In recent decades, climate change has led to more frequent and severe drought events, causing serious consequences such as increased forest mortality and significant crop yield losses.... Show moreIn recent decades, climate change has led to more frequent and severe drought events, causing serious consequences such as increased forest mortality and significant crop yield losses. Understanding how drought affects plants, especially economically important herbaceous species, is crucial for predicting and developing drought-resistant crops. To address this issue, this study analyzed a comprehensive dataset of anatomical and hydraulic traits in different genotypes of Arabidopsis thaliana and tomato, including both wild-type and transgenic mutants. The study also investigated the expression of four well-known drought marker genes associated with ABA-dependent and ABA-independent pathways and the impact of overexpressing the JUNGBRUNNEN1 (JUB1) gene on drought response. The findings revealed that each genotype had a unique set of traits to cope with drought, which could be categorized into two response strategies. One group enhanced their drought resistance through traits like a more negative stem P50, thicker intervessel pit membranes, a more lignified inflorescence stem, and a gradual reduction of the low initial stomatal conductance during drought. This strategy enabled them to maintain a relatively high and stable leaf water potential (Ψl). The second group, represented by JUB1 overexpression genotypes, relied primarily on maintaining a high Ψl which is possibly due to osmoprotectant accumulation in leaves, while the other traits have not been recorded. Overall, this research demonstrated the adaptive capabilities of herbaceous plants to drought conditions, highlighting the intraspecific variation in drought responses that underscores the need for a detailed assessment of drought-responsive traits to improve crop yield in a warming world. Show less
BackgroundLoss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through... Show moreBackgroundLoss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the aging process in women.MethodsWe analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males (Illumina 450k methylation array) and replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variably methylated CpGs (aVMCs), whose methylation level becomes more variable with age.ResultsIn females, aDMCs were relatively uncommon (n = 33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n = 987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (94%), indicating an independence of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI suggesting that they stemmed from the inactive X. In males, carrying an active copy of the X chromosome only, aDMCs (n = 316) were primarily driven by cell composition, while aVMCs replicated well (95%) but were infrequent (n = 37).ConclusionsOur results imply that age-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability. Show less
The use of existing medications for diseases they were not originally developed for is called drug repositioning. A popular drug repositioning method to find new drugs against specific cancer types... Show moreThe use of existing medications for diseases they were not originally developed for is called drug repositioning. A popular drug repositioning method to find new drugs against specific cancer types is to search for drugs which are expected to bring back the gene expression activity of cancer cells to that of healthy cells (‘normalization’). One of the main research goals of this thesis was to investigate of this method could also be used on the gene expression profiles of individual tumors, enabling personalization of drug repositioning candidates for each patient. We initially had some success with this approach but this eventually lead to a systematic validation of the underlying principle using almost 10,000 tumor samples across 18 different tumor types. Unfortunately, the predictive power of the method was found to be much lower than previously reported and the part that remained could be nullified by correcting the gene expression profiles of the drugs for the downstream effects of reduced cell division. These results indicate that the current use of the method does not result in drug repositioning candidates specific for a tumor type but is only able to select generally cell-toxic drugs. Show less
