scholarly journals Aortic Gene Expression Profiles Show How ApoA-I Levels Modulate Inflammation, Lysosomal Activity, and Sphingolipid Metabolism in Murine Atherosclerosis

2020 ◽  
Author(s):  
Marco Busnelli ◽  
Stefano Manzini ◽  
Matteo Chiara ◽  
Alice Colombo ◽  
Fabrizio Fontana ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Sphingolipid Metabolism ◽  
Gene Expression Patterns ◽  
Peripheral Tissues ◽  
Lysosomal Activity ◽  
Better Regulation ◽  
Atherosclerosis Development

Objective: HDL (high-density lipoprotein) particles are known to possess several antiatherogenic properties that include the removal of excess cholesterol from peripheral tissues, the maintenance of endothelial integrity, antioxidant, and anti-inflammatory activities. ApoA-I overexpression in apoE-deficient (EKO) mice has been shown to increase HDL levels and to strongly reduce atherosclerosis development. The aim of the study was to investigate gene expression patterns associated with atherosclerosis development in the aorta of EKO mice and how HDL plasma levels relate to gene expression patterns at different stages of atherosclerosis development and with different dietary treatments. Approach and Results: Eight-week-old EKO mice, EKO mice overexpressing human apoA-I, and wild-type mice as controls were fed either normal laboratory or Western diet for 6 or 22 weeks. Cholesterol distribution among lipoproteins was evaluated, and atherosclerosis of the aorta was quantified. High-throughput sequencing technologies were used to analyze the transcriptome of the aorta of the 3 genotypes in each experimental condition. In addition to the well-known activation of inflammation and immune response, the impairment of sphingolipid metabolism, phagosome-lysosome system, and osteoclast differentiation emerged as relevant players in atherosclerosis development. The reduced atherosclerotic burden in the aorta of EKO mice expressing high levels of apoA-I was accompanied by a reduced activation of immune system markers, as well as reduced perturbation of lysosomal activity and a better regulation of the sphingolipid synthesis pathway. Conclusions: ApoA-I modulates atherosclerosis development in the aorta of EKO mice affecting the expression of pathways additional to those associated with inflammation and immune response.

scholarly journals Early Response of CD8+ T Cells in COVID-19 Patients

2021 ◽  
Vol 11 (12) ◽  
pp. 1291
Author(s):  
Deni Ramljak ◽  
Martina Vukoja ◽  
Marina Curlin ◽  
Katarina Vukojevic ◽  
Maja Barbaric ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Mrna Expression ◽  
Cd8 T Cells ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Effector Memory ◽  
Healthy Controls ◽  
Ifn Γ

Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

scholarly journals 415. Airway Gene-Expression Classifiers for Respiratory Syncytial Virus (RSV) Disease Severity in Infants

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S210-S210
Author(s):  
Mary T Caserta ◽  
Lu Wang ◽  
Chin-Yi Chu ◽  
Christopher Slaunwhite ◽  
Jeanne Holden-Wiltse ◽  
...  
Keyword(s):  
Gene Expression ◽  
Model Selection ◽  
Disease Severity ◽  
Severity Score ◽  
Cross Validation ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Multivariate Linear Regression Analysis ◽  
Linear Predictor

Abstract Background RSV infection is common in infants with a majority of those affected displaying mild clinical symptoms. However, a substantial number develop severe symptoms requiring hospitalization. We currently lack sensitive and specific predictors to identify a majority of those who develop severe disease. Methods High throughput RNA sequencing (RNAseq) of nasal epithelial cells defined airway gene expression patterns in RSV-infected subjects. Using multivariate linear regression analysis with AIC-based model selection, we built a sparse linear predictor of RSV disease severity, the Nasal Gene Severity Score-NGSS1. Using a similar statistical approach, we built an alternate predictor based upon genes displaying stable expression over time (NGSS2). We evaluated predictive performance of both models using leave-one-out cross-validation analyses. Results We defined comprehensive airway gene expression profiles from 106 full-tem previously healthy RSV-infected subjects with a range of RSV disease severity prospectively enrolled in the AsPIRES study. Nasal samples were obtained during acute infection (day 1–10 of illness; 106 samples), and convalescence (day 14–28 of illness; 69 samples). All subjects had a primary infection and were assigned a cumulative clinical illness severity score (GRSS) (Table 1). From the RNA seq data 41 genes were identified as the NGSS1 which is strongly correlated with disease severity (GRSS) in both the naive (ρ=0.935) and cross-validated analysis (ρ of 0.813). As a binary classifier (mild vs. severe), NGSS1 correctly classifies 89.6% of the subjects following cross-validation (Figure 1). Next, we evaluated genes that were stably expressed in both acute illness and convalescence samples in 54 subjects with data from both time points. Repeating the regression based step wise model selection identified 13 genes as NGSS2, which was significantly correlated with GRSS (ρ = 0.741). This model has slightly less, but comparable, prediction accuracy with a cross-validated correlation of 0.741 and cross-validated classification accuracy of 84.0% (Figure 2). Conclusion Airway gene expression patterns, obtained following a minimally-invasive nasal procedure, have potential utility as prognostic biomarkers for severe infant RSV infections. Disclosures All authors: No reported disclosures.

