RESUMO
Using information from allele-specific gene expression (ASE) can improve the power to map gene expression quantitative trait loci (eQTLs). However, such practice has been limited, partly due to computational challenges and lack of clarification on the size of power gain or new findings besides improved power. We have developed geoP, a computationally efficient method to estimate permutation p-values, which makes it computationally feasible to perform eQTL mapping with ASE counts for large cohorts. We have applied geoP to map eQTLs in 28 human tissues using the data from the Genotype-Tissue Expression (GTEx) project. We demonstrate that using ASE data not only substantially improve the power to detect eQTLs, but also allow us to quantify individual-specific genetic effects, which can be used to study the variation of eQTL effect sizes with respect to other covariates. We also compared two popular methods for eQTL mapping with ASE: TReCASE and RASQUAL. TReCASE is ten times or more faster than RASQUAL and it provides more robust type I error control.
Assuntos
Locos de Características Quantitativas , Alelos , Humanos , Locos de Características Quantitativas/genéticaRESUMO
MOTIVATION: Association testing on genome-wide association studies (GWAS) data is commonly performed under a single (mostly additive) genetic model framework. However, the underlying true genetic mechanisms are often unknown in practice for most complex traits. When the employed inheritance model deviates from the underlying model, statistical power may be reduced. To overcome this challenge, an integrative association test that directly infers the underlying genetic model from GWAS data has previously been proposed for single-SNP analysis. RESULTS: In this article, we propose a Cauchy combination Genetic Model-based association test (CauchyGM) under a generalized linear model framework for SNP-set level analysis. CauchyGM does not require prior knowledge on the underlying inheritance pattern of each SNP. It performs a score test that first estimates an individual P-value of each SNP in an SNP-set with both minor allele frequency (MAF) > 1% and three genotypes and further aggregates the rest SNPs using SKAT. CauchyGM then combines the correlated P-values across multiple SNPs and different genetic models within the set using Cauchy Combination Test. To further accommodate both sparse and dense signal patterns, we also propose an omnibus association test (CauchyGM-O) by combining CauchyGM with SKAT and the burden test. Our extensive simulations show that both CauchyGM and CauchyGM-O maintain the type I error well at the genome-wide significance level and provide substantial power improvement compared to existing methods. We apply our methods to a pharmacogenomic GWAS data from a large cardiovascular randomized clinical trial. Both CauchyGM and CauchyGM-O identify several novel genome-wide significant genes. AVAILABILITY AND IMPLEMENTATION: The R package CauchyGM is publicly available on github: https://github.com/ykim03517/CauchyGM. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Estudo de Associação Genômica Ampla , Modelos Genéticos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único , GenótipoRESUMO
Studies have confirmed that P2 purinergic receptors (P2X receptors and P2Y receptors) expressed in gastric cancer (GC) cells and GC tissues and correlates with their function. Endogenous nucleotides including ATP, ADP, UTP, and UDP, as P2 purinergic receptors activators, participate in P2 purinergic signal transduction pathway. These activated P2 purinergic receptors regulate the progression of GC mainly by mediating ion channels and intracellular signal cascades. It is worth noting that there is a difference in the expression of P2 purinergic receptors in GC, which may play different roles in the progression of GC as a tumor promoting factor or a tumor suppressor factor. Among them, P2 × 7, P2Y2 and P2Y6 receptors have certain clinical significance in patients with GC and may be used as biological molecular markers for the prediction of patients with GC. Therefore, in this paper, we discuss the functional role of nucleotide / P2 purinergic receptors signal axis in regulating the progression of GC and that these P2 purinergic receptors may be used as potential molecular targets for the prevention and treatment of GC.