Transcriptome signature reversion (TSR) has been extensively proposed and used to discover new indications for existing drugs (i.e. drug repositioning, drug repurposing) for various cancer types.... Show moreTranscriptome signature reversion (TSR) has been extensively proposed and used to discover new indications for existing drugs (i.e. drug repositioning, drug repurposing) for various cancer types. TSR relies on the assumption that a drug that can revert gene expression changes induced by a disease back to original, i.e. healthy, levels is likely to be therapeutically active in treating the disease. Here, we aimed to validate the concept of TSR using the PRISM repurposing data set, which is-as of writing-the largest pharmacogenomic data set. The predictive utility of the TSR approach as it has currently been used appears to be much lower than previously reported and is completely nullified after the drug gene expression signatures are adjusted for the general anti-proliferative downstream effects of drug-induced decreased cell viability. Therefore, TSR mainly relies on generic anti-proliferative drug effects rather than on targeting cancer pathways specifically upregulated in tumor types. Show less
Straat, M.E.; Martinez-Tellez, B.; Janssen, L.G.M.; Veen, S. van; Eenige, R. van; Kharagjitsing, A.V.; ... ; Boon, M.R. 2022
Objectives: Although cold exposure is commonly believed to be causally related to acute viral respiratory infections, its effect on the immune system is largely unexplored. In this study, we... Show moreObjectives: Although cold exposure is commonly believed to be causally related to acute viral respiratory infections, its effect on the immune system is largely unexplored. In this study, we determined transcript levels of a large panel of immune genes in blood before and after cold exposure. We included both Dutch Europid and Dutch South Asian men to address whether the immune system is differently regulated in the metabolically vulnerable South Asian population.Methods: Fasted blood samples were obtained from nonobese Dutch Europid (n = 11; mean age 26 +/- 3 y) and Dutch South Asian (n = 12; mean age 28 +/- 3 y) men before and directly after short-term (similar to 2.5 h) mild cold exposure. Transcript levels of 144 immune genes were measured using a dual-color reverse transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) assay.Results: Cold exposure acutely upregulated mRNA levels of GNLY (+35%, P < 0.001) and PRF1 (+45%, P < 0.001), which encode cytotoxic proteins, and CCL4 (+8%, P < 0.01) and CCL5 (+5%, P < 0.05), both proinflammatory chemokines. At thermoneutrality, mRNA levels of four markers of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR)-family, involved in inflammasomes, were lower in Dutch South Asians compared to Dutch Europids, namely NLRP2 (-57%, P < 0.05), NLRP7 (-17%, P < 0.05), NLRP10 (-21%, P < 0.05), and NLRC4 (-23%, P < 0.05).Conclusions: Mild cold exposure acutely increases mRNA levels of genes involved in cytotoxicity of immune cells in blood. In addition, Dutch South Asians display lower circulating mRNA levels of inflammasome genes compared to Dutch Europids. Show less
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mild symptoms in the majority of infected individuals, yet in some cases it leads to a life-threatening condition.... Show moreThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mild symptoms in the majority of infected individuals, yet in some cases it leads to a life-threatening condition. Determination of early predictive biomarkers enabling risk stratification for coronavirus disease 2019 (COVID-19) patients can inform treatment and intervention strategies. Herein, we analyzed whole blood samples obtained from individuals infected with SARS-CoV-2, varying from mild to critical symptoms, approximately one week after symptom onset. In order to identify blood-specific markers of disease severity status, a targeted expression analysis of 143 immune-related genes was carried out by dual-color reverse transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA). The clinically well-defined subgroups of COVID-19 patients were compared with healthy controls. The transcriptional profile of the critically ill patients clearly separated from that of healthy individuals. Moreover, the number of differentially expressed genes increased by severity of COVID-19. It was also found that critically ill patients can be distinguished by reduced peripheral blood expression of several genes, which most likely reflects the lower lymphocyte counts. There was a notable predominance of IFN-associated gene expression in all subgroups of COVID-19, which was most profound in critically ill patients. Interestingly, the gene encoding one of the main TNF-receptors, TNFRS1A, had selectively lower expression in mild COVID-19 cases. This report provides added value in understanding COVID-19 disease, and shows potential of determining early immune transcript signatures in the blood of patients with different disease severity. These results can guide further explorations to uncover mechanisms underlying immunity and immunopathology in COVID-19. Show less
