33 results on '"Holland CH"'
Search Results
2. Metabolic reprogramming in livers of mice with chronic liver disease
- Author
-
Myllys, M, additional, Holland, CH, additional, Saez-Rodriquez, J, additional, Murad, W, additional, Zaza, A, additional, Hassan, R, additional, Ahmed, YA, additional, Abbas, T, additional, Abdelrahim, EA, additional, Schneider, KM, additional, Jörg, R, additional, Drasdo, D, additional, Berres, ML, additional, Trautwein, C, additional, Hengstler, JG, additional, and Ghallab, A, additional
- Published
- 2020
- Full Text
- View/download PDF
3. Design Criteria for Visual Cues Used in Disruptive Learning Interventions Within Sustainability Education
- Author
-
Tillmanns Tanja, Holland Charlotte, and Filho Alfredo Salomão
- Subjects
disruptive learning ,visual cue ,pedagogy ,sustainability education ,higher education ,Special aspects of education ,LC8-6691 - Abstract
This paper presents the design criteria for Visual Cues – visual stimuli that are used in combination with other pedagogical processes and tools in Disruptive Learning interventions in sustainability education – to disrupt learners’ existing frames of mind and help re-orient learners’ mind-sets towards sustainability. The theory of Disruptive Learning rests on the premise that if learners’ frames of mind or frames of reference can be disrupted (in other words, challenged), then learners’ mind-sets can be re-oriented towards sustainability, and indeed learners can be motivated to engage in change agency for sustainability. The use of Visual Cues thus unsettle or challenge learners’ mind-sets, and in doing so, set them on the pathway towards re-orientation in becoming more sustainability oriented, and/or in motivating engagement in sustainability change agency. The findings form part of a broader research study on ESD conducted in a higher education institution in Ireland within an undergraduate degree of teacher education. Kathy Charmaz’ Constructivist Grounded Theory approach guided the entire study, resulting in the articulation of the theory of, and processes within, Disruptive Learning. This paper presents design criteria for Visual Cues that were articulated through a thematic analysis approach from data emerging from reflective diaries, follow-up interviews, audio recordings and observational notes. The findings from this study in respect of design criteria state that Visual Cues must disrupt rather than disturb; must represent (have impressions of) real life contexts, scenarios, practices or events; must provoke controversy; must contain a visual stimulation; and can have a critical question.
- Published
- 2017
- Full Text
- View/download PDF
4. Early mucosal sensing of SIV infection by paneth cells induces IL-1β production and initiates gut epithelial disruption.
- Author
-
Lauren A Hirao, Irina Grishina, Olivier Bourry, William K Hu, Monsicha Somrit, Sumathi Sankaran-Walters, Chris A Gaulke, Anne N Fenton, Jay A Li, Robert W Crawford, Frank Chuang, Ross Tarara, Maria L Marco, Andreas J Bäumler, Holland Cheng, and Satya Dandekar
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
HIV causes rapid CD4+ T cell depletion in the gut mucosa, resulting in immune deficiency and defects in the intestinal epithelial barrier. Breakdown in gut barrier integrity is linked to chronic inflammation and disease progression. However, the early effects of HIV on the gut epithelium, prior to the CD4+ T cell depletion, are not known. Further, the impact of early viral infection on mucosal responses to pathogenic and commensal microbes has not been investigated. We utilized the SIV model of AIDS to assess the earliest host-virus interactions and mechanisms of inflammation and dysfunction in the gut, prior to CD4+ T cell depletion. An intestinal loop model was used to interrogate the effects of SIV infection on gut mucosal immune sensing and response to pathogens and commensal bacteria in vivo. At 2.5 days post-SIV infection, low viral loads were detected in peripheral blood and gut mucosa without CD4+ T cell loss. However, immunohistological analysis revealed the disruption of the gut epithelium manifested by decreased expression and mislocalization of tight junction proteins. Correlating with epithelial disruption was a significant induction of IL-1β expression by Paneth cells, which were in close proximity to SIV-infected cells in the intestinal crypts. The IL-1β response preceded the induction of the antiviral interferon response. Despite the disruption of the gut epithelium, no aberrant responses to pathogenic or commensal bacteria were observed. In fact, inoculation of commensal Lactobacillus plantarum in intestinal loops led to rapid anti-inflammatory response and epithelial tight junction repair in SIV infected macaques. Thus, intestinal Paneth cells are the earliest responders to viral infection and induce gut inflammation through IL-1β signaling. Reversal of the IL-1β induced gut epithelial damage by Lactobacillus plantarum suggests synergistic host-commensal interactions during early viral infection and identify these mechanisms as potential targets for therapeutic intervention.
- Published
- 2014
- Full Text
- View/download PDF
5. Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice.
- Author
-
Fendt R, Ghallab A, Myllys M, Hofmann U, Hassan R, Hobloss Z, González D, Brackhagen L, Marchan R, Edlund K, Seddek AL, Abdelmageed N, Blank LM, Schlender JF, Holland CH, Hengstler JG, and Kuepfer L
- Abstract
Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult. Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls. Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers ( Abcc3 and Abcc4 ). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29 , were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers. Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms., Competing Interests: Author J-FS was employed by the company Bayer AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fendt, Ghallab, Myllys, Hofmann, Hassan, Hobloss, González, Brackhagen, Marchan, Edlund, Seddek, Abdelmageed, Blank, Schlender, Holland, Hengstler and Kuepfer.)