RESUMO
BACKGROUND: Cartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), is characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead to apoptosis during CEP degeneration and IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis and IVDD. Despite their major success in drug delivery, the full potential of exosomes remains untapped. MATERIALS AND METHODS: In vitro and in vivo models of CEP degeneration were established by using lipopolysaccharide (LPS). We designed genetically engineered exosomes (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on the surface and carrying the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). The affinity between CAP-Nrf2-Exos and CEP was evaluated by in vitro internalization assays and in vivo imaging assays. qRTâPCR, Western blotting and immunofluorescence assays were performed to examine the expression level of Nrf2 and the subcellular localization of Nrf2 and Drp1. Mitochondrial function was measured by the JC-1 probe and MitoSOX Red. Mitochondrial morphology was visualized by MitoTracker staining and transmission electron microscopy (TEM). After subendplate injection of the engineered exosomes, the degree of CEP degeneration and IVDD was validated radiologically and histologically. RESULTS: We found that the cargo delivery efficiency of exosomes after cargo packaging was increased by surface modification. CAP-Nrf2-Exos facilitated chondrocyte-targeted delivery of Nrf2 and activated the endogenous antioxidant defence system in CEP cells. The engineered exosomes inhibited Drp1 S616 phosphorylation and mitochondrial translocation, thereby preventing mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was alleviated by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, the engineered exosomes successfully attenuated CEP degeneration and IVDD and exhibited better repair capacity than natural exosomes. CONCLUSION: Collectively, our findings showed that exosome-mediated chondrocyte-targeted delivery of Nrf2 was an effective strategy for treating CEP degeneration.
Assuntos
Condrócitos , Exossomos , Degeneração do Disco Intervertebral , Dinâmica Mitocondrial , Fator 2 Relacionado a NF-E2 , Animais , Masculino , Ratos , Apoptose , Cartilagem/metabolismo , Cartilagem/patologia , Condrócitos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Dinaminas/metabolismo , Dinaminas/genética , Exossomos/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-DawleyRESUMO
BACKGROUND: Females are considered to have an increased susceptibility to neuromyelitis optica spectrum disorder (NMOSD) than males, especially aquaporin-4 (AQP4) antibody positive NMOSD, indicating that sex hormones may be involved in the NMOSD pathogenesis. However, the causality between sex hormones and NMOSD still remains unclear. METHODS: Based on the genome-wide association study (GWAS) data of three sex hormones (estradiol (E2), progesterone (PROG) and bioavailable testosterone (BAT)), sex hormone-binding globulin (SHBG), age of menarche, age of menopause, and NMOSD (total, AQP4 + and AQP4 -), we performed a two-sample bidirectional Mendelian randomization (MR) study. Sex-stratified GWAS data of E2, PROG, BAT, and SHBG was obtained for gender-specific MR analysis. Causal inferences were based on the inverse variance weighted method, MR-Egger regression, and weighted median method. The reverse MR analysis was also performed to assess the impact of NMOSD on hormone levels. RESULTS: PROG in females had aggravative effects on NMOSD (P < 0.001), especially AQP4 - NMOSD (P < 0.001). In the reverse MR analysis, total NMOSD was found to decrease the level of BAT (P < 0.001) and increase the level of SHBG (P = 0.001) in females. CONCLUSION: Findings of this MR analysis revealed mutual causal associations between sex hormones and NMOSD, which provided novel perspectives about the gender-related pathogenesis of NMOSD.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Neuromielite Óptica , Globulina de Ligação a Hormônio Sexual , Humanos , Neuromielite Óptica/genética , Neuromielite Óptica/sangue , Feminino , Masculino , Globulina de Ligação a Hormônio Sexual/genética , Globulina de Ligação a Hormônio Sexual/metabolismo , Hormônios Esteroides Gonadais/sangue , Aquaporina 4/imunologia , Aquaporina 4/genética , Estradiol/sangue , Progesterona/sangue , Testosterona/sangueRESUMO
