents (BCSCs) and simultaneously nourished with culture medium flowing beneath the permeable PC membranes. The ALI-DC method was compared with the traditional submerged culture approach. BCSC particle morphology and dosages deposited on the chip were determined for particle characterization. Flow cytometry, scanning electron microscopy, and transmission electron microscopy were used to investigate the apoptosis rate of HPAEpiC and changes in the cell ultrastructure induced by BCSCs. Additionally, the underlying apoptotic pathway was examined by determining the protein expression levels by western blotting. RESULTS: Scanning electron microscope images demonstrated that the sample processing and delivering approach of the ALI-DC platform were suitable for pollutant exposure. Compared with the submerged culture method, a significant decline in cell viability and increase in apoptosis rate was observed after BCSC exposure on the ALI-DC platform, indicating that the ALI-DC platform is a more sensitive system for investigating cytotoxicity of indoor air pollutants in lung cells. The morphology and ultrastructure of the cells were damaged after exposure to BCSCs, and the p53 pathway was activated. The Bcl-2/Bax ratio was reduced, upregulating caspase-9 and caspase-3 expression and subsequently inducing apoptosis of HPAEpiC. The addition of N-acetyl cysteine antioxidant significantly alleviated the cytotoxicity induced by BCSCs. CONCLUSION: A novel ALI-DC platform was developed to study the cytotoxicity of air pollutants on lung cells. Using the platform, we demonstrated that BCSCs could damage the mitochondria, produce reactive oxygen species, and activate p53 in HPAEpiC, ultimately inducing apoptosis.


Assuntos
Poluentes Atmosféricos , Células Epiteliais Alveolares , Biomassa , Sobrevivência Celular , Células Epiteliais , Humanos , Pulmão
3.
Front Physiol ; 12: 699253, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349667

RESUMO

Background: Alcohol-associated liver disease (ALD) is an important cause of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of ALD; however, little is known about commensal fungi therein. Methods: We studied the dynamic changes of the intestinal fungal microbiome, or mycobiome, in 66 patients with alcohol use disorder (AUD) and after 2 weeks of alcohol abstinence using internal transcribed spacer 2 (ITS2) amplicon sequencing of fecal samples. Results: Patients with AUD had significantly increased abundance of the genera Candida, Debaryomyces, Pichia, Kluyveromyces, and Issatchenkia, and of the species Candida albicans and Candida zeylanoides compared with control subjects. Significantly improved liver health markers caspase-cleaved and intact cytokeratin 18 (CK18-M65) levels and controlled attenuation parameter (CAP) in AUD patients after 2 weeks of alcohol abstinence were associated with significantly lower abundance of the genera Candida, Malassezia, Pichia, Kluyveromyces, Issatchenkia, and the species C. albicans and C. zeylanoides. This was mirrored by significantly higher specific anti-C. albicans immunoglobulin G (IgG) and M (IgM) serum levels in AUD patients in relation to control participants, and significantly decreased anti-C. albicans IgG levels in AUD subjects after 2 weeks of abstinence. The intestinal abundance of the genus Malassezia was significantly higher in AUD subjects with progressive liver disease compared with non-progressive liver disease. Conclusion: In conclusion, improved liver health in AUD patients after alcohol abstinence was associated with lower intestinal abundances of Candida and Malassezia, and lower serum anti-C. albicans IgG levels. Intestinal fungi might serve as a therapeutic target to improve the outcome of patients in ALD.