- Published
- 2023
- Full Text
- View/download PDF
6. Tolerance of repeated toxic injuries of murine livers is associated with steatosis and inflammation.
- Author
-
Hammad S, Ogris C, Othman A, Erdoesi P, Schmidt-Heck W, Biermayer I, Helm B, Gao Y, Piorońska W, Holland CH, D'Alessandro LA, de la Torre C, Sticht C, Al Aoua S, Theis FJ, Bantel H, Ebert MP, Klingmüller U, Hengstler JG, Dooley S, and Mueller NS
- Subjects
- Humans, Animals, Mice, Inflammation, Liver Cirrhosis chemically induced, Reinjuries, Fatty Liver
- Abstract
The human liver has a remarkable capacity to regenerate and thus compensate over decades for fibrosis caused by toxic chemicals, drugs, alcohol, or malnutrition. To date, no protective mechanisms have been identified that help the liver tolerate these repeated injuries. In this study, we revealed dysregulation of lipid metabolism and mild inflammation as protective mechanisms by studying longitudinal multi-omic measurements of liver fibrosis induced by repeated CCl
4 injections in mice (n = 45). Based on comprehensive proteomics, transcriptomics, blood- and tissue-level profiling, we uncovered three phases of early disease development-initiation, progression, and tolerance. Using novel multi-omic network analysis, we identified multi-level mechanisms that are significantly dysregulated in the injury-tolerant response. Public data analysis shows that these profiles are altered in human liver diseases, including fibrosis and early cirrhosis stages. Our findings mark the beginning of the tolerance phase as the critical switching point in liver response to repetitive toxic doses. After fostering extracellular matrix accumulation as an acute response, we observe a deposition of tiny lipid droplets in hepatocytes only in the Tolerant phase. Our comprehensive study shows that lipid metabolism and mild inflammation may serve as biomarkers and are putative functional requirements to resist further disease progression., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
7. Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment.
- Author
-
Schneider KM, Mohs A, Gui W, Galvez EJC, Candels LS, Hoenicke L, Muthukumarasamy U, Holland CH, Elfers C, Kilic K, Schneider CV, Schierwagen R, Strnad P, Wirtz TH, Marschall HU, Latz E, Lelouvier B, Saez-Rodriguez J, de Vos W, Strowig T, Trebicka J, and Trautwein C
- Subjects
- Animals, Dysbiosis complications, Mice, Tumor Microenvironment, Carcinoma, Hepatocellular metabolism, Gastrointestinal Microbiome, Liver Neoplasms metabolism, Microbiota
- Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6
-/- mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
8. FUNKI: interactive functional footprint-based analysis of omics data.
- Author
-
Hernansaiz-Ballesteros R, Holland CH, Dugourd A, and Saez-Rodriguez J
- Subjects
- Data Interpretation, Statistical, Software, Transcriptome
- Abstract
Motivation: Omics data are broadly used to get a snapshot of the molecular status of cells. In particular, changes in omics can be used to estimate the activity of pathways, transcription factors and kinases based on known regulated targets, that we call footprints. Then the molecular paths driving these activities can be estimated using causal reasoning on large signalling networks., Results: We have developed FUNKI, a FUNctional toolKIt for footprint analysis. It provides a user-friendly interface for an easy and fast analysis of transcriptomics, phosphoproteomics and metabolomics data, either from bulk or single-cell experiments. FUNKI also features different options to visualize the results and run post-analyses, and is mirrored as a scripted version in R., Availability and Implementation: FUNKI is a free and open-source application built on R and Shiny, available at https://github.com/saezlab/ShinyFUNKI and https://saezlab.shinyapps.io/funki/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)
- Published
- 2022
- Full Text
- View/download PDF
9. decoupleR: ensemble of computational methods to infer biological activities from omics data.
- Author
-
Badia-I-Mompel P, Vélez Santiago J, Braunger J, Geiss C, Dimitrov D, Müller-Dott S, Taus P, Dugourd A, Holland CH, Ramirez Flores RO, and Saez-Rodriguez J
- Abstract
Summary: Many methods allow us to extract biological activities from omics data using information from prior knowledge resources, reducing the dimensionality for increased statistical power and better interpretability. Here, we present decoupleR, a Bioconductor and Python package containing computational methods to extract these activities within a unified framework. decoupleR allows us to flexibly run any method with a given resource, including methods that leverage mode of regulation and weights of interactions, which are not present in other frameworks. Moreover, it leverages OmniPath, a meta-resource comprising over 100 databases of prior knowledge. Using decoupleR, we evaluated the performance of methods on transcriptomic and phospho-proteomic perturbation experiments. Our findings suggest that simple linear models and the consensus score across top methods perform better than other methods at predicting perturbed regulators., Availability and Implementation: decoupleR's open-source code is available in Bioconductor (https://www.bioconductor.org/packages/release/bioc/html/decoupleR.html) for R and in GitHub (https://github.com/saezlab/decoupler-py) for Python. The code to reproduce the results is in GitHub (https://github.com/saezlab/decoupleR_manuscript) and the data in Zenodo (https://zenodo.org/record/5645208)., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2022. Published by Oxford University Press.)