BACKGROUND: Cervical sagittal alignment is essential, and there is considerable debate as to what constitutes physiological sagittal alignment. The purpose of this study was to identify constant parameters for characterizing cervical sagittal alignment under physiological conditions. METHODS: A cross-sectional study was conducted in which asymptomatic subjects were recruited to undergo lateral cervical spine radiographs. Each subject was classified according to three authoritative cervical sagittal morphology classifications, followed by the evaluation of variations in radiological parameters across morphotypes. Moreover, the correlations among cervical sagittal parameters, age, and cervicothoracic junction parameters were also investigated. RESULTS: A total of 183 asymptomatic Chinese subjects were enrolled with a mean age of 48.4 years. Subjects with various cervical sagittal morphologies had comparable C4 endplate slope angles under all three different typing systems. Among patients of different ages, C2-C4 endplate slope angles remained constant. Regarding the cervicothoracic junction parameters, T1 slope and thoracic inlet angle affected cervical sagittal parameters, including cervical lordosis and C2-7 sagittal vertical axis, and were correlated with the endplate slope angles of C5 and below and did not affect the endplate slope angles of C4 and above. In general, the slope of the C4 inferior endplate ranges between 13° and 15° under different physiological conditions. CONCLUSIONS: In the asymptomatic population, the C4 vertebral body maintains a constant slope angle under physiological conditions. The novel concept of C4 as a constant vertebra would provide a vital benchmark for diagnosing pathological sagittal alignment abnormalities and planning the surgical reconstruction of cervical lordosis.
Assuntos
Cifose , Lordose , Humanos , Pessoa de Meia-Idade , Lordose/diagnóstico por imagem , Benchmarking , Estudos Transversais , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Pescoço , Estudos Retrospectivos , Cifose/cirurgiaRESUMO
OBJECTIVE: The traditional VBQ scoring method may lead to overestimation due to the concentration of intravertebral fat and vascular structures in the posterior half of vertebral bodies, potentially resulting in false-positive outcomes. This study aims to modify the measurement method of VBQ score (Modified-VBQ) and evaluate its effectiveness in evaluating bone quality of lumbar degenerative diseases. METHODS: Retrospective analysis was conducted on clinical data from patients undergoing lumbar surgery for degenerative diseases between September 2022 and September 2023. Preoperative lumbar t1-weighted Magnetic resonance imaging was used for both modified and traditional VBQ scoring. Computed tomography (CT) images and dual-energy X-ray absorptiometry (DEXA) data were collected through the picture archiving and communication system. The effectiveness of the modified VBQ score was evaluated, considering P < 0.05 as statistically significant. RESULTS: The study included 212 patients, revealing a significant difference between the modified VBQ and VBQ scores (P < 0.0001). Notably, patients with a history of hyperlipidemia exhibited a significant difference between the two scores (P = 0.0037). The area under the ROC curve (AUC) for the modified VBQ was 0.86, surpassing the VBQ score (AUC = 0.74). Linear regression analysis demonstrated a moderate to strong correlation between the modified VBQ and DEXA T-score (r = - 0.49, P < 0.0001) and a high correlation with CT Hounsfield units (HU) values (r = - 0.60, P < 0.0001). CONCLUSION: The modified VBQ score provides a simple, effective, and relatively accurate means of assessing bone quality in lumbar degenerative diseases. Preoperative implementation of the modified VBQ score facilitates rapid screening for patients with abnormal bone quality.