4.
PLoS One ; 16(7): e0254635, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34264974

RESUMO

BACKGROUND: Statins have anti-inflammatory and immunomodulatory effects that may reduce the severity of coronavirus disease 2019 (COVID-19), in which organ dysfunction is mediated by severe inflammation. Large studies with diverse populations evaluating statin use and outcomes in COVID-19 are lacking. METHODS AND RESULTS: We used data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 US hospitals enrolled in the American Heart Association's COVID-19 Cardiovascular Disease (CVD) Registry to evaluate the associations between statin use and outcomes. Prior to admission, 42% of subjects (n = 4,449) used statins (7% on statins alone, 35% on statins plus anti-hypertensives). Death (or discharge to hospice) occurred in 2,212 subjects (21%). Outpatient use of statins, either alone or with anti-hypertensives, was associated with a reduced risk of death (adjusted odds ratio [aOR] 0.59, 95% CI 0.50-0.69), adjusting for demographic characteristics, insurance status, hospital site, and concurrent medications by logistic regression. In propensity-matched analyses, use of statins and/or anti-hypertensives was associated with a reduced risk of death among those with a history of CVD and/or hypertension (aOR 0.68, 95% CI 0.58-0.81). An observed 16% reduction in odds of death among those without CVD and/or hypertension was not statistically significant. CONCLUSIONS: Patients taking statins prior to hospitalization for COVID-19 had substantially lower odds of death, primarily among individuals with a history of CVD and/or hypertension. These observations support the continuation and aggressive initiation of statin and anti-hypertensive therapies among patients at risk for COVID-19, if these treatments are indicated based upon underlying medical conditions.


Assuntos
Anti-Hipertensivos/administração & dosagem , COVID-19/epidemiologia , Doenças Cardiovasculares/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Sistema de Registros/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , American Heart Association , Anti-Hipertensivos/uso terapêutico , COVID-19/mortalidade , Doenças Cardiovasculares/tratamento farmacológico , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Grupos Populacionais/estatística & dados numéricos , Estados Unidos
5.
Anal Chem ; 93(28): 9835-9844, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34232631

RESUMO

Insulin resistance (IR) is a typical sign of metabolic dysregulation caused by fine particulate matter (PM2.5), but the underlying signaling has not been clearly determined. Herein, a microfluidic liver-kidney microphysiological system (LK-MPS) is presented to assess the signaling pathways of IR generated by PM2.5 at 200 µg/mL for 24 h. The LK-MPS device consisted of a biomimetic liver-kidney architecture and reconstructed two circulation paths: the liver metabolism-kidney excretion (LM-KE) and kidney excretion-liver metabolism (KE-LM), by which PM2.5 is feasibly distributed in the two organs. Transmission electron microscopy (TEM) analysis revealed that PM2.5 can embed in the cytoplasm and nuclei, undergo transport by vesicles, and lead to the destruction of mitochondria. Further comprehensive immunofluorescence, enzyme-linked immunosorbent assays (ELISAs) and untargeted metabolomic analyses confirmed that PM2.5 disturbed the classic IRS-1/AKT signaling pathway (INSR, IRS-1, PI3K, AKT, GLUT2, GLUT4, and FOXO1 downregulated) and IR-related metabolic pathways: UDP-hexosamine (UDP-GlcNAc), gluconeogenesis (ß-d-glucose 6-phosphate), and lipid biosynthesis (ceramide (Cer) and triacylglycerol (TG)) pathways, leading to the disorder of glucose levels. Collectively, these disorders aggravate hepatic and renal IR. Pearson's correlation coefficient test showed that elemental carbon (EC), polycyclic aromatic hydrocarbons (PAHs), and metals (Ca, Co, and V) were negatively correlated to the dysregulated proteins (INSR, IRS-1, AKT, FOXO1, GLUT2, and GLUT4). These findings may partially explain IR-related signaling pathways triggered by PM2.5.


Assuntos
Resistência à Insulina , Insulina , Humanos , Rim/metabolismo , Fígado/metabolismo , Microfluídica , Material Particulado/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
6.
J Mater Chem B ; 9(25): 5128-5135, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34132315

RESUMO

In this work, we constructed a target-triggered and controlled-release plasmon-enhanced fluorescent AIE probe to realize the purpose of conformational monitoring of insulin fibrillation. We synthesized a novel water-soluble anthracene derivative, 4,4',4'',4'''-(anthracene-9,10-diylbis(ethene-2,1,1-triyl))tetrakis(N,N,N-trimethylbenzenaminium) iodide (BDVAI), with AIE properties, high biocompatibility and good self-assembly effect. Gold nanocages (AuNCs) were selected as the substrate for PEF, and the inner space of hollow AuNCs was filled with BDVAI. Thiol-modified DNA chains were bonded to the surface of AuNCs by Au-S bonds, and an insulin aptamer was combined with the sulfhydryl chain to seal the AuNCs. This PEF-AIE sensor produces different fluorescence signals when interacting with native insulin and fibrillar insulin; thus, monitoring conformational changes in insulin can be realized by detecting fluorescence intensity changes during insulin fibrillation. Based on this design, this system realized sensitive detection of fibrillar insulin with a detection limit of 23.6 pM. This AIE molecular-based PEF fluorescence enhancement system improves the optical properties of fluorescent substances, which is of great significance in improving the detection sensitivity of amyloid fibrils conformational changes and providing a reliable basis for further understanding the pathogenesis of amyloidosis.