- Published
- 2022
- Full Text
- View/download PDF
10. Stabilization but No Functional Influence of HIF-1α Expression in the Intestinal Epithelium during Salmonella Typhimurium Infection.
- Author
-
Robrahn L, Dupont A, Jumpertz S, Zhang K, Holland CH, Guillaume J, Rappold S, Roth J, Cerovic V, Saez-Rodriguez J, Hornef MW, and Cramer T
- Subjects
- Animals, Epithelial Cells microbiology, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Intestinal Mucosa microbiology, Macrophages, Mice, Salmonella Infections genetics, Salmonella typhimurium genetics
- Abstract
Hypoxia-inducible transcription factor 1 (HIF-1) has been shown to enhance microbial killing and ameliorate the course of bacterial infections. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the gastrointestinal tract remains largely elusive. With the help of a publicly available gene expression data set, we inferred significant activation of HIF-1 after oral infection of mice with Salmonella enterica serovar Typhimurium. Immunohistochemistry and Western blot analyses confirmed marked HIF-1α protein stabilization, especially in the intestinal epithelium. This prompted us to analyze conditional Hif1a -deficient mice to examine cell type-specific functions of HIF-1 in this model. Our results demonstrate enhanced noncanonical induction of HIF-1 activity upon Salmonella infection in the intestinal epithelium as well as in macrophages. Surprisingly, Hif1a deletion in intestinal epithelial cells did not impact inflammatory gene expression, bacterial spread, or disease outcomes. In contrast, Hif1a deletion in myeloid cells enhanced intestinal Cxcl2 expression and reduced the cecal Salmonella load. In vitro , HIF-1α-deficient macrophages showed overall impaired transcription of mRNA encoding proinflammatory factors; however, the intracellular survival of Salmonella was not impacted by HIF-1α deficiency.
- Published
- 2022
- Full Text
- View/download PDF
11. Transcriptomic Cross-Species Analysis of Chronic Liver Disease Reveals Consistent Regulation Between Humans and Mice.
- Author
-
Holland CH, Ramirez Flores RO, Myllys M, Hassan R, Edlund K, Hofmann U, Marchan R, Cadenas C, Reinders J, Hoehme S, Seddek AL, Dooley S, Keitel V, Godoy P, Begher-Tibbe B, Trautwein C, Rupp C, Mueller S, Longerich T, Hengstler JG, Saez-Rodriguez J, and Ghallab A
- Subjects
- Animals, Chronic Disease, Down-Regulation, Humans, Mice, Species Specificity, Up-Regulation, Disease Models, Animal, Gene Expression Profiling, Liver Diseases genetics, Transcriptome
- Abstract
Mouse models are frequently used to study chronic liver diseases (CLDs). To assess their translational relevance, we quantified the similarity of commonly used mouse models to human CLDs based on transcriptome data. Gene-expression data from 372 patients were compared with data from acute and chronic mouse models consisting of 227 mice, and additionally to nine published gene sets of chronic mouse models. Genes consistently altered in humans and mice were mapped to liver cell types based on single-cell RNA-sequencing data and validated by immunostaining. Considering the top differentially expressed genes, the similarity between humans and mice varied among the mouse models and depended on the period of damage induction. The highest recall (0.4) and precision (0.33) were observed for the model with 12-months damage induction by CCl
4 and by a Western diet, respectively. Genes consistently up-regulated between the chronic CCl4 model and human CLDs were enriched in inflammatory and developmental processes, and mostly mapped to cholangiocytes, macrophages, and endothelial and mesenchymal cells. Down-regulated genes were enriched in metabolic processes and mapped to hepatocytes. Immunostaining confirmed the regulation of selected genes and their cell type specificity. Genes that were up-regulated in both acute and chronic models showed higher recall and precision with respect to human CLDs than exclusively acute or chronic genes. Conclusion: Similarly regulated genes in human and mouse CLDs were identified. Despite major interspecies differences, mouse models detected 40% of the genes significantly altered in human CLD. The translational relevance of individual genes can be assessed at https://saezlab.shinyapps.io/liverdiseaseatlas/., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)- Published
- 2022
- Full Text
- View/download PDF
12. Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression.
- Author
-
Ghallab A, Myllys M, Friebel A, Duda J, Edlund K, Halilbasic E, Vucur M, Hobloss Z, Brackhagen L, Begher-Tibbe B, Hassan R, Burke M, Genc E, Frohwein LJ, Hofmann U, Holland CH, González D, Keller M, Seddek AL, Abbas T, Mohammed ESI, Teufel A, Itzel T, Metzler S, Marchan R, Cadenas C, Watzl C, Nitsche MA, Kappenberg F, Luedde T, Longerich T, Rahnenführer J, Hoehme S, Trauner M, and Hengstler JG
- Subjects
- Animals, Disease Models, Animal, Disease Progression, Liver metabolism, Mice, Mice, Inbred C57BL, Carcinoma, Hepatocellular pathology, Diet, Western adverse effects, Liver Neoplasms pathology, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of 'rest-and-jump genes' that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30-48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.