Assuntos
Vértebras Lombares , Imageamento por Ressonância Magnética , Humanos , Masculino , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Feminino , Pessoa de Meia-Idade , Idoso , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Adulto , Densidade Óssea/fisiologia , Absorciometria de Fóton/métodos , Idoso de 80 Anos ou mais , Tomografia Computadorizada por Raios X/métodosRESUMO
The discovery of MPTP, an industrial chemical and contaminant of illicit narcotics, which causes parkinsonism in humans, non-human primates and rodents, has led to environmental pollutants exposure being convicted as key candidate in Parkinson's disease (PD) pathogenesis. Though MPTP-induced mitochondrial dysfunction and neuroinflammation are mainly responsible for the causative issue of MPTP neurotoxicity, the underlying mechanism involved remains unclear. Here, we reveal a novel signaling mechanism of CDK5-USP30-MAVS regulating MPTP/MPP+ induced PD. MPP+ (the toxic metabolite of MPTP) treatment not only led to the increased protein levels of USP30 but also to mitophagy inhibition, mitochondrial dysfunction, and MAVS-mediated inflammation in BV2 microglial cells. Both mitophagy stimulation (Urolithin A administration) and USP30 knockdown relieved MAVS-mediated inflammation via restoring mitophagy and mitochondrial function in MPP+-induced cell model. Notably, MPTP/MPP+-induced CDK5 activation regulated USP30 phosphorylation at serine 216 to stabilize USP30. Moreover, CDK5-USP30 pathway promoted MAVS-mediated inflammation in MPTP/MPP+-induced PD model. Inhibition of CDK5 not only had a protective effect on MPP+-induced cell model of PD via suppressing the upregulation of USP30 and the activation of MAVS inflammation pathway in vitro, but also prevented neurodegeneration in vivo and alleviated movement impairment in MPTP mouse model of PD. Overall, our study reveal that CDK5 blocks mitophagy through phosphorylating USP30 and activates MAVS inflammation pathway in MPTP/MPP+-induced PD model, which suggests that CDK5-USP30-MAVS signaling pathway represents a valuable treatment strategy for PD induced by environmental neurotoxic pollutants in relation to MPTP.
Assuntos
Quinase 5 Dependente de Ciclina , Inflamação , Mitofagia , Transdução de Sinais , Animais , Masculino , Camundongos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular , Quinase 5 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Doença de ParkinsonRESUMO
Polystyrene microplastics (PS-MPs) are new types of environmental pollutant that have garnered significant attention in recent years since they were found to cause damage to the human respiratory system when they are inhaled. The pulmonary fibrosis is one of the serious consequences of PS-MPs inhalation. However, the impact and underlying mechanisms of PS-MPs on pulmonary fibrosis are not clear. In this study, we studied the potential lung toxicity and PS-MPs-developed pulmonary fibrosis by long-term intranasal inhalation of PS-MPs. The results showed that after exposing to the PS-MPs, the lungs of model mouse had different levels of damage and fibrosis. Meanwhile, exposing to the PS-MPs resulted in a markedly decrease in glutathione (GSH), an increase in malondialdehyde (MDA), and iron overload in the lung tissue of mice and alveolar epithelial cells (AECs). These findings suggested the occurrence of PS-MP-induced ferroptosis. Inhibitor of ferroptosis (Fer-1) had alleviated the PS-MPs-induced ferroptosis. Mechanically, PS-MPs triggered cell ferroptosis and promoted the development of pulmonary fibrosis via activating the cGAS/STING signaling pathway. Inhibition of cGAS/STING with G150/H151 attenuated pulmonary fibrosis after PS-MPs exposure. Together, these data provided novel mechanistic insights of PS-MPs-induced pulmonary fibrosis and a potential therapeutic paradigm.