Assuntos
Técnicas Biossensoriais , Corantes Fluorescentes/química , Insulina/análise , Corantes Fluorescentes/síntese química , Insulina/metabolismo , Conformação Molecular
7.
Biometrics ; 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34010477

RESUMO

The human microbiome plays an important role in our health and identifying factors associated with microbiome composition provides insights into inherent disease mechanisms. By amplifying and sequencing the marker genes in high-throughput sequencing, with highly similar sequences binned together, we obtain operational taxonomic units (OTUs) profiles for each subject. Due to the high-dimensionality and nonnormality features of the OTUs, the measure of diversity is introduced as a summarization at the microbial community level, including the distance-based beta-diversity between individuals. Analyses of such between-subject attributes are not amenable to the predominant within-subject-based statistical paradigm, such as t-tests and linear regression. In this paper, we propose a new approach to model beta-diversity as a response within a regression setting by utilizing the functional response models (FRMs), a class of semiparametric models for between- as well as within-subject attributes. The new approach not only addresses limitations of current methods for beta-diversity with cross-sectional data, but also provides a premise for extending the approach to longitudinal and other clustered data in the future. The proposed approach is illustrated with both real and simulated data.

8.
Liver Int ; 41(7): 1576-1591, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33896117

RESUMO

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is a global health burden. Risk factors for disease severity include older age, increased body mass index (BMI), diabetes, genetic variants, dietary factors and gut microbiota alterations. However, the interdependence of these factors and their individual impact on disease severity remain unknown. METHODS: In this cross-sectional study, we performed 16S gene sequencing using fecal samples, collected dietary intake, PNPLA3 gene variants and clinical and liver histology parameters in a well-described cohort of 180 NAFLD patients. Principal component analyses were used for dimensionality reduction of dietary and microbiota data. Simple and multiple stepwise ordinal regression analyses were performed. RESULTS: Complete data were available for 57 NAFLD patients. In the simple regression analysis, features associated with the metabolic syndrome had the highest importance regarding liver disease severity. In the multiple regression analysis, BMI was the most important factor associated with the fibrosis stage (OR per kg/m2 : 1.23, 95% CI 1.10-1.37, P < .001). The PNPLA3 risk allele had the strongest association with the histological grade of steatosis (OR 5.32, 95% CI 1.56-18.11, P = .007), followed by specific dietary patterns. Low abundances of Faecalibacterium, Bacteroides and Prevotella and high abundances of Gemmiger were associated with the degree of inflammation, ballooning and stages of fibrosis, even after taking other cofactors into account. CONCLUSIONS: BMI had the strongest association with histological fibrosis, but PNPLA3 gene variants, gut bacterial features and dietary factors were all associated with different histology features, which underscore the multifactorial pathogenesis of NAFLD.


Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Idoso , Biópsia , Estudos Transversais , Dieta , Humanos , Lipase/genética , Fígado , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único
9.
Front Psychiatry ; 12: 648475, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841213

RESUMO

Loneliness and wisdom have opposite effects on health and well-being. Loneliness is a serious public health problem associated with increased morbidity and mortality. Wisdom is associated with better health and well-being. We have consistently found a strong negative correlation between loneliness and wisdom. The present study aimed to investigate the association of loneliness and wisdom with the gut microbiome. One hundred eighty-four community-dwelling adults (28-97 years) completed validated self-report-based measures of loneliness, wisdom, compassion, social support, and social engagement. Fecal samples were collected and profiled using 16S rRNA sequencing. Linear regression analyses, controlling for age and body mass index, revealed that lower levels of loneliness and higher levels of wisdom, compassion, social support, and social engagement were associated with greater phylogenetic richness and diversity of the gut microbiome. Partial least squares (PLS) analysis to investigate multivariate relationships extracted two composite variables. Linear regression model predicting alpha-diversity with PLS components revealed that a linear combination of all psychosocial predictors (with negative loading for loneliness and positive loadings for all others, including wisdom, compassion, social support, and social engagement) was significantly associated with alpha-diversity. For beta-diversity, compassion and wisdom accounted for a significant proportion of variance in overall microbial community composition. Findings may have implications for interventions to reduce loneliness and possibly its health-related adverse consequences. Future research should explore whether increasing compassion and wisdom may improve loneliness and overall well-being as well as microbial diversity.