- Published
- 2021
- Full Text
- View/download PDF
13. Consensus Transcriptional Landscape of Human End-Stage Heart Failure.
- Author
-
Ramirez Flores RO, Lanzer JD, Holland CH, Leuschner F, Most P, Schultz JH, Levinson RT, and Saez-Rodriguez J
- Subjects
- Consensus, Heart Failure metabolism, Heart Failure physiopathology, Humans, Signal Transduction, Gene Expression Profiling methods, Heart Failure genetics, Myocardium metabolism, Transcription Factors genetics, Transcriptome genetics, Ventricular Remodeling physiology
- Abstract
Background Transcriptomic studies have contributed to fundamental knowledge of myocardial remodeling in human heart failure (HF). However, the key HF genes reported are often inconsistent between studies, and systematic efforts to integrate evidence from multiple patient cohorts are lacking. Here, we aimed to provide a framework for comprehensive comparison and analysis of publicly available data sets resulting in an unbiased consensus transcriptional signature of human end-stage HF. Methods and Results We curated and uniformly processed 16 public transcriptomic studies of left ventricular samples from 263 healthy and 653 failing human hearts. First, we evaluated the degree of consistency between studies by using linear classifiers and overrepresentation analysis. Then, we meta-analyzed the deregulation of 14 041 genes to extract a consensus signature of HF. Finally, to functionally characterize this signature, we estimated the activities of 343 transcription factors, 14 signaling pathways, and 182 micro RNAs, as well as the enrichment of 5998 biological processes. Machine learning approaches revealed conserved disease patterns across all studies independent of technical differences. These consistent molecular changes were prioritized with a meta-analysis, functionally characterized and validated on external data. We provide all results in a free public resource (https://saezlab.shinyapps.io/reheat/) and exemplified usage by deciphering fetal gene reprogramming and tracing the potential myocardial origin of the plasma proteome markers in patients with HF. Conclusions Even though technical and sampling variability confound the identification of differentially expressed genes in individual studies, we demonstrated that coordinated molecular responses during end-stage HF are conserved. The presented resource is crucial to complement findings in independent studies and decipher fundamental changes in failing myocardium.
- Published
- 2021
- Full Text
- View/download PDF
14. Transcription Factor Activity Inference in Systemic Lupus Erythematosus.
- Author
-
Lopez-Dominguez R, Toro-Dominguez D, Martorell-Marugan J, Garcia-Moreno A, Holland CH, Saez-Rodriguez J, Goldman D, Petri MA, Alarcon-Riquelme ME, and Carmona-Saez P
- Abstract
Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to decipher TFs implicated in SLE., Methods: In order to decipher regulatory mechanisms in SLE, we have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE patients based on the estimated TF activities and analyzed the differential activity patterns among SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used to stratify SLE patients and define sets of TFs with statistically significant differential activity among the disease and control samples., Results: TF activities were able to identify two main subgroups of patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns in two independent datasets-one from pediatric patients and other from adults. Furthermore, after contrasting all subgroups of patients and controls, we obtained a significant and robust list of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new pathways that might have important roles in SLE., Conclusions: These results provide a foundation to comprehend the regulatory mechanism underlying SLE and the established regulatory factors behind SLE heterogeneity that could be potential therapeutic targets.
- Published
- 2021
- Full Text
- View/download PDF
15. Corrigendum: Benchmark and integration of resources for the estimation of human transcription factor activities.
- Author
-
Garcia-Alonso L, Holland CH, Ibrahim MM, Turei D, and Saez-Rodriguez J
- Published
- 2021
- Full Text
- View/download PDF
16. Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis.
- Author
-
Mohs A, Otto T, Schneider KM, Peltzer M, Boekschoten M, Holland CH, Hudert CA, Kalveram L, Wiegand S, Saez-Rodriguez J, Longerich T, Hengstler JG, and Trautwein C
- Subjects
- Adolescent, Animals, Apoptosis genetics, Carcinogenesis genetics, Cell Cycle genetics, Child, Cohort Studies, Disease Models, Animal, Disease Progression, Down-Regulation genetics, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Humans, Kelch-Like ECH-Associated Protein 1 genetics, Kelch-Like ECH-Associated Protein 1 metabolism, Liver pathology, Liver Cirrhosis genetics, Male, Mice, Mice, Knockout, Non-alcoholic Fatty Liver Disease diagnosis, Non-alcoholic Fatty Liver Disease genetics, Oxidative Stress genetics, Carcinogenesis metabolism, Hepatocytes metabolism, Liver Cirrhosis metabolism, NF-E2-Related Factor 2 metabolism, Non-alcoholic Fatty Liver Disease metabolism, Signal Transduction genetics
- Abstract
Background & Aims: In chronic liver diseases, inflammation induces oxidative stress and thus may contribute to the progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is a major regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in humans and mice., Methods: The clinical relevance of oxidative stress was investigated by liver RNA sequencing in a well-characterized cohort of patients with non-alcoholic fatty liver disease (n = 63) and correlated with histological and clinical parameters. For functional analysis, hepatocyte-specific Nemo knockout (NEMO
Δhepa ) mice were crossed with hepatocyte-specific Keap1 knockout (KEAP1Δhepa ) mice., Results: Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that Keap1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g., Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMOΔhepa livers was rescued after deleting Keap1. As a consequence, NEMOΔhepa /KEAP1Δhepa livers showed reduced apoptosis compared to NEMOΔhepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMOΔhepa /KEAP1Δhepa compared to NEMOΔhepa livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size., Conclusions: NRF2 activation in patients with non-alcoholic steatohepatitis correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis., Lay Summary: The KEAP1 (Kelch-like ECH-associated protein-1)/NRF2 (erythroid 2-related factor 2) axis has a major role in regulating cellular redox balance. Herein, we show that NRF2 activity correlates with the grade of inflammation in patients with non-alcoholic steatohepatitis. Functional studies in mice actually show that NRF2 activation, resulting from KEAP1 deletion, protects against fibrosis and cancer., Competing Interests: Conflict of interest The authors have declared that no conflict of interest exists. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