Kuijper, E.C.; Toonen, L.J.A.; Overzier, M.; Tsonaka, R.; Hettne, K.; Roos, M.; ... ; Mina, E. 2022
While the genetic cause of Huntington disease (HD) is known since 1993, still no cure exists. Therapeutic development would benefit from a method to monitor disease progression and treatment... Show moreWhile the genetic cause of Huntington disease (HD) is known since 1993, still no cure exists. Therapeutic development would benefit from a method to monitor disease progression and treatment efficacy, ideally using blood biomarkers. Previously, HD-specific signatures were identified in human blood representing signatures in human brain, showing biomarker potential. Since drug candidates are generally first screened in rodent models, we aimed to identify HD signatures in blood and brain of YAC128 HD mice and compare these with previously identified human signatures. RNA sequencing was performed on blood withdrawn at two time points and four brain regions from YAC128 and control mice. Weighted gene co-expression network analysis was used to identify clusters of co-expressed genes (modules) associated with the HD genotype. These HD-associated modules were annotated via text-mining to determine the biological processes they represented. Subsequently, the processes from mouse blood were compared with mouse brain, showing substantial overlap, including protein modification, cell cycle, RNA splicing, nuclear transport, and vesicle-mediated transport. Moreover, the disease-associated processes shared between mouse blood and brain were highly comparable to those previously identified in human blood and brain. In addition, we identified HD blood-specific pathology, confirming previous findings for peripheral pathology in blood. Finally, we identified hub genes for HD-associated blood modules and proposed a strategy for gene selection for development of a disease progression monitoring panel. Show less
Zhang, Y.; Verwilligen, R.A.F.; Boer, M. de; Sijsenaar, T.J.P.; Eck, M. van; Hoekstra, M. 2021
Atherosclerotic cardiovascular disease is a metabolic and inflammatory disorder. In vitro studies have suggested that protein arginine methyltransferase 4 (PRMT4) may act as a transcriptional... Show moreAtherosclerotic cardiovascular disease is a metabolic and inflammatory disorder. In vitro studies have suggested that protein arginine methyltransferase 4 (PRMT4) may act as a transcriptional coactivator to modulate inflammatory and metabolic processes. Here we investigated the potential anti-atherogenic effect of PRMT4 inhibitor TP-064 in vivo.\nMale apolipoprotein E knockout mice fed a high cholesterol/high fat Western-type diet were intraperitoneally injected three times a week with 2.5 mg/kg (low dose) or 10 mg/kg (high dose) TP-064 or with DMSO control.\nTP-064 induced a dose-dependent decrease in lipopolysaccharide-induced ex vivo blood monocyte Tnfα secretion (p < 0.05 for trend) in the context of unchanged blood monocyte concentrations and neutrophilia induction (p < 0.01 for trend). A dose-dependent decrease in gonadal white adipose tissue expression levels of PPARγ target genes was detected, which translated into a reduced body weight gain after high dose TP-064 treatment (p < 0.05). TP-064 treatment also dose-dependently downregulated gene expression of the glycogen metabolism related protein G6pc in the liver (p < 0.001 for trend). In addition, a trend towards lower plasma insulin and higher blood glucose levels was observed, which was paralleled by a reduction in hepatic mRNA expression levels of the insulin-responsive genes Fasn (-55%; p < 0.001) and Gck (-47%; p < 0.001) in high dose-treated mice. Plasma triglyceride levels were reduced by high dose TP-064 treatment (-30%; p < 0.05). However, no change was observed in the size or composition of aortic root atherosclerotic lesions.\nThe PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice. Show less
Zhang, Y.; Boer, M. de; Wel, E.J. van der; Eck, M. van; Hoekstra, M. 2021