10.
Toxins (Basel) ; 13(2)2021 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672887

RESUMO

Alcohol-related liver disease is one of the most prevalent types of chronic liver diseases globally. Alcohol-related liver disease begins with fatty liver, which further develops into hepatic inflammation, hepatocyte injury, and progresses to fibrosis and cirrhosis. Compositional changes of gut bacteria and fungi were found in patients with alcohol-related liver disease. However, the functional changes of fungi and correlations between fungi and bacteria have not been investigated. In this study, we first examined the functional capacity of fungi in patients with alcohol-related liver disease using shotgun metagenomics. Among 24 MetaCyc pathways contributed by fungi, superpathway of allantoin degradation in yeast was enriched in patients with alcoholic hepatitis. Furthermore, we compared the predictive power of bacteria versus fungi and found that bacteria performed better than fungi to separate patients with alcoholic hepatitis from non-alcoholic controls and patients with alcohol use disorder. Finally, we investigated the associations between the intestinal fungi and bacteria in alcoholic hepatitis patients. Positive association between fungi and bacteria was found between Cladosporium and Gemmiger, meanwhile negative association was found between Cryptococcus and Pseudomonas in alcoholic hepatitis patients.


Assuntos
Bactérias/genética , Fungos/genética , Microbioma Gastrointestinal , Hepatite Alcoólica/microbiologia , Intestinos/microbiologia , Metagenoma , Adulto , Idoso , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Estudos de Casos e Controles , Disbiose , Fezes/microbiologia , Feminino , Fungos/crescimento & desenvolvimento , Fungos/metabolismo , Regulação Bacteriana da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Hepatite Alcoólica/diagnóstico , Humanos , Masculino , Metagenômica , Pessoa de Meia-Idade , Ribotipagem
11.
J Biol Chem ; 296: 100575, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33757768

RESUMO

How organs sense circulating metabolites is a key question. Here, we show that the multispecific organic anion transporters of drugs, OAT1 (SLC22A6 or NKT) and OAT3 (SLC22A8), play a role in organ sensing. Metabolomics analyses of the serum of Oat1 and Oat3 knockout mice revealed changes in tryptophan derivatives involved in metabolism and signaling. Several of these metabolites are derived from the gut microbiome and are implicated as uremic toxins in chronic kidney disease. Direct interaction with the transporters was supported with cell-based transport assays. To assess the impact of the loss of OAT1 or OAT3 function on the kidney, an organ where these uptake transporters are highly expressed, knockout transcriptomic data were mapped onto a "metabolic task"-based computational model that evaluates over 150 cellular functions. Despite the changes of tryptophan metabolites in both knockouts, only in the Oat1 knockout were multiple tryptophan-related cellular functions increased. Thus, deprived of the ability to take up kynurenine, kynurenate, anthranilate, and N-formylanthranilate through OAT1, the kidney responds by activating its own tryptophan-related biosynthetic pathways. The results support the Remote Sensing and Signaling Theory, which describes how "drug" transporters help optimize levels of metabolites and signaling molecules by facilitating organ cross talk. Since OAT1 and OAT3 are inhibited by many drugs, the data implies potential for drug-metabolite interactions. Indeed, treatment of humans with probenecid, an OAT-inhibitor used to treat gout, elevated circulating tryptophan metabolites. Furthermore, given that regulatory agencies have recommended drugs be tested for OAT1 and OAT3 binding or transport, it follows that these metabolites can be used as endogenous biomarkers to determine if drug candidates interact with OAT1 and/or OAT3.