17. Transfer of regulatory knowledge from human to mouse for functional genomics analysis.
- Author
-
Holland CH, Szalai B, and Saez-Rodriguez J
- Subjects
- Animals, Benchmarking, Disease genetics, Gene Expression Regulation, Humans, Mice, Gene Expression Profiling, Genomics methods, Transcription Factors metabolism
- Abstract
Transcriptome profiling followed by differential gene expression analysis often leads to lists of genes that are hard to analyze and interpret. Functional genomics tools are powerful approaches for downstream analysis, as they summarize the large and noisy gene expression space into a smaller number of biological meaningful features. In particular, methods that estimate the activity of processes by mapping transcripts level to process members are popular. However, footprints of either a pathway or transcription factor (TF) on gene expression show superior performance over mapping-based gene sets. These footprints are largely developed for humans and their usability in the broadly-used model organism Mus musculus is uncertain. Evolutionary conservation of the gene regulatory system suggests that footprints of human pathways and TFs can functionally characterize mice data. In this paper we analyze this hypothesis. We perform a comprehensive benchmark study exploiting two state-of-the-art footprint methods, DoRothEA and an extended version of PROGENy. These methods infer TF and pathway activity, respectively. Our results show that both can recover mouse perturbations, confirming our hypothesis that footprints are conserved between mice and humans. Subsequently, we illustrate the usability of PROGENy and DoRothEA by recovering pathway/TF-disease associations from newly generated disease sets. Additionally, we provide pathway and TF activity scores for a large collection of human and mouse perturbation and disease experiments (2374). We believe that this resource, available for interactive exploration and download (https://saezlab.shinyapps.io/footprint_scores/), can have broad applications including the study of diseases and therapeutics., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
18. Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data.
- Author
-
Holland CH, Tanevski J, Perales-Patón J, Gleixner J, Kumar MP, Mereu E, Joughin BA, Stegle O, Lauffenburger DA, Heyn H, Szalai B, and Saez-Rodriguez J
- Subjects
- Animals, Benchmarking, Gene Regulatory Networks, Humans, RNA-Seq standards, Single-Cell Analysis standards, Transcription Factors metabolism, Transcriptome, RNA-Seq methods, Single-Cell Analysis methods, Software standards
- Abstract
Background: Many functional analysis tools have been developed to extract functional and mechanistic insight from bulk transcriptome data. With the advent of single-cell RNA sequencing (scRNA-seq), it is in principle possible to do such an analysis for single cells. However, scRNA-seq data has characteristics such as drop-out events and low library sizes. It is thus not clear if functional TF and pathway analysis tools established for bulk sequencing can be applied to scRNA-seq in a meaningful way., Results: To address this question, we perform benchmark studies on simulated and real scRNA-seq data. We include the bulk-RNA tools PROGENy, GO enrichment, and DoRothEA that estimate pathway and transcription factor (TF) activities, respectively, and compare them against the tools SCENIC/AUCell and metaVIPER, designed for scRNA-seq. For the in silico study, we simulate single cells from TF/pathway perturbation bulk RNA-seq experiments. We complement the simulated data with real scRNA-seq data upon CRISPR-mediated knock-out. Our benchmarks on simulated and real data reveal comparable performance to the original bulk data. Additionally, we show that the TF and pathway activities preserve cell type-specific variability by analyzing a mixture sample sequenced with 13 scRNA-seq protocols. We also provide the benchmark data for further use by the community., Conclusions: Our analyses suggest that bulk-based functional analysis tools that use manually curated footprint gene sets can be applied to scRNA-seq data, partially outperforming dedicated single-cell tools. Furthermore, we find that the performance of functional analysis tools is more sensitive to the gene sets than to the statistic used.
- Published
- 2020
- Full Text
- View/download PDF
19. Influence of Liver Fibrosis on Lobular Zonation.
- Author
-
Ghallab A, Myllys M, Holland CH, Zaza A, Murad W, Hassan R, Ahmed YA, Abbas T, Abdelrahim EA, Schneider KM, Matz-Soja M, Reinders J, Gebhardt R, Berres ML, Hatting M, Drasdo D, Saez-Rodriguez J, Trautwein C, and Hengstler JG
- Subjects
- Animals, Biopsy, Computational Biology methods, Disease Models, Animal, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Immunohistochemistry, Liver Cirrhosis diagnostic imaging, Liver Cirrhosis pathology, Male, Mice, Optical Imaging, Disease Susceptibility, Liver Cirrhosis etiology, Liver Cirrhosis metabolism
- Abstract
Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl
4 administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 days) and mdr2- / - mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl4 ; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated 'periportalization' was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds., Competing Interests: the authors declare no conflicts of interest.- Published