Previous in vitro studies have shown that protein arginine N-methyltransferase 4 (PRMT4) is a co-activator for an array of cellular activities, including NF-κB-regulated pro-inflammatory responses.... Show morePrevious in vitro studies have shown that protein arginine N-methyltransferase 4 (PRMT4) is a co-activator for an array of cellular activities, including NF-κB-regulated pro-inflammatory responses. Here we investigated the effect of PRMT4 inhibitor TP-064 treatment on macrophage inflammation in vitro and in vivo. Exposure of RAW 264.7 monocyte/macrophages to TP-064 was associated with a significant decrease in the production of pro-inflammatory cytokines upon a lipopolysaccharide challenge. Similarly, thioglycollate-elicited peritoneal cells isolated from wildtype mice treated with TP-064 showed lowered mRNA expression levels and cytokine production of pro-inflammatory mediators interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor-α in response to lipopolysaccharide exposure. However, TP-064-treated mice exhibited an ongoing pro-inflammatory peritonitis after 5 days of thioglycollate exposure, as evident from a shift in the peritoneal macrophage polarization state from an anti-inflammatory LY6ClowCD206hi to a pro-inflammatory LY6ChiCD206low phenotype. In addition, TP-064-treated mice accumulated (activated) neutrophils within the peritoneum as well as in the blood (7-fold higher; P < 0.001) and major organs such as kidney and liver, without apparent tissue toxicity. TP-064 treatment downregulated hepatic mRNA expression levels of the PRMT4 target genes glucose-6-phosphatase catalytic subunit (-50%, P < 0.05) and the cyclin-dependent kinases 2 (-50%, P < 0.05) and 4 (-30%, P < 0.05), suggesting a direct transcriptional effect of PRMT4 also in hepatocytes. In conclusion, we have shown that the PRMT4 inhibitor TP-064 induces peritonitis-associated neutrophilia in vivo and inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo. Our findings suggest that TP-064 can possibly be applied as therapy in NF-κB-based inflammatory diseases. Show less
Bauduin, S.E.E.C.; Rooijen, I.L.B. den; Meijer, M.; Werff, S.J.A. van der; Keo, A.; Dzyubachyk, O.; ... ; Mahfouz, A. 2021
Introduction: Cushing's disease (CD) is a rare and severe endocrine disease characterized by hypercortisolemia. Previous studies have found structural brain alterations in remitted CD patients... Show moreIntroduction: Cushing's disease (CD) is a rare and severe endocrine disease characterized by hypercortisolemia. Previous studies have found structural brain alterations in remitted CD patients compared to healthy controls, specifically in the anterior cingulate cortex (ACC). However, potential mechanisms through which these persistent alterations may have occurred are currently unknown. Methods: Structural 3T MRI's from 25 remitted CD patients were linked with gene expression data from neurotypical donors, derived from the Allen Human Brain Atlas. Differences in gene expression between the ACC and an unaffected control cortical region were examined, followed by a Gene Ontology (GO) enrichment analysis. A cell type enrichment analysis was conducted on the differentially expressed genes, and a disease association enrichment analysis was conducted to determine possible associations between differentially expressed genes and specific diseases. Subsequently, cortisol sensitivity of these genes in existing datasets was examined. Results: The gene expression analysis identified 300 differentially expressed genes in the ACC compared to the cortical control region. GO analyses found underexpressed genes to represent immune function. The cell type specificity analysis indicated that underexpressed genes were enriched for deactivated microglia and oligodendrocytes. Neither significant associations with diseases, nor evidence of cortisol sensitivity with the differentially expressed genes were found. Discussion: Underexpressed genes in the ACC, the area vulnerable to permanent changes in remitted CD patients, were often associated with immune functioning. The specific lack of deactivated microglia and oligodendrocytes implicates protective effects of these cell types against the long-term effects of cortisol overexposure. Show less
Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that... Show moreSomatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1(R132H) mutations. Patients harbouring IDH1(R132H) mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1(R132H) have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1(R132H) mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication. Show less
Background Aging is a multifactorial process that affects multiple tissues and is characterized by changes in homeostasis over time, leading to increased morbidity. Whole blood gene expression... Show moreBackground Aging is a multifactorial process that affects multiple tissues and is characterized by changes in homeostasis over time, leading to increased morbidity. Whole blood gene expression signatures have been associated with aging and have been used to gain information on its biological mechanisms, which are still not fully understood. However, blood is composed of many cell types whose proportions in blood vary with age. As a result, previously observed associations between gene expression levels and aging might be driven by cell type composition rather than intracellular