Assuntos
Rim/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Triptofano/metabolismo , Animais , Rim/citologia , Camundongos , Estresse Oxidativo , Transporte Proteico , Transdução de Sinais
12.
Microbiome ; 9(1): 57, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637135

RESUMO

BACKGROUND: Plants are naturally associated with root microbiota, which are microbial communities influential to host fitness. Thus, it is important to understand how plants control root microbiota. Epigenetic factors regulate the readouts of genetic information and consequently many essential biological processes. However, it has been elusive whether RNA-directed DNA methylation (RdDM) affects root microbiota assembly. RESULTS: By applying 16S rRNA gene sequencing, we investigated root microbiota of Arabidopsis mutants defective in the canonical RdDM pathway, including dcl234 that harbors triple mutation in the Dicer-like proteins DCL3, DCL2, and DCL4, which produce small RNAs for RdDM. Alpha diversity analysis showed reductions in microbe richness from the soil to roots, reflecting the selectivity of plants on root-associated bacteria. The dcl234 triple mutation significantly decreases the levels of Aeromonadaceae and Pseudomonadaceae, while it increases the abundance of many other bacteria families in the root microbiota. However, mutants of the other examined key players in the canonical RdDM pathway showed similar microbiota as Col-0, indicating that the DCL proteins affect root microbiota in an RdDM-independent manner. Subsequently gene analysis by shotgun sequencing of root microbiome indicated a selective pressure on microbial resistance to plant defense in the dcl234 mutant. Consistent with the altered plant-microbe interactions, dcl234 displayed altered characters, including the mRNA and sRNA transcriptomes that jointly highlighted altered cell wall organization and up-regulated defense, the decreased cellulose and callose deposition in root xylem, and the restructured profile of root exudates that supported the alterations in gene expression and cell wall modifications. CONCLUSION: Our findings demonstrate an important role of the DCL proteins in influencing root microbiota through integrated regulation of plant defense, cell wall compositions, and root exudates. Our results also demonstrate that the canonical RdDM is dispensable for Arabidopsis root microbiota. These findings not only establish a connection between root microbiota and plant epigenetic factors but also highlight the complexity of plant regulation of root microbiota. Video abstract.


Assuntos
Arabidopsis/metabolismo , Arabidopsis/microbiologia , Metilação de DNA/genética , Microbiota , Raízes de Plantas/microbiologia , RNA de Plantas , Ribonuclease III/metabolismo , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas/genética , Microbiota/genética , Raízes de Plantas/genética , RNA Ribossômico 16S/genética , Ribonuclease III/genética
13.
Talanta ; 224: 121867, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33379077

RESUMO

Acute toxicity assay presents vital significance in modern environmental monitoring, including online detection and in-situ assay for emergency events. Although photobacteria related detection methods were established and verified in the past decades with combination of photomultiplier tube (PMT), the price and size of PMT sensor hampered application of rapid acute toxicity assay and detection system miniaturization, especially in the resource-limited occasions. Wide application of smartphones with great low-light performance cameras could be used in photobacteria-based toxicity assay instead of the PMT methods. Herein a box-type portable detection system had been successfully established, including a disc-chip for detection, detection device, and smartphones with a high-performance camera. The system performed well showing stable temperature and rotation control. Results captured by CMOS-based camera presented a linear relationship with PMT-based detection method. An image progress algorithm was also established and tested by series diluted zinc sulfate solution as a reference substance. The system also performed well for toxicity analysis for real Atmospheric particle matter sample. The system could be used in some environmental monitoring scenarios as an alternative solution.


Assuntos
Smartphone , Miniaturização
14.
Sci Total Environ ; 753: 141758, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-32898806

