Publications

Nuclear receptors (NRs) are widely expressed transcription factors that bind small, lipophilic compounds and regulate diverse biological processes. In the small intestine, NRs are known to act as sensors that control transcriptional responses to endogenous and exogenous signals, yet their downstream effects have not been characterized extensively. Here, we investigate the activation of six different NRs individually in human intestinal organoids using small molecules agonists. We observe changes in key enterocyte functions such as lipid, glucose, and amino acid absorption, the regulation of electrolyte balance, and drug metabolism. Our findings reinforce PXR, LXR, FXR, and PPARα as regulators of lipid absorption. Furthermore, known hepatic effects of AHR and VDR activation were recapitulated in the human small intestine. Finally, we identify unique target genes for intestinal PXR activation (ERG28, TMEM97, and TM7SF2), LXR activation (RAB6B), and VDR activation (CA12). This study provides an unbiased and comprehensive transcriptomic description of individual NR pathways in the human small intestine. By gaining a deeper understanding of the effects of individual NRs, we might better harness their pharmacological and therapeutic potential.

<p>Extension of the methods related to the scRNA-seq data analysis</p>

Conjunctival goblet cell (GC) loss in dry eye is associated with ocular surface inflammation. This study investigated if conjunctival GCs contribute to ocular surface immune tolerance. Antigens applied to the ocular surface, imaged by confocal microscopy, passed into the conjunctival stroma through goblet cell associated passages (GAPs) in wild type C57BL/6 (WT), while ovalbumin (OVA) was retained in the epithelium of SAM pointed domain containing ETS transcription factor (Spdef) knockout mice (Spdef−/−) that lack GCs and are a novel model of dry eye. Stimulated GC degranulation increased antigen binding to GC mucins. Induction of tolerance to topically applied OVA measured by cutaneous delayed type hypersensitivity (DTH) was observed in WT, but not Spdef−/−. OTII CD4+ T cells primed by dendritic cells (DCs) from the conjunctival draining lymph nodes of Spdef−/− had greater IFN-γ production and lower Foxp3 positivity than those primed by WT DCs. These findings indicate that conjunctival GCs contribute to ocular surface immune tolerance by modulating antigen distribution and antigen specific immune response. GC loss may contribute to the abrogation of ocular surface immune tolerance that is observed in dry eye.

Additional file 23. Table S22

<div>Abstract<p>Inactivation of the <i>Apc</i> gene is recognized as the key early event in the development of sporadic colorectal cancer (CRC), where its loss leads to constitutive activation of β-catenin/T-cell factor 4 signaling and hence transcription of Wnt target genes such as c-Myc. Our and other previous studies have shown that although cyclin D1 is required for adenoma formation, it is not immediately upregulated following Apc loss within the intestine, suggesting that proliferation following acute Apc loss may be dependent on another D-type cyclin. In this study, we investigated the expression and functional relevance of cyclin D2 following Apc loss in the intestinal epithelium. Cyclin D2 is upregulated immediately following Apc loss, which corresponded with a significant increase in cyclin-dependent kinase 4 (CDK4) and hyperphosphorylated Rb levels. Deficiency of cyclin D2 resulted in a reduction in enterocyte proliferation and crypt size within Apc-deficient intestinal epithelium. Moreover, cyclin D2 dramatically reduced tumor growth and development in <i>Apc<sup>Min/+</sup></i> mice. Importantly, cyclin D2 knockout did not affect proliferation of normal enterocytes, and furthermore, CDK4/6 inhibition also suppressed the proliferation of adenomatous cells and not normal cells from <i>Apc<sup>Min/+</sup></i> mice. Taken together, these results indicate that cyclin D–CDK4/6 complexes are required for the efficient proliferation of cells with deregulated Wnt signaling, and inhibiting this complex may be an effective chemopreventative strategy in CRC. Cancer Res; 70(20); 8149–58. ©2010 AACR.</p></div>

Additional file 15. Table S14

Dit boek is een handleiding voor het opzetten en uitvoeren van gezondheidsbevorderende activiteiten binnen bedrijven. Het doel van die activiteiten is het bevorderen van de veiligheid, de gezondheid en het welzijn van werknemers en daarmee het terugdringen van het ziekteverzuim. Ook wordt aandacht geschonken aan de kosten en baten van integrale gezondheidsbevordering. Het boek bevat een zeven-stappenplan om te komen tot verbetering van de werksituatie, verbetering van mogelijkheden van werknemers om met eisen die het werk stelt om te gaan en een gezondere leefstijl. Het bijzondere van deze aanpak is het integrale karakter: zowel het werk, de persoon als zijn of haar leefstijl staan centraal.

<p>PDF file - 36KB, Mating strategy for generating Lgr5 Cre+ Catnb+/lox(ex3) Klf5flox/flox mice. Lgr5 Cre+ (Lgr5-EGFP-ires-CreERT2) mice had the activation of Cre recombinase, specific in Lgr5+ intestinal epithelial stem cells, by the intraperitoneal medication of Tamoxifen.</p>

Purpose The opposite of absenteeism, presenteeism, is the phenomenon of employees staying at work when they should be off sick. Presenteeism is an important problem for organizations, because employees who turn up for work, when sick, cause a reduction in productivity levels. The central aim of the present study is to examine the longitudinal relationships between job demands, burnout (exhaustion and depersonalization), and presenteeism. We hypothesized that job demands and exhaustion (but not depersonalization) would lead to presenteeism, and that presenteeism would lead to both exhaustion and depersonalization over time. Design/methodology/approach The hypotheses were tested in a sample of 258 staff nurses who filled out questionnaires at three measurement points with 1.5 years in‐between the waves. Findings Results were generally in line with predictions. Job demands caused more presenteeism, while depersonalization was an outcome of presenteeism over time. Exhaustion and presenteeism were found to be reciprocal, suggesting that when employees experience exhaustion, they mobilize compensation strategies, which ultimately increases their exhaustion. Research limitations/implications These findings suggest that presenteeism can be seen as a risk‐taking organizational behavior and shows substantial longitudinal relationships with job demands and burnout. Practical implications The study suggests that presenteeism should be prevented at the workplace. Originality/value The expected contribution of the manuscript is not only to put presenteeism on the research agenda but also to make both organizations and scientists attend to its detrimental effects on employees' wellbeing and (consequently) on the organization.

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