aging mechanisms. To overcome this, previous aging studies already accounted for major cell types, but the possibility that the reported associations are false positives driven by less prevalent cell subtypes remains. Results Here, we compared the regression model from our previous work to an extended model that corrects for 33 additional white blood cell subtypes. Both models were applied to whole blood gene expression data from 3165 individuals belonging to the general population (age range of 18-81 years). We evaluated that the new model is a better fit for the data and it identified fewer genes associated with aging (625, compared to the 2808 of the initial model; P <= 2.5x10(-6)). Moreover, 511 genes (similar to 18% of the 2808 genes identified by the initial model) were found using both models, indicating that the other previously reported genes could be proxies for less abundant cell types. In particular, functional enrichment of the genes identified by the new model highlighted pathways and GO terms specifically associated with platelet activity. Conclusions We conclude that gene expression analyses in blood strongly benefit from correction for both common and rare blood cell types, and recommend using blood-cell count estimates as standard covariates when studying whole blood gene expression. Show less
Niemantsverdriet, E.; Akker, E.B. van den; Boeters, D.M.; Eeden, S.J.F. van den; Geluk, A.; Helm-van Mil, A.H.M. van der 2020
Background Established rheumatoid arthritis (RA) patients display differentially expressed genes coding for cytokine/chemokine-mediated immunity compared to healthy controls. It is unclear, however... Show moreBackground Established rheumatoid arthritis (RA) patients display differentially expressed genes coding for cytokine/chemokine-mediated immunity compared to healthy controls. It is unclear, however, if in the pre-arthritis phase of clinically suspect arthralgia (CSA) expression of immune genes differ between patients who do or do not develop clinically evident inflammatory arthritis (IA). Methods Two hundred thirty-six consecutive patients presenting with arthralgia clinically suspected for progression to RA were followed until IA development or else for median 24 months (IQR 12-26). Baseline whole blood RNA expression was determined for a previously identified set of 133 genes associated with the innate and adaptive immune system by dual-color reverse-transcription multiplex ligation-dependent probe amplification (dcRT-MLPA) profiling. Cox proportional hazard models were used. Results Twenty percent of CSA patients developed IA. After correction for multiple testing, expression levels of six genes (IFNG, PHEX, IGF-1, IL-7R, CD19, CCR7) at the time of presentation were associated with progression to IA. PHEX and IGF-1 were highly correlated with each other (rho = 0.97). In multivariable analysis correcting for the different genes, expressions of IL-7R and IGF-1 were independently associated with IA development (p = 0.025, p = 0.046, respectively). Moreover, IL-7R and IGF-1 remained significantly associated even after correction for known predictors (ACPA, CRP, imaging-detected subclinical joint inflammation; p = 0.039, p = 0.005, respectively). These genes are also associated with RA development. Conclusions IL-7R and IGF-1 were differentially expressed between CSA patients who did or did not progress to IA, independent from regularly used predictors. These biomarkers may become helpful in prognostication of CSA patients. Furthermore, because both genes are associated with T cell functioning, T cell dysregulation may mediate progression from arthralgia to arthritis. Show less
This thesis sought to obtain a better understanding of the composition of the immune microenvironment in NSCLC and how to modulate this tumor immune microenvironment by RT to induce amplified... Show moreThis thesis sought to obtain a better understanding of the composition of the immune microenvironment in NSCLC and how to modulate this tumor immune microenvironment by RT to induce amplified antitumor immune responses to ICIs in advanced NSCLC patients. In the first part of this thesis, a multiangular approach of a combination of protein and mRNA expression with clinicopathological characteristics in a large cohort of early stage, resected NSCLC samples will be discussed. The second part focusses on the immune modulating effects of RT, in particular when combined with immunotherapy treatment in metastatic NSCLC. Show less