Assuntos
Células Epiteliais Alveolares , Ferroptose , Proteínas de Membrana , Microplásticos , Poliestirenos , Fibrose Pulmonar , Transdução de Sinais , Ferroptose/efeitos dos fármacos , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Poliestirenos/toxicidade , Camundongos , Transdução de Sinais/efeitos dos fármacos , Microplásticos/toxicidade , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/patologia , Proteínas de Membrana/metabolismo , Masculino , Camundongos Endogâmicos C57BLRESUMO
Despite recent advances in treatment, non-small cell lung cancer (NSCLC) continues to have a high mortality rate. Currently, NSCLC pathogenesis requires further investigation, and therapeutic drugs are still under development. Homologous recombination repair (HRR) repairs severe DNA double-strand breaks. Homologous recombination repair deficiency (HRD) occurs when HRR is impaired and causes irreparable double-strand DNA damage, leading to genomic instability and increasing the risk of cancer development. Poly(ADP-ribose) polymerase (PARP) inhibitors can effectively treat HRD-positive tumors. Extracellular heat shock protein 90α (eHSP90α) is highly expressed in hypoxic environments and inhibits apoptosis, thereby increasing cellular tolerance. Here, we investigated the relationship between eHSP90α and HRR in NSCLC. DNA damage models were established in NSCLC cell lines (A549 and H1299). The activation of DNA damage and HRR markers, apoptosis, proliferation, and migration were investigated. In vivo tumor models were established using BALB/c nude mice and A549 cells. We found that human recombinant HSP90α stimulation further activated HRR and reduced DNA damage extent; however, eHSP90α monoclonal antibody, 1G6-D7, effectively inhibited HRR. HRR inhibition and increased apoptosis were observed after LRP1 knockdown; this effect could not be reversed with hrHSP90α addition. The combined use of 1G6-D7 and olaparib caused significant apoptosis and HRR inhibition in vitro and demonstrated promising anti-tumor effects in vivo. Extracellular HSP90α may be involved in HRR in NSCLC through LRP1. The combined use of 1G6-D7 and PARP inhibitors may exert anti-tumor effects by inhibiting DNA repair and further inducing apoptosis of NSCLC cells.
RESUMO
BACKGROUND: Lingering symptoms have been reported by survivors of Ebola virus disease (EVD). There are few data describing the persistence and severity of these symptoms over time. METHODS: Symptoms of headache, fatigue, joint pain, muscle pain, hearing loss, visual loss, numbness of hands or feet were longitudinally assessed among participants in the Liberian Ebola Survivors Cohort study. Generalized linear mixed effects models, adjusted for sex and age, were used to calculate the odds of reporting a symptom and it being rated as highly interfering with life. RESULTS: From June 2015 to June 2016, 326 survivors were enrolled a median of 389 days (range 51-614) from acute EVD. At baseline 75.2% reported at least 1 symptom; 85.8% were highly interfering with life. Over a median follow-up of 5.9 years, reporting of any symptom declined (odds ratio for each 90 days of follow-up = 0.96, 95% confidence interval [CI]: .95, .97; P < .0001) with all symptoms declining except for numbness of hands or feet. Rating of any symptom as highly interfering decreased over time. Among 311 with 5 years of follow-up, 52% (n = 161) reported a symptom and 29% (n = 47) of these as highly interfering with their lives. CONCLUSIONS: Major post-EVD symptoms are common early during convalescence and decline over time along with severity. However, even 5 years after acute infection, a majority continue to have symptoms and, for many, these continue to greatly impact their lives. These findings call for investigations to identify the mechanisms of post-EVD sequelae and therapeutic interventions to benefit the thousands of effected EVD survivors.
Assuntos
Ebolavirus , Doença pelo Vírus Ebola , Humanos , Estudos de Coortes , Hipestesia/complicações , Artralgia , Cefaleia , Surtos de Doenças , Serra LeoaRESUMO
Recent advances in single-cell RNA sequencing (scRNA-seq) enable characterization of transcriptomic profiles with single-cell resolution and circumvent averaging artifacts associated with traditional bulk RNA sequencing (RNA-seq) data. Here, we propose SCDC, a deconvolution method for bulk RNA-seq that leverages cell-type specific gene expression profiles from multiple scRNA-seq reference datasets. SCDC adopts an ENSEMBLE method to integrate deconvolution results from different scRNA-seq datasets that are produced in different laboratories and at different times, implicitly addressing the problem of batch-effect confounding. SCDC is benchmarked against existing methods using both in silico generated pseudo-bulk samples and experimentally mixed cell lines, whose known cell-type compositions serve as ground truths. We show that SCDC outperforms existing methods with improved accuracy of cell-type decomposition under both settings. To illustrate how the ENSEMBLE framework performs in complex tissues under different scenarios, we further apply our method to a human pancreatic islet dataset and a mouse mammary gland dataset. SCDC returns results that are more consistent with experimental designs and that reproduce more significant associations between cell-type proportions and measured phenotypes.