RESUMO

SARS-Cov-2 has erupted across the globe, and confirmed cases of COVID-19 pose a high infection risk. Infected patients typically receive their treatment in specific isolation wards, where they are confined for at least 14 days. The virus may contaminate any surface of the room, especially frequently touched surfaces. Therefore, surface contamination in wards should be monitored for disease control and hygiene purposes. Herein, surface contamination in the ward was detected on-site using an RNA extraction-free rapid method. The whole detection process, from surface sample collection to readout of the detection results, was finished within 45 min. The nucleic acid extraction-free method requires minimal labor. More importantly, the tests were performed on-site and the results were obtained almost in real-time. The test confirmed that 31 patients contaminated seven individual sites. Among the sampled surfaces, the electrocardiogram fingertip presented a 72.7% positive rate, indicating that this surface is an important hygiene site. Meanwhile, the bedrails showed the highest correlation with other surfaces, so should be detected daily. Another surface with high contamination risk was the door handle in the bathroom. To our knowledge, we present the first on-site analysis of COVID-19 surface contamination in wards. The results and applied technique provide a potential further reference for disease control and hygiene suggestions.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Contaminação de Equipamentos , Pandemias , Pneumonia Viral , COVID-19 , Hospitais , Humanos , Pneumonia Viral/epidemiologia , SARS-CoV-2
15.
ACS Sens ; 5(11): 3483-3492, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33135418

RESUMO

Fine particulate matter (PM2.5)-induced metabolic diseases have attracted a great deal of attention recently. However, the relevant metabolic mechanisms of PM2.5 in vivo have not yet been fully described due to the lack of reliable platforms. Herein, a membrane-free liver-gut-on-chip (L-GOC) platform was developed to investigate metabolism dysregulation induced by PM2.5. A multiple organ system with a liver-gut structure and two circulation paths (L-G and G-L circulation paths) was created, and then cells were exposed to PM2.5 on this platform. Secreted high-density lipoprotein (HDL) levels were detected, which demonstrates that this multiple organ system functioned with normal physiological metabolism at the organ level. Untargeted metabolomic analysis showed that there were 364 metabolites of LO2 cells dysregulated after exposure to PM2.5 at a concentration of 200 µg/mL. Moreover, cholesterol and bile acid metabolism were significantly dysregulated. Further immunofluorescence and ELISA assays confirmed that signal transduction pathways related to cholesterol metabolism (LCAT-CE, PON1-HDL, and SRB1-HDL metabolic pathways) and bile acid metabolism (CYP7A1-CA/CDCA/DCA metabolic pathways) were disturbed. These results indicate that PM2.5 primarily disturbed cholesterol metabolism of the liver and then disrupted bile acid metabolism of the liver (primary bile acid biosynthesis) and gut (secondary bile acid biosynthesis) via related metabolic pathways. These findings may partially explain the metabolic mechanisms of cells triggered by PM2.5 exposure.


Assuntos
Microbioma Gastrointestinal , Ácidos e Sais Biliares , Colesterol , Fígado , Material Particulado/toxicidade
16.
Invest Ophthalmol Vis Sci ; 61(12): 11, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33049059

RESUMO

Purpose: Although zebrafish rods begin to develop as early as 2 days postfertilization (dpf), they are not deemed anatomically mature and functional until 15 to 21 dpf. A recent study detected a small electroretinogram (ERG) from rods in a cone mutant called no optokinetic response f (nof) at 5 dpf, suggesting that young rods are functional. Whether they can mediate behavioral responses in larvae is unknown. Methods: We first confirmed rod function by measuring nof ERGs under photopic and scotopic illumination at 6 dpf. We evaluated the role of rods in visual behaviors using two different assays: the visual-motor response (VMR) and optokinetic response (OKR). We measured responses from wild-type (WT) larvae and nof mutants under photopic and scotopic illuminations at 6 dpf. Results: Nof mutants lacked a photopic ERG. However, after prolonged dark adaptation, they displayed scotopic ERGs. Compared with WT larvae, the nof mutants displayed reduced VMRs. The VMR difference during light onset gradually diminished with decreased illumination and became nearly identical at lower light intensities. Additionally, light-adapted nof mutants did not display an OKR, whereas dark-adapted nof mutants displayed scotopic OKRs. Conclusions: Because the nof mutants lacked a photopic ERG but displayed scotopic ERGs after dark adaptation, the mutants clearly had functional rods. WT larvae and the nof mutants displayed comparable scotopic light-On VMRs and scotopic OKRs after dark adaptation, suggesting that these responses were driven primarily by rods. Together, these observations indicate that rods contribute to zebrafish visual behaviors as early as 6 dpf.