171 THE EFFECT OF TRICHOSTATIN A ON THE DEVELOPMENT AND THE GLOBAL GENE EXPRESSION PATTERNS IN MOUSE EMBRYOS DEVELOPING IN VITRO

2008 ◽  
Vol 20 (1) ◽  
pp. 165
Author(s):  
X. S. Cui ◽  
X. Y. Li ◽  
T. Kim ◽  
N.-H. Kim
Keyword(s):  
Gene Expression ◽  
Trichostatin A ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Mouse Embryos ◽  
Differentially Expressed ◽  
Gene Expression Patterns ◽  
Cell Stage

Trichostatin A (TSA) is an inhibitor of histone deacetylase and is able to alter gene expression patterns by interfering with the removal of acetyl groups from histones. The aim of this study was to determine the effect of TSA treatment on the development and gene expression patterns of mouse zygotes developing in vitro. The addition of 100 nm TSA to the culture medium did not affect the cleavage of mouse embryos (TSA treatment, 148/150 (99%) v. control, 107/107 (100%)); however, embryos that were treated with TSA arrested at the 2-cell stage (145/148, 98%). We estimated the number of nuclei in control and TSA-treated embryos by propidium iodide staining, taking into account the presence of any cells with two or more nuclei. At 62–63 h post-hCG stimulation, control zygotes had developed to the 4-cell stage and exhibited one nucleus in each blastomere, indicative of normal development. In contrast, we observed tetraploid nuclei in at least one blastomere in 20.8% (11/53) of the embryos that had been treated with TSA. At 28–29 h post-hCG stimulation (metaphase of the 1-cell stage), there was no difference in the mitotic index (as determined by analyzing the microtubule configuration) in the TSA group compared to the control group. At the 2-cell stage, however, we did not observe mitotic spindles and metaphase chromatin in embryos in the TSA treatment group compared to the controls. Interestingly, when embryos were cultured in TSA-free medium from 35 h post-hCG stimulation (S- or early G2-phase of the 2-cell stage) onward, almost all of them (47/50) developed to the blastocyst stage. In contrast, when embryos were cultured in TSA-free medium from 42 h post-hCG stimulation (middle G2-phase of the 2-cell stage) onward, they did not develop to the 4-cell stage. We used Illumina microarray technology to analyze the gene expression profiles in control and TSA-treated late 2-cell-stage embryos. Applied Biosystems Expression System software was used to extract assay signals and assay signal-to-noise ratio values from the microarray images. Our data showed that 897 genes were significantly (P < 0.05; 2-sample t-test) up- or down-regulated by TSA treatment compared to controls. Analysis using the PANTHER classification system (https://panther.appliedbiosystems.com) revealed that the 575 genes that were differentially expressed in the TSA group compared to the control were classified as being associated with putative biological processes or molecular function. Overall, in terms of putative biological processes, more nucleoside, nucleotide, and nucleic acid metabolism, protein metabolism and modification, signal transduction, developmental process, and cell cycle genes were differentially expressed between the TSA and control groups. In terms of putative molecular function, more nucleic acid-binding transcription factor and transferase genes were differentially expressed between the groups. The results collectively suggest that inhibition of histone acetylation in mouse embryos affects gene expression profiles at the time of zygotic genome activation, and this subsequently affects further development.

Clinical phenotype and gene expression profile in Crohn's disease

2007 ◽  
Vol 292 (1) ◽  
pp. G298-G304 ◽  
Author(s):  
Claudio Csillag ◽  
Ole Haagen Nielsen ◽  
Rehannah Borup ◽  
Finn Cilius Nielsen ◽  
Jørgen Olsen
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intracellular Transport ◽  
Clinical Phenotype ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Principal Component ◽  
Gene Profiling ◽  
Gene Expression Patterns

The clinical course varies significantly among patients with Crohn's disease (CD). This study investigated whether gene expression profiles generated by DNA microarray technology might predict disease progression. Biopsies from the descending colon were obtained colonoscopically from 40 CD patients. Gene profiling analyses were performed using a Human Genome U133 Plus 2.0 GeneChip Array, and summarization into a single expression measure for each probe set was performed using the robust multiple array procedure. Principal component analysis demonstrated that three components explain two-thirds of the total variation. The most important parameters for the determination of the colonic gene expression patterns were the presence of disease (CD) and presence of inflammation. Superimposition of clinical phenotype data revealed a grouping of the samples from patients with stenosis toward negative values on the axis of the second principal component. The functional annotation analysis suggested that the expression of genes involved in intracellular transport and cytoskeletal organization might influence the development of stenosis. In conclusion, even though most variation in the colonic gene expression patterns is due to presence or absence of CD and inflammation status, the development of stenosis is a parameter that affects colonic gene expression to some extent.