Assuntos
RNA-Seq/métodos , Análise de Célula Única/métodos , Software/normas , Animais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ilhotas Pancreáticas/metabolismo , Células MCF-7 , Glândulas Mamárias Animais/metabolismo , Camundongos , RNA-Seq/normas , Padrões de Referência , Análise de Célula Única/normasRESUMO
BACKGROUND: Lung fibroblast activation is associated with airway remodeling during asthma progression. Stearoyl-CoA desaturase 1 (SCD1) plays an important role in the response of fibroblasts to growth factors. This study aimed to explore the effects of SCD1 on fibroblast activation induced by transforming growth factor-ß1 (TGF-ß1) and the role of the phosphatidylinositol-3-kinase-AKT serine-threonine protein kinase-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway on the regulation of SCD1 expression in airway remodeling. METHODS: Female C57BL/6 mice were sensitized and challenged with house dust mites to generate a chronic asthma model. The inhibitor of SCD1 was injected i.g. before each challenge. The airway hyper-responsiveness to methacholine was evaluated, and airway remodeling and airway inflammation were assessed by histology. The effects of SCD1 on fibroblast activation were evaluated in vitro using an SCD1 inhibitor and oleic acid and via the knockdown of SCD1. The involvement of the PI3K-Akt-mTOR-sterol regulatory element-binding protein 1 (SREBP1) pathway in lung fibroblasts was investigated using relevant inhibitors. RESULTS: The expression of SCD1 was increased in fibroblasts exposed to TGF-ß1. The inhibition of SCD1 markedly ameliorated airway remodeling and lung fibroblast activation in peripheral airways. The knockdown or inhibition of SCD1 resulted in significantly reduced extracellular matrix production in TGF-ß1-treated fibroblasts, but this effect was reversed by the addition of exogenous oleic acid. The PI3K-Akt-mTOR-SREBP1 pathway was found to be involved in the regulation of SCD1 expression and lung fibroblast activation. CONCLUSIONS: The data obtained in this study indicate that SCD1 expression contributes to fibroblast activation and airway remodeling and that the inhibition of SCD1 may be a therapeutic strategy for airway remodeling in asthma.
Assuntos
Asma , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Feminino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Ácido Oleico/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/farmacologia , Remodelação das Vias Aéreas , Camundongos Endogâmicos C57BL , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Pulmão/metabolismo , Asma/patologia , Fibroblastos/metabolismo , Sirolimo/farmacologia , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismoRESUMO
Asthma is a disease characterized by airway epithelial barrier destruction, chronic airway inflammation, and airway remodeling. Repeated damage to airway epithelial cells by allergens in the environment plays an important role in the pathophysiology of asthma. Ferroptosis is a novel form of regulated cell death mediated by lipid peroxidation in association with free iron-mediated Fenton reactions. In this study, we explored the contribution of ferroptosis to house dust mite (HDM)-induced asthma models. Our in vivo and in vitro models showed labile iron accumulation and enhanced lipid peroxidation with concomitant nonapoptotic cell death upon HDM exposure. Treatment with ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (Fer-1) illuminated the role of ferroptosis and related damage-associated molecular patterns in HDM-treated airway epithelial cells. Furthermore, DFO and Fer-1 reduced HDM-induced airway inflammation in model mice. Mechanistically, NCOA4-mediated ferritin-selective autophagy (ferritinophagy) was initiated during ferritin degradation in response to HDM exposure. Together, these data suggest that ferroptosis plays an important role in HDM-induced asthma and that ferroptosis may be a potential treatment target for HDM-induced asthma.