Assuntos
Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Visão Ocular/fisiologia , Peixe-Zebra/fisiologia , Animais , Visão de Cores/fisiologia , Eletrorretinografia , Técnicas de Genotipagem , Larva , Visão Noturna/fisiologia , Nistagmo Optocinético/fisiologia
17.
Biometrika ; 107(3): 723-735, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32831354

RESUMO

We consider the problem of approximating smoothing spline estimators in a nonparametric regression model. When applied to a sample of size [Formula: see text], the smoothing spline estimator can be expressed as a linear combination of [Formula: see text] basis functions, requiring [Formula: see text] computational time when the number [Formula: see text] of predictors is two or more. Such a sizeable computational cost hinders the broad applicability of smoothing splines. In practice, the full-sample smoothing spline estimator can be approximated by an estimator based on [Formula: see text] randomly selected basis functions, resulting in a computational cost of [Formula: see text]. It is known that these two estimators converge at the same rate when [Formula: see text] is of order [Formula: see text], where [Formula: see text] depends on the true function and [Formula: see text] depends on the type of spline. Such a [Formula: see text] is called the essential number of basis functions. In this article, we develop a more efficient basis selection method. By selecting basis functions corresponding to approximately equally spaced observations, the proposed method chooses a set of basis functions with great diversity. The asymptotic analysis shows that the proposed smoothing spline estimator can decrease [Formula: see text] to around [Formula: see text] when [Formula: see text]. Applications to synthetic and real-world datasets show that the proposed method leads to a smaller prediction error than other basis selection methods.

18.
Nat Commun ; 11(1): 4128, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807809

RESUMO

Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates in female and younger patients. Although immune responses differ with sex and age, the role of MHC-based immune selection in this context is unknown. We find that tumors in younger and female individuals accumulate more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. Younger patients show the strongest effects of MHC-based driver mutation selection, with younger females showing compounded effects and nearly twice as much MHC-II based selection. This study presents evidence that strength of immune selection during tumor development varies with sex and age, and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy.


Assuntos
Mutação/genética , Neoplasias/genética , Neoplasias/imunologia , Fatores Etários , Alelos , Feminino , Genótipo , Humanos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Fatores Sexuais
19.
Gastroenterology ; 159(5): 1839-1852, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32652145

RESUMO

BACKGROUND & AIMS: Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD. METHODS: In a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0-4, 44 patients had an NAS of 5-8 or liver cirrhosis (LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary cholangitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles. RESULTS: Patients with NAFLD and NAS 5-8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0-4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5-8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity. CONCLUSIONS: In a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data.


Assuntos
Microbioma Gastrointestinal , Intestinos/virologia , Cirrose Hepática/virologia , Hepatopatia Gordurosa não Alcoólica/virologia , Viroma , Adulto , Idoso , Estudos de Casos e Controles , Estudos Transversais , Fezes/virologia , Feminino , Humanos , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
20.
Gut Microbes ; 12(1): 1785251, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-32684075

RESUMO

BACKGROUND AND AIMS: Alcoholic hepatitis is the most severe form of alcohol-related liver disease. While the gut microbiome is known to play a role in disease development and progression, less is known about specific compositional changes of the gut bacterial microbiome associated with disease severity. Therefore, the aim of our study was to correlate gut microbiota features with disease severity in alcoholic hepatitis patients. METHODS: We used 16S rRNA gene sequencing on fecal samples from 74 alcoholic hepatitis patients, which were enrolled at 9 centers in Europe, the United States, and Mexico in a multi-center observational study. The relative abundance of gut bacterial taxa on genus level, as well as the microbiome diversity, was correlated to various clinical, laboratory, and histologic parameters. RESULTS: We observed a negative correlation between the model for end-stage liver disease score and Shannon diversity, independent of potentially confounding factors (Padjust = 0.046). Alcoholic hepatitis patients with more severe disease had significantly decreased relative abundances of Akkermansia while the relative abundance of Veillonella was increased. We observed a reduction in the Bacteroides abundance (Padjust = 0.048) and Shannon diversity (Padjust = 0.018) in antibiotic-treated patients and patients receiving steroids had an increase in Veillonella abundance (Padjust = 0.005), which was both independent of potentially confounding factors. CONCLUSION: We observed distinct changes in the gut bacterial microbiome of alcoholic hepatitis patients with more severe disease. The gut bacterial microbiome might be an attractive target to prevent and treat this deadly disease.

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