Likewise, in the study by Dorsay and Orange [12] who reviewed ret

Likewise, in the study by Dorsay and Orange [12] who reviewed retrospectively a group of 24 children with THI, as much as twenty patients carried at least one atopic diagnosis despite elevated IgE levels in 7 patients. These findings are supported by other authors’ opinions that patients with hypogammaglobulinemia and concomitant allergic diseases may show poor correlation between clinical symptoms and results of serum total and allergen-specific IgE tests [13], [14] and [15]. Therefore, serum IgE levels cannot be considered as suitable diagnostic criteria for allergic disease in patients with defective antibody

synthesis. Interestingly, an early onset of clinical manifestations of food allergy that in 16 of 17 children falls on the first Dabrafenib molecular weight 6 months and in 12 children even on the first 3 months of life supports the initial Selleckchem Proteasome inhibitor hypothesis that hypogammaglobulinemia, among others genetic and environmental factors, may substantially contribute to the development of food allergy in children. The first symptoms of allergic disease are thus present in infants in parallel to the breakdown of protective maternal transplacentally obtained IgG antibodies and resulting hypogammaglobulinemia. In these considerations on reciprocal pathomechanisms of low serum immunoglobulin levels and breakdown of tolerance to alimentary antigens one should also take into account the protein loss through the inflamed gastrointestinal mucosa and the enteropathy Vildagliptin secondary to food allergy

as the primary cause of hypogammaglobulinemia [16], [17] and [18]. As the immune competence later in life is affected by the ability to

mount an appropriate immune response upon infection as well as to develop tolerogenic immune mechanisms, the immunomodulatory role of breastfeeding in shaping the immune maturation must be stressed [19] and [20]. This study has several limitations, namely a relatively small study group and its retrospective character that does not enable to define either prognosis in terms of hypogammaglobulinemia or the outcome of food allergy. The natural history of early allergy to milk, egg, wheat and soy is generally associated with development of spontaneous clinical tolerance in food-allergic individuals [10], but there is a lack of one universal parameter that might enable to predict the spontaneous immunocorrection and resolution or progression of allergy. These issues might be the subject of further case-controlled prospective studies. Antibody production defects in infants and young children may be associated with health problems beyond just hypogammaglobulinemia, but pose the increased risk of allergy to alimentary antigens. Symptomatology of food allergy correlates better with serum IgG and IgA deficiency than laboratory markers of atopy. Dysregulation of the immune response contributing to defective antigen elimination in predisposed immunodeficient individuals might be considered as a critical risk factor accompanying development of allergy.

Icy, an open source image analysis platform, also provides a plug

Icy, an open source image analysis platform, also provides a plug-in for viewing and editing tracks (de Chaumont et al., 2012). Performance evaluation, also referred as performance analysis, in image analysis compares the results obtained from an automated procedure against the manually established ‘ground truth’. Herein, a ground truth track represents

the ‘true’ positions of a cell as a sequence of bounding boxes. We used the Video Performance Evaluation Resource (ViPER) software (Doermann and Mihalcik, 2000) to manually draw bounding boxes around cells in each video frame and index the sequences of bounding boxes corresponding JQ1 in vitro to each individual cell to designate tracks. Performance evaluation metrics were employed to quantitatively and comprehensively assess the detection and tracking performance of TIAM and the third-party tools. We used the Sequence Frame Selleckchem RO4929097 Detection Accuracy (SFDA) and Average Tracking Accuracy (ATA) metrics (Kasturi et al.,

2009) as these can be computed in a fully automated fashion and thus allow for reproducible quantification of the success of detection and tracking of objects. Further, they do not suffer from the risk of human error or bias. These metrics have been adopted as standardized metrics by the Video Analysis and Content Extraction (VACE) program ( and the Classification of Events, Activities, and Relationships

(CLEAR) consortium (; which are two large-scale and community-wide efforts concerned with video tracking and interaction analysis. The metrics are based on Jaccard Similarity (Fig. S5 for intuitive illustration and and Supplementary methods for mathematical description). In order to compute SFDA and ATA, a one-to-one correspondence between ground truth Etomidate and result must be established. To establish this mapping we employed the Hungarian algorithm (Munkres, 1957) with metrics based on Jaccard Similarity used to construct the similarity matrix (see Supplementary methods for details). We have consolidated the software routines to carry out performance analysis in a separate MATLAB-based suite that we call PACT (Performance Analysis of Cell Tracking). The PACT code, its user guide and relevant ground truth datasets are available at The user guide also includes specific instructions on using ViPER for ground truth annotation. Performance of feature extraction was also evaluated against ground truth. Outlines drawn manually or by semi-automated procedures in ImageJ (Schneider et al., 2012) were listed as ROIs and used as ground truth (see Supplementary methods for details). A one-to-one correspondence between individual cells in ground truth and TIAM result was obtained using the Hungarian algorithm (Munkres, 1957).