Plant-microbe interaction resulted in different physio/chemical responses by host plant and interacting rhizobacteria. This thesis focuses on how different plants and rhizobacteria combinations... Show morePlant-microbe interaction resulted in different physio/chemical responses by host plant and interacting rhizobacteria. This thesis focuses on how different plants and rhizobacteria combinations modulate plant metabolism. Factorial combinations of different plant species, including Arabidopsis thaliana (model plant), Brassica oleracea var. italica (crop) and Artemisia annua (medicinal plant), and phylogenetically distinct rhizobacterial species, including Pseudomonas fluorescens SS101 (Pf SS101), Microbacterium and three Paraburkholderia species, were used as study model systems in this thesis. Untargeted metabolomics was used to assess the impact of these rhizobacteria on the shoot chemistry of the host plant species. This study revealed that root treatment of different plant species with rhizobacteria altered 18-78% of the detected plant secondary metabolites in the shoot. We also assessed the impact of a known bacterial trait on plant phenotype and chemistry. cysH mutation of Pf SS101 affected the chain elongation of aliphatic glucosinolate biosynthesis in Arabidopsis whereas it led to an accumulation of indolic glucosinolates and flavonoids in Broccoli. To further discover the bacterial traits affected during the interaction with Broccoli roots, genome wide transcriptome analysis was carried out, resulting in upregulation of genes involved in flagellar assembly, chemotaxis, and motility together with nutrient uptake and (an)ion transporter in Paraburkholderia species. Show less
Hoekstra, M.; Ouweneel, A.B.; Nahon, J.E.; Geest, R. van der; Kröner, M.J.; Sluis, R.J. van der; Eck, M. van 2019
ObjectiveSince cholesterol is the sole precursor for glucocorticoid synthesis, it is hypothesized that genetic defects in proteins that impact the cellular cholesterol pool may underlie... Show moreObjectiveSince cholesterol is the sole precursor for glucocorticoid synthesis, it is hypothesized that genetic defects in proteins that impact the cellular cholesterol pool may underlie glucocorticoid insufficiency in humans. In the current study, we specifically focused on the cholesterol efflux mediator ATP-binding cassette transporter G1 (ABCG1) as gene candidate.MethodsThe adrenal transcriptional response to fasting stress was measured in wild-type mice to identify putative novel gene candidates. Subsequently, the adrenal glucocorticoid function was compared between ABCG1 knockout mice and wild-type controls.ResultsOvernight food deprivation induced a change in relative mRNA expression levels of cholesterol metabolism-related proteins previously linked to steroidogenesis, i.e. scavenger receptor class B type I (+149%; P < 0.001), LDL receptor (−70%; P < 0.001) and apolipoprotein E (−41%; P < 0.01). Strikingly, ABCG1 transcript levels were also markedly decreased (−61%; P < 0.05). In contrast to our hypothesis that decreasing cholesterol efflux would increase the adrenal cholesterol pool and enhance glucocorticoid output, ABCG1 knockout mice as compared to wild-type mice exhibited a reduced ability to secrete corticosterone in response to an ACTH challenge (two-way ANOVA: P < 0.001 for genotype) or fasting stress. As a result, glucocorticoid target gene expression levels in liver and hypothalamus were reduced and blood lymphocyte concentrations and spleen weights increased in ABCG1 knockout mice under fasting stress conditions. This was paralleled by a 48% reduction in adrenal cholesteryl ester stores and stimulation of adrenal NPC intracellular cholesterol transporter 2 (+37%; P < 0.05) and apolipoprotein E (+59%; P < 0.01) mRNA expression.ConclusionABCG1 deficiency is associated with mild glucocorticoid insufficiency in mice. Show less
Yang, J.X.; Snijders, M.L.H.; Haasnoot, G.W.; Kooten, C. van; Mallat, M.; Fijter, J.W. de; ... ; Eikmans, M. 2018
The work described in this thesis presents part of a framework that can be used to extract detailed disease biological information from peripheral tissue. This framework is based on the... Show moreThe work described in this thesis presents part of a framework that can be used to extract detailed disease biological information from peripheral tissue. This framework is based on the central dogma of biology “DNA to RNA to protein” and on a systems biology approach that aims to produce synergetic data whose disease pathological, prognostic and predictive value is greater than the sum of the individual experiment results. HD patients are often characterized by a multifaceted clinical profile, consisting of several symptoms and variable disease progression rates. Therefore, a systems approach such as the one described above is expected to be the most effective in identifying potential treatments and predictive biomarkers that will be most informative for the different patient subpopulations. Show less