- 2019
- Full Text
- View/download PDF
20. A Functional Landscape of CKD Entities From Public Transcriptomic Data.
- Author
-
Tajti F, Kuppe C, Antoranz A, Ibrahim MM, Kim H, Ceccarelli F, Holland CH, Olauson H, Floege J, Alexopoulos LG, Kramann R, and Saez-Rodriguez J
- Abstract
Introduction: To develop effective therapies and identify novel early biomarkers for chronic kidney disease, an understanding of the molecular mechanisms orchestrating it is essential. We here set out to understand how differences in chronic kidney disease (CKD) origin are reflected in gene expression. To this end, we integrated publicly available human glomerular microarray gene expression data for 9 kidney disease entities that account for most of CKD worldwide. Our primary goal was to demonstrate the possibilities and potential on data analysis and integration to the nephrology community., Methods: We integrated data from 5 publicly available studies and compared glomerular gene expression profiles of disease with that of controls from nontumor parts of kidney cancer nephrectomy tissues. A major challenge was the integration of the data from different sources, platforms, and conditions that we mitigated with a bespoke stringent procedure., Results: We performed a global transcriptome-based delineation of different kidney disease entities, obtaining a transcriptomic diffusion map of their similarities and differences based on the genes that acquire a consistent differential expression between each kidney disease entity and nephrectomy tissue. We derived functional insights by inferring the activity of signaling pathways and transcription factors from the collected gene expression data and identified potential drug candidates based on expression signature matching. We validated representative findings by immunostaining in human kidney biopsies indicating, for example, that the transcription factor FOXM1 is significantly and specifically expressed in parietal epithelial cells in rapidly progressive glomerulonephritis (RPGN) whereas not expressed in control kidney tissue. Furthermore, we found drug candidates by matching the signature on expression of drugs to that of the CKD entities, in particular, the Food and Drug Administration-approved drug nilotinib., Conclusion: These results provide a foundation to comprehend the specific molecular mechanisms underlying different kidney disease entities that can pave the way to identify biomarkers and potential therapeutic targets. To facilitate further use, we provide our results as a free interactive Web application: https://saezlab.shinyapps.io/ckd_landscape/. However, because of the limitations of the data and the difficulties in its integration, any specific result should be considered with caution. Indeed, we consider this study rather an illustration of the value of functional genomics and integration of existing data., (© 2019 International Society of Nephrology. Published by Elsevier Inc.)
- Published
- 2019
- Full Text
- View/download PDF
21. Signatures of cell death and proliferation in perturbation transcriptomics data-from confounding factor to effective prediction.
- Author
-
Szalai B, Subramanian V, Holland CH, Alföldi R, Puskás LG, and Saez-Rodriguez J
- Subjects
- Cell Death genetics, Cell Line, Tumor, Cell Proliferation genetics, Cell Survival genetics, Drug Discovery, Humans, Gene Expression Profiling methods, Gene Regulatory Networks genetics, Software, Transcriptome genetics
- Abstract
Transcriptional perturbation signatures are valuable data sources for functional genomics. Linking perturbation signatures to screenings opens the possibility to model cellular phenotypes from expression data and to identify efficacious drugs. We linked perturbation transcriptomics data from the LINCS-L1000 project with cell viability information upon genetic (Achilles project) and chemical (CTRP screen) perturbations yielding more than 90 000 signature-viability pairs. An integrated analysis showed that the cell viability signature is a major factor underlying perturbation signatures. The signature is linked to transcription factors regulating cell death, proliferation and division time. We used the cell viability-signature relationship to predict viability from transcriptomics signatures, and identified and validated compounds that induce cell death in tumor cell lines. We showed that cellular toxicity can lead to unexpected similarity of signatures, confounding mechanism of action discovery. Consensus compound signatures predicted cell-specific drug sensitivity, even if the signature is not measured in the same cell line, and outperformed conventional drug-specific features. Our results can help in understanding mechanisms behind cell death and removing confounding factors of transcriptomic perturbation screens. To interactively browse our results and predict cell viability in new gene expression samples, we developed CEVIChE (CEll VIability Calculator from gene Expression; https://saezlab.shinyapps.io/ceviche/)., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2019