1) This broadly agreed with the detection of a 10-fold lower exp

1). This broadly agreed with the detection of a 10-fold lower expression of DEK in mature cells from

peripheral blood compared to normal CD34 + cells as revealed in a previous study [6]. However, not all terminally differentiated cells from different hematopoietic lineages exhibited similar expression of DEK, as higher DEK levels were observed in lymphoid cells as compared to mature myeloid cells. Within the myeloid lineage, monocytes had a 3-fold higher DEK expression than granulocytes (Fig. 1). Since DEK could be important in regulating granulocytic differentiation it may be expected that its expression this website could subsequently promote terminal differentiation in AML. In contrast, mice exhibited a markedly different expression pattern compared to that of humans (Fig. 1C & Supplementary Fig. 1). Most significantly, murine cells expressed elevated levels of Dek in GMPs and mature granulocytes as compared to the human myeloid cell equivalent (p < 0.001). However, DEK expression levels in monocytes were similar ( Fig. 1C). Overall, distinct DEK expression patterns

were observed during the progression of normal hematopoiesis, with DEK levels substantially reduced in mature cells compared Ku-0059436 cost to HSCs. Thus it appears that DEK levels during murine and human hematopoiesis highlight potential differences which may reflect cell type specific functions of DEK. However, the precise function of DEK in myeloid proliferation/differentiation remains unknown and requires further elucidation. Since DEK is generally found up-regulated in multiple human malignancies and is associated with the AML subgroup harboring the t(6:9) translocation it is possible that AML may also exhibit up-regulated DEK. However, four previous studies analyzing DEK expression in AML have given discordant results with over-expression in two studies and either no significant change or decreased expression in the others. Consequently this study aimed to clarify the expression status Selleck Rucaparib of DEK in AML. Analysis of DEK expression in three datasets of AML patients

indicated that DEK was not over-expressed and may actually be under-expressed in the majority of cases. Furthermore, dividing the AML patients into different subtypes detected no significant change or decreased DEK expression (Fig. 2). In agreement with our findings, a previous study of 14 APL cases, which possess the t(15;17) translocation and have a favorable prognosis, showed that there was no significant change in DEK expression. Analysis of over 500 pediatric AML samples from the Oncomine dataset [26], combined with over 600 adult samples in the MILE and LAML studies plus collated microarrays from the Hemaexplorer dataset, totaling more than 1000 cases of AML, supported an association of reduced DEK expression in AML.

Subjects were classified as obese, overweight and non-overweight

Subjects were classified as obese, overweight and non-overweight according to the International Obesity Task Force [12]. The non-overweight group includes normal weight (n = 533) and underweight (n = 2) children and for the purposes of this study has been called the normal weight group (n = 535). Table 1 summarises the baseline characteristics of a selection of lipid and anthropometric measures, comparing the overweight and obese children (n = 343) in the study to their normal weight counterparts (n = 535). Measures of blood pressure, insulin, TG, height and insulin resistance MK-2206 molecular weight were significantly higher (p < 0.0001) and HDL-C significantly lower

(p < 0.0001) in the overweight and obese group compared to their normal weight counterparts. The mean BMI of the mothers and fathers of the children was 24.6 ± 4.8 and 27.2 ± 3.6, respectively. Children whose parents were both overweight (BMI ≥ 25) had a BMI 2.2 units larger than children whose parents were both of a normal weight (BMI < 25) (p < 0.00001) ( Appendices Table 1a). Children of parents who were hypercholesterolemic (Cholesterol >240 mg/dl) had significantly higher cholesterol levels compared to children of parents who’s cholesterol PD0332991 levels were