Distinct Gene Expression Patterns Defining Human Osteoblasts' Response to BMP2 Treatment: Is the Therapeutic Success All a Matter of Timing?

2016 ◽  
Vol 57 (3-4) ◽  
pp. 197-210 ◽  
Author(s):  
Sabrina Ehnert ◽  
Romina Haydée Aspera-Werz ◽  
Thomas Freude ◽  
Marie Karolina Reumann ◽  
Björn Gunnar Ochs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Therapeutic Success ◽  
Human Osteoblasts ◽  
Osteoblast Function ◽  
Repulsive Guidance Molecule

Background: Bone morphogenetic proteins (BMPs) play a key role in bone formation. Local application of BMP2 (Dibotermin alfa) supports bone formation when applied to complex fractures. However, up to 33% of patients do not respond to this therapy. Purpose: Aiming to investigate whether inter-individual responses to BMP2 treatment can be predicted by gene expression patterns, we investigated the effect of BMP2 on primary human osteoblasts and THP-1 cell-derived osteoclasts from 110 donors. Methods: Osteoblasts were obtained by collagenase digestion of spongy bone tissues. Osteoclasts were differentiated from THP-1 cells using the conditioned media of the osteoblasts. Viability was determined by resazurin conversion. As functional characteristics AP and Trap5B activity were measured. Gene expression levels were determined by RT-PCR in 21 of the 110 evaluated donors and visualized by electrophoresis. Results: Based on our data, we could classify three response groups: (i) In 51.8% of all donors, BMP2 treatment induced osteoblast function. These donors strongly expressed the BMP2 inhibitor Noggin (NOG), the alternative BMP2 receptors repulsive guidance molecule B (RGMb) and activin receptor-like kinase 6 (Alk6), as well as the Wnt inhibitor sclerostin (SOST). (ii) In 17.3% of all donors, BMP2 treatment induced viability. In these donors, the initial high SOST expression significantly dropped with BMP2 treatment. (iii) 30.9% of all donors were not directly affected by BMP2 treatment. These donors expressed high levels of the pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) and lacked SOST expression. In all donors, SOST expression correlated directly with receptor activator of NF-κB ligand (RANKL) expression, defining the cells' potential to stimulate osteoclastogenesis. Conclusions: Our data identified three donor groups profiting from BMP2 treatment either directly via stimulation of osteoblast function or viability and/or indirectly via inhibition of osteoclastogenesis, depending on their expression of BAMBI, SOST, NOG, and RANKL. On the basis of patients' respective expression profiles, the clinical application of BMP2 as well as its timing might be modified in order to better fit the patients' needs to promote bone formation or to inhibit bone resorption.

Gene expression profiling of cerebellar development with high-throughput functional analysis

2005 ◽  
Vol 22 (1) ◽  
pp. 8-13 ◽  
Author(s):  
Sakae Saito ◽  
Kimi Honma ◽  
Hiroko Kita-Matsuo ◽  
Takahiro Ochiya ◽  
Kikuya Kato
Keyword(s):  
Gene Expression ◽  
Neurite Outgrowth ◽  
High Throughput ◽  
Functional Data ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Principal Component ◽  
Data Matrix ◽  
Cerebellar Development ◽  
Gene Expression Patterns

We measured the expression levels of 450 genes during mouse postnatal cerebellar development by quantitative PCR using RNA purified from layers of the cerebellar cortex. Principal component analysis of the data matrix demonstrated that the first and second components corresponded to general levels of gene expression and gene expression patterns, respectively. We introduced 288 of the 450 genes into PC12 cells using a high-throughput transfection assay based on atelocollagen and determined the ability of each gene to promote neurite outgrowth or cell proliferation. Five genes induced neurite outgrowth, and seven genes enhanced proliferation. Evaluation of the functional data and gene expression patterns showed that none of these genes exhibited elevated expression at maturation, suggesting that genes characteristic of mature neurons are not likely to participate in neuronal development. These results demonstrate that functional data can facilitate interpretation of expression profiles and identification of new molecules that participate in biological processes.