- Full Text
- View/download PDF
22. Benchmark and integration of resources for the estimation of human transcription factor activities.
- Author
-
Garcia-Alonso L, Holland CH, Ibrahim MM, Turei D, and Saez-Rodriguez J
- Subjects
- Binding Sites, Chromatin chemistry, Chromatin metabolism, Chromatin Immunoprecipitation, Computational Biology methods, DNA, Neoplasm metabolism, Datasets as Topic, Gene Regulatory Networks, Humans, Neoplasm Proteins metabolism, Neoplasms classification, Neoplasms metabolism, Neoplasms pathology, Promoter Regions, Genetic, Protein Binding, Regulon, Transcription Factors metabolism, Benchmarking, DNA, Neoplasm genetics, Neoplasm Proteins genetics, Neoplasms genetics, Transcription Factors genetics, Transcription, Genetic
- Abstract
The prediction of transcription factor (TF) activities from the gene expression of their targets (i.e., TF regulon) is becoming a widely used approach to characterize the functional status of transcriptional regulatory circuits. Several strategies and data sets have been proposed to link the target genes likely regulated by a TF, each one providing a different level of evidence. The most established ones are (1) manually curated repositories, (2) interactions derived from ChIP-seq binding data, (3) in silico prediction of TF binding on gene promoters, and (4) reverse-engineered regulons from large gene expression data sets. However, it is not known how these different sources of regulons affect the TF activity estimations and, thereby, downstream analysis and interpretation. Here we compared the accuracy and biases of these strategies to define human TF regulons by means of their ability to predict changes in TF activities in three reference benchmark data sets. We assembled a collection of TF-target interactions for 1541 human TFs and evaluated how different molecular and regulatory properties of the TFs, such as the DNA-binding domain, specificities, or mode of interaction with the chromatin, affect the predictions of TF activity. We assessed their coverage and found little overlap on the regulons derived from each strategy and better performance by literature-curated information followed by ChIP-seq data. We provide an integrated resource of all TF-target interactions derived through these strategies, with confidence scores, as a resource for enhanced prediction of TF activities., (© 2019 Garcia-Alonso et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2019
- Full Text
- View/download PDF
23. Naturally occurring neoplasms in pigeons in a research colony: a retrospective study.
- Author
-
Shimonohara N, Holland CH, Lin TL, and Wigle WL
- Subjects
- Age Factors, Animals, Bird Diseases etiology, Bird Diseases pathology, Female, Incidence, Indiana, Male, Neoplasms epidemiology, Neoplasms etiology, Neoplasms pathology, Prevalence, Retrospective Studies, Bird Diseases epidemiology, Columbidae, Neoplasms veterinary
- Abstract
This study reports the gross and microscopic pathology of naturally occurring neoplasms in adult pigeons that were presented for necropsy at the Indiana Animal Disease Diagnostic Laboratory from 2001 to 2011. The study population consisted of white carneau and mixed-breed pigeons used in behavioral studies in the Department of Psychological Sciences at Purdue University. Twelve types of neoplasms or proliferative disorders were identified in 28 of 83 pigeons (33.7%). Five pigeons had two or three types of neoplasms-proliferative disorders. Of the 83 pigeons, 11 (13.3%) had seminoma, five (6.0%) had thyroid adenoma, four (4.8%) had lymphoma, four (4.8%) had adenocarcinoma of female reproductive tract origin, two (2.4%) had pulmonary carcinoma, and two (2.4%) had cutaneous vascular hamartomas. Also identified were single incidences of dysgerminoma, mesothelioma, liposarcoma, cloacal papilloma, cloacal adenocarcinoma, and gizzard carcinoma. The most frequently occurring tumor was seminoma; 7/11 cases effaced both testicles and 3/11 cases had metastasis to the liver or kidney. The relatively high prevalence of neoplasms in pigeons in the present study is most likely related to the advanced ages of pigeons kept in the research colony.
- Published
- 2013
- Full Text
- View/download PDF
24. Consequences of intratumoral injection of a herbal preparation containing blood root (Sanguinaria canadensis) extract in two dogs.
- Author
-
Childress MO, Burgess RC, Holland CH, and Gelb HR
- Subjects
- Animals, Dog Diseases therapy, Dogs, Female, Male, Neoplasms pathology, Neoplasms surgery, Plant Extracts chemistry, Postoperative Complications, Dog Diseases chemically induced, Neoplasms veterinary, Plant Extracts adverse effects, Sanguinaria chemistry
- Abstract
Case Description: 2 dogs were referred for surgical removal of cutaneous tumors that had previously been treated by intratumoral injection of a herbal preparation containing blood-root (Sanguinaria canadensis) extract., Clinical Findings: 11 days following injection of bloodroot extract into a small dermal tumor, dog 1 developed a large, soft, fluctuant cutaneous mass at the site of injection. Ultrasonographic evaluation of the mass revealed a fluid-filled central cavity with increased echogenicity of the surrounding subcutaneous tissues. Dog 2 had a small dermal tumor under the left mandible that had been treated in similar fashion. However, an exuberant reaction was not observed following injection of bloodroot extract in this dog., Treatment and Outcome: Both dogs underwent surgical excision of the cutaneous tumors. Histologic evaluation revealed severe necrosis and inflammation in the excised tissues from dog 1. This dog experienced postsurgical wound complications and had a prolonged postsurgical recovery. Similar, although less severe, histopathologic findings were apparent in the excised tissues from dog 2; this dog recovered without complications., Clinical Relevance: Various products containing bloodroot are marketed on the Internet for topical and parenteral treatment of cutaneous neoplasms in domestic animals. However, the antineoplastic properties, therapeutic efficacy, and adverse effects of these products are poorly described in the veterinary literature. Clinicians should be aware of the potential for harm caused by the use of these products.
- Published
- 2011
- Full Text
- View/download PDF
25. Assessment and management of bone health in adolescents with anorexia nervosa. Part two: bone health in adolescents with anorexia nervosa.