Assuntos
Asma , Ferroptose , Animais , Células Epiteliais/metabolismo , Ferritinas/metabolismo , Inflamação , Ferro/metabolismo , Camundongos , PyroglyphidaeRESUMO
In the era of big data, univariate models have widely been used as a workhorse tool for quickly producing marginal estimators; and this is true even when in a high-dimensional dense setting, in which many features are "true," but weak signals. Genome-wide association studies (GWAS) epitomize this type of setting. Although the GWAS marginal estimator is popular, it has long been criticized for ignoring the correlation structure of genetic variants (i.e., the linkage disequilibrium [LD] pattern). In this paper, we study the effects of LD pattern on the GWAS marginal estimator and investigate whether or not additionally accounting for the LD can improve the prediction accuracy of complex traits. We consider a general high-dimensional dense setting for GWAS and study a class of ridge-type estimators, including the popular marginal estimator and the best linear unbiased prediction (BLUP) estimator as two special cases. We show that the performance of GWAS marginal estimator depends on the LD pattern through the first three moments of its eigenvalue distribution. Furthermore, we uncover that the relative performance of GWAS marginal and BLUP estimators highly depends on the ratio of GWAS sample size over the number of genetic variants. Particularly, our finding reveals that the marginal estimator can easily become near-optimal within this class when the sample size is relatively small, even though it ignores the LD pattern. On the other hand, BLUP estimator has substantially better performance than the marginal estimator as the sample size increases toward the number of genetic variants, which is typically in millions. Therefore, adjusting for the LD (such as in the BLUP) is most needed when GWAS sample size is large. We illustrate the importance of our results by using the simulated data and real GWAS.
Assuntos
Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação , Herança Multifatorial , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Confiabilidade dos Dados , Tamanho da Amostra , Simulação por ComputadorRESUMO
In contrast to differential gene expression analysis at the single-gene level, gene regulatory network (GRN) analysis depicts complex transcriptomic interactions among genes for better understandings of underlying genetic architectures of human diseases and traits. Recent advances in single-cell RNA sequencing (scRNA-seq) allow constructing GRNs at a much finer resolution than bulk RNA-seq and microarray data. However, scRNA-seq data are inherently sparse, which hinders the direct application of the popular Gaussian graphical models (GGMs). Furthermore, most existing approaches for constructing GRNs with scRNA-seq data only consider gene networks under one condition. To better understand GRNs across different but related conditions at single-cell resolution, we propose to construct Joint Gene Networks with scRNA-seq data (JGNsc) under the GGMs framework. To facilitate the use of GGMs, JGNsc first proposes a hybrid imputation procedure that combines a Bayesian zero-inflated Poisson model with an iterative low-rank matrix completion step to efficiently impute zero-inflated counts resulted from technical artifacts. JGNsc then transforms the imputed data via a nonparanormal transformation, based on which joint GGMs are constructed. We demonstrate JGNsc and assess its performance using synthetic data. The application of JGNsc on two cancer clinical studies of medulloblastoma and glioblastoma gains novel insights in addition to confirming well-known biological results.
Assuntos
Redes Reguladoras de Genes , Glioblastoma , Humanos , Análise de Sequência de RNA/métodos , Teorema de Bayes , RNA-Seq , Perfilação da Expressão Gênica/métodos , RNA/genéticaRESUMO
Cancer (treatment) vaccines that are made of neoantigens, or peptides unique to tumor cells due to somatic mutations, have emerged as a promising method to reinvigorate the immune response against cancer. A key step to prioritizing neoantigens for cancer vaccines is computationally predicting which neoantigens are presented on the cell surface by a human leukocyte antigen (HLA). We propose to address this challenge by training a neural network using mass spectrometry (MS) data composed of peptides presented by at least one of several HLAs of a subject. We embed the neural network within a mixture model and train the neural network by maximizing the likelihood of the mixture model. After evaluating our method using data sets where the peptide presentation status was known, we applied it to analyze somatic mutations of 60 melanoma patients and identified a group of neoantigens more immunogenic in tumor cells than in normal cells. Moreover, neoantigen burden estimated by our method was significantly associated with a measurement of the immune system activity, suggesting these neoantigens could induce an immune response.