scholarly journals Moderate alcohol consumption alters both leucocyte gene expression profiles and circulating proteins related to immune response and lipid metabolism in men

2011 ◽  
Vol 108 (4) ◽  
pp. 620-627 ◽  
Author(s):  
Michel M. Joosten ◽  
Marjan J. van Erk ◽  
Linette Pellis ◽  
Renger F. Witkamp ◽  
Henk F. J. Hendriks
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Lipid Metabolism ◽  
Alcohol Consumption ◽  
Orange Juice ◽  
Large Scale ◽  
Disease Risk ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Moderate Alcohol Consumption

Moderate alcohol consumption has various effects on immune and inflammatory processes, which could accumulatively modulate chronic disease risk. So far, no comprehensive, integrative profiling has been performed to investigate the effects of longer-term alcohol consumption. Therefore, we studied the effects of alcohol consumption on gene expression patterns using large-scale profiling of whole-genome transcriptomics in blood cells and on a number of proteins in blood. In a randomised, open-label, cross-over trial, twenty-four young, normal-weight men consumed 100 ml vodka (30 g alcohol) with 200 ml orange juice or only orange juice daily during dinner for 4 weeks. After each period, blood was sampled for measuring gene expression and selected proteins. Pathway analysis of 345 down-regulated and 455 up-regulated genes revealed effects of alcohol consumption on various signalling responses, immune processes and lipid metabolism. Among the signalling processes, the most prominently changed was glucocorticoid receptor signalling. A network on immune response showed a down-regulated NF-κB gene expression together with increased plasma adiponectin and decreased pro-inflammatory IL-1 receptor antagonist and IL-18, and acute-phase proteins ferritin and α1-antitrypsin concentrations (all P < 0·05) after alcohol consumption. Furthermore, a network of gene expression changes related to lipid metabolism was observed, with a central role for PPARα which was supported by increased HDL-cholesterol and several apo concentrations (all P < 0·05) after alcohol consumption. In conclusion, an integrated approach of profiling both genes and proteins in blood showed that 4 weeks of moderate alcohol consumption altered immune responses and lipid metabolism.

scholarly journals NIMG-44. NON-INVASIVE ADVANCED IMAGING METRICS PROVIDE POTENTIAL BIOMARKERS FOR GBM BIOLOGICAL HETEROGENEITY AND IMMUNE LANDSCAPE VARIANCE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi171-vi171
Author(s):  
Cymon Kersch ◽  
Leslie Muldoon ◽  
Rochelle Fu ◽  
Cheryl Claunch ◽  
Edward Neuwelt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Set Enrichment Analysis ◽  
Immune Gene ◽  
Biological Processes ◽  
Non Invasive ◽  
Mri Features ◽  
Inflammatory Immune Response

Abstract BACKGROUND Treatment of glioblastoma multiforme (GBM) is complicated by extensive tumor heterogeneity. We hypothesize that transcriptomic analysis of brain tumor regions with different magnetic resonance imaging (MRI) characteristics will define specific biological processes, providing a non-invasive method for tumor characterization and stratification. METHODS Previously at the University of California San Francisco, treatment naïve GBM tissue from gadolinium contrast enhancing lesion (CEL) and non-enhancing lesion (NCEL) regions were stereotactically sampled; prior to resection, relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were determined. The tissue samples were characterized by immunohistochemistry and assessed for gene expression by microarray analysis. We correlated gene expression patterns in the CEL, NCEL, and non-tumor gliotic brain samples with multimodal physiological imaging metrics and immunohistochemical phenotypes. Gene expression networks were probed using Gene Set Enrichment Analysis. Key immunologic genes were examined individually. RESULTS Samples with differing MRI and histological phenotypes demonstrated transcriptomic variance reflecting distinct biological networks. We found significant differences in immune pathways, with immune gene signature prominent in CEL areas, moderate in NCEL and low in gliotic non-tumor brain. Within homogenously enhancing areas of CEL and NCEL there was underlying heterogeneity detectable by variable rCBV, ADC and histological phenotypes, which correlate with differing gene expression profiles indicative of biological and immunological tumor microenvironments. Increasing rCBV was correlated with an anti-inflammatory immune response in the CEL and a pro-inflammatory immune response in the NCEL. ADC was negatively correlated with cell cycle and immune networks in CEL, while NCEL ADC was positively correlated with immune processes. GBM samples with the mesenchymal molecular subtype had the greatest immune response. CONCLUSIONS Multimodal MRI features identify regionally diverse transcriptomic-based biological and immunological phenotypes in GBM. We propose that imaging genomics provides a technique for localizing biological processes and tumor immune microenvironments across space and time in GBM.

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