- Author
-
Hall CH, Hewitt G, and Stevens SL
- Subjects
- Adolescent, Bone Density drug effects, Bone Density Conservation Agents therapeutic use, Calcium therapeutic use, Female, Humans, Osteoporosis etiology, Vitamin D therapeutic use, Anorexia Nervosa complications, Bone Density physiology, Osteoporosis prevention & control
- Published
- 2008
- Full Text
- View/download PDF
26. Hormone therapy for treatment of colonic vascular ectasia in 2 dogs.
- Author
-
Goldman CK, Parnell NK, and Holland CH
- Subjects
- Angiodysplasia drug therapy, Animals, Colonic Diseases drug therapy, Dogs, Male, Angiodysplasia veterinary, Colonic Diseases veterinary, Diethylstilbestrol therapeutic use, Dog Diseases drug therapy, Hormones therapeutic use
- Published
- 2008
- Full Text
- View/download PDF
27. Assessment and management of bone health in adolescents with anorexia nervosa part one: assessment of bone health in adolescents.
- Author
-
Hall CH, Hewitt G, and Stevens SL
- Subjects
- Absorptiometry, Photon, Adolescent, Bone Density, Female, Humans, Lumbar Vertebrae diagnostic imaging, Anorexia Nervosa complications, Osteoporosis diagnosis, Osteoporosis etiology
- Published
- 2008
- Full Text
- View/download PDF
28. Clinical ehrlichiosis in a cat.
- Author
-
Bouloy RP, Lappin MR, Holland CH, Thrall MA, Baker D, and O'Neil S
- Subjects
- Animals, Antibodies, Bacterial blood, Cat Diseases drug therapy, Cats, Doxycycline therapeutic use, Ehrlichia immunology, Ehrlichia isolation & purification, Ehrlichiosis diagnosis, Ehrlichiosis drug therapy, Female, Leukocytes, Mononuclear microbiology, Lymph Nodes microbiology, Lymph Nodes pathology, Cat Diseases diagnosis, Ehrlichiosis veterinary
- Abstract
Clinical ehrlichiosis was diagnosed in a cat from Colorado on the basis of cytologic, serologic, and clinical findings. Clusters of gram-negative organisms that were morphologically similar to morulae of Ehrlichia spp were found only in mononuclear cells. The cat had clinical signs that were referable to infection by a rickettsial organism, and antibodies against E canis (titer, 1:80) and E risticii (titer, 1:40) were detected in serum. Exclusion of other obvious causes inducing similar clinical signs, and positive clinical response to doxycycline, an antibiotic with known antirickettsial actions, aided in diagnosis. The cat was clinically normal within days following initiation of treatment, and was clinically normal, as well as seronegative for antibodies against E canis and E risticii, 1,365 days after discharge.
- Published
- 1994
29. Effect of dipyridamole on ischemia-induced changes in cardiac performance and metabolism.
- Author
-
Feinberg H, Levitsky S, Coughlin TR, Merchant F, Holland CH, and O'Donaghue M
- Subjects
- Animals, Coronary Circulation drug effects, Coronary Disease physiopathology, Dogs, Myocardial Contraction drug effects, Nifedipine pharmacology, Coronary Disease metabolism, Dipyridamole pharmacology, Heart drug effects, Myocardium metabolism
- Abstract
The effect of the coronary vasocilator agents dipyridamole and nifedapine on ischemia-induced changes in cardiac performance and coronary flow was studied in extra-corporeal-circulation supported, open-chest dogs during cardio-pulmonary bypass. Coronary flow and isovolumic cardiac performance were measured prior to clamping the aorta to induce global ischemic for 60 min and again after 30 min of reperfusion. Both agents given prior to ischemia significantly enhanced the coronary flow measured 30 min after reperfusion. Almost complete complete return of pre-ischemic left ventricular dp/dt and diastolic compliance was seen if dipyridamole was administered prior to the onset of ischemia. Dipridamole administered at the end of the ischemic period and prior to reperfusion also prevented the ischemia-induced fall in dp/dt but not the decrease in compliance. Myocardial high energy phosphate compounds decreased markedly during global ischemia and dipyridamole administration had no effect on the rate or extent of their depletion. Nifedapine administration led to even greater post-ischemic coronary vasodilation; however, the ischemia-induced decline in myocardial performance was not prevented.
- Published
- 1980
- Full Text
- View/download PDF
30. Role of stigma and set in interpersonal interaction.
- Author
-
Farina A, Holland CH, and Ring K
- Subjects
- Humans, Attitude, Interpersonal Relations, Mental Disorders, Set, Psychology
- Published
- 1966
- Full Text
- View/download PDF
31. Phlegmonous Abscess.
- Author
-
Holland CH
- Published
- 1891
32. Attitudes toward computers among employees of a psychiatric hospital.
- Author
-
Reznikoff M, Holland CH, and Stroebel CF
- Subjects
- Connecticut, Factor Analysis, Statistical, Female, Humans, Male, Attitude, Computers, Hospitals, Psychiatric, Personnel, Hospital
- Published
- 1967
33. Personality factors in discrimination learning in children.
- Author
-
Crowne DP, Holland CH, and Conn LK
- Subjects
- Achievement, Analysis of Variance, Anxiety, Attention, Child, Female, Heart Rate, Humans, Impulsive Behavior, Intelligence Tests, Male, Reaction Time, Reinforcement, Psychology, Sex Factors, Discrimination Learning, Personality
- Published
- 1968
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.