Assuntos
Vacinas Anticâncer , Melanoma , Neoplasias , Humanos , Vacinas Anticâncer/química , Antígenos de Neoplasias/genética , Neoplasias/genética , Peptídeos/química , Peptídeos/genética , Antígenos HLA/genética , Melanoma/genéticaRESUMO
Computation of hypervolume under ROC manifold (HUM) is necessary to evaluate biomarkers for their capability to discriminate among multiple disease types or diagnostic groups. However the original definition of HUM involves multiple integration and thus a medical investigation for multi-class receiver operating characteristic (ROC) analysis could suffer from huge computational cost when the formula is implemented naively. We introduce a novel graph-based approach to compute HUM efficiently in this article. The computational method avoids the time-consuming multiple summation when sample size or the number of categories is large. We conduct extensive simulation studies to demonstrate the improvement of our method over existing R packages. We apply our method to two real biomedical data sets to illustrate its application.
RESUMO
BACKGROUND: The aim of this study was to explore whether ice slush (IS) causing local hypothermia can effectively inhibit the oculocardiac reflex (OCR) during strabismus surgery. METHODS: This prospective, randomized, double-blind study included 58 patients with concomitant strabismus scheduled for lateral rectus (LR) recession under general anesthesia. Patients were randomly allocated to receive IS (IS group) or standard treatment (control group) with sterile saline at room temperature before surgery. OCR was defined as a sudden decrease in heart rate (HR) of >15% from baseline. If one incidence of the OCR was found in 1 patient in any stage (0/I/II/III), the patient was defined as an OCR responder, and the incidence of overall OCR was the incidence of OCR responders. The primary outcome was the incidence of overall OCR during all stages of the surgery, which was analyzed by the Z test and computed based on the absolute risk difference with 2-sided 95% confidence intervals (CIs) using the Newcombe method. RESULTS: The overall OCR occurred in 19 of 29 patients (62.5% [95% CI, 45.7-82.1]) in the IS group and 28 of 29 patients (96.6% [95% CI, 82.2-99.9]) in the control group (absolute risk difference, -31.0% [95% CI, -49.4 to -11.0]; Z test, P < .001), which demonstrated that the incidence of overall OCR in IS group was significantly lower than that in the control group. CONCLUSIONS: IS on the ocular surface causing local hypothermia is a promising and easily accessible method to reduce the overall OCR, which can improve the safety of strabismus surgery.
Assuntos
Hipotermia , Reflexo Oculocardíaco , Estrabismo , Humanos , Gelo , Reflexo Oculocardíaco/fisiologia , Estudos Prospectivos , Estrabismo/cirurgiaRESUMO
Chronic exposure to inorganic arsenic (iAs) has been linked to diabetes in both humans and mice, but the role of iAs exposure prior to conception and its transgenerational effects are understudied. The present study investigated transgenerational effects of preconception iAs exposure in C57BL/6J mice, focusing on metabolic phenotypes of G1 and G2 offspring. Body composition and diabetes indicators, including fasting blood glucose, fasting plasma insulin, glucose tolerance, and indicators of insulin resistance and beta cell function, were examined in both generations. The results suggest that the preconception iAs exposure in the parental (G0) generation induced diabetic phenotypes in G1 and G2 offspring in a sex-dependent manner. G1 females from iAs-exposed parents developed insulin resistance while no significant effects were found in G1 males. In the G2 generation, insulin resistance was observed only in males from iAs-exposed grandparents and was associated with higher bodyweights and adiposity. Similar trends were observed in G2 females from iAs-exposed grandparents, but these did not reach statistical significance. Thus, preconception iAs exposure altered metabolic phenotype across two generations of mouse offspring. Future research will investigate the molecular mechanisms underlying these transgenerational effects, including epigenomic and transcriptomic profiles of germ cells and tissues from G0, G1 and G2 generations.