normal (p < 0.00001) and the same observation was observed between parents and their children with LDL levels (p = 0.003) ( Appendices Table 1c and 1b, respectively). There were no allele frequency differences between boys and girls for any of the ten variants (data not shown). The genotype and minor allele frequency (MAF) for the ten variants are shown in Table 2. The genotype distribution of APOC3 1100C > T deviated from those expected under HWE (p = 0.02). There was a borderline statistically significant difference in allele frequency distribution of the LPL S447X variant between normal weight

children and their overweight and obese counterparts, MAF 0.14 (95% confidence intervals (CI) 0.11, 0.16) vs. 0.11 (95% CI 0.08, 0.14) (p = 0.02). Significant data for lipid and anthropometric variables, according to genotype, are presented in Table 3. APOE genotype, defined by two variant sites at residues 112 and 158 creating the ɛ2, ɛ3 and ɛ4 alleles, was significantly associated with TC (p = 0.0001) with ɛ2 carriers having TC plasma levels 11.3% lower Edoxaban than ɛ3/ɛ3 subjects (p < 0.001) and ɛ4 carriers with 1.3% higher TC plasma levels than ɛ3/ɛ3 subjects (p = 0.522). APOE genotype was also significantly associated with LDL-C (p < 0.0001). ɛ2 carriers had LDL-C plasma levels that were 17.6% lower than ɛ3/ɛ3 subjects (p < 0.001) and ɛ4 carriers had a mean LDL-C plasma level that was 2.8% higher than ɛ3/ɛ3 subjects (p = 0.258). ɛ2 carriers were also observed with a significantly lower mean TC: HDL-C ratio of 3.26 (95% CI 3.1, 3.5) compared to 3.62 (95% CI 3.6, 3.7) and 3.81 (95% CI 3.7, 4.

At 3434 and 3399 cm−1, the characteristic band of the hydroxyl gr

At 3434 and 3399 cm−1, the characteristic band of the hydroxyl group (OH) is recorded, overlapping with N–H stretch at 3270 cm−1. At 1646 cm−1 the characteristic bands of chitosan

appear with high intensity that correspond to the vibration of amid. At 1380 cm−1 the C–H stretch of the CH3 group is recorded. At 1322 cm−1 the C–N stretch is recorded and finally at 1080 cm−1 the band of C–O stretch group appears (Costa and Mansur, 2008 and Papadimitriou et al., 2008). The success in the production of the cross-linked nanoparticles may be demonstrated by the reduced particle size obtained, which remained smaller than BGJ398 in vitro 200 nm for all formulations. The experimental data obtained for size and zeta potential are shown in Table 1. In addition, a high value of encapsulation efficiency was obtained for different venom:chitosan ratios used (5 and 10%) (Table 1). The mice were immunized for 6 weeks with 100 μL of subcutaneous injections of T. serrulatus venom proteins in different concentrations (0; 5.0 and 10.0%), encapsulated in chitosan nanoparticles or associated with the aluminum hydroxide. The experimental mice were bled by cardiac puncture, and the serum was obtained. Antigen-specific serum antibody responses

were measured 1 week see more following the vaccination boosters by ELISA. The results displayed in Fig. 3 demonstrate that significant difference was found in the mice group of immune protection of vaccines with the adjuvant chitosan associated with the venom in the concentration 5.0% and the adjuvant aluminum hydroxide associated with the venom in the concentration 10.0% (P < 0.05). However, the group that received hydroxide associated with the venom in the concentration 10.0% when compared with the adjuvant chitosan associated

with the venom in the concentration (-)-p-Bromotetramisole Oxalate 10.0% did not exhibit significant difference in the antibody title produced ( Table 2). The data also reveal that when the control group immunized with chitosan nanoparticles was compared with the adjuvant chitosan nanoparticles associated with the venom in both concentrations (5.0 and 10.0%) a significant difference of immune protection was found in the mice. The same was shown when comparing the title of antibody in animals vaccinated with the adjuvant aluminum hydroxide associated with the venom in both concentrations (5.0 and 10.0%) and groups of animals, which received only aluminum hydroxide ( Table 2). All effective vaccines need a suitable antigen-presenting system that depends on adjuvant or vehicle (Xie et al., 2007). The development of a novel adjuvant is necessary to decrease the side effects and maximize the efficacy of new or available vaccines and serums. The chitosan is a non-toxic and biodegradable copolymer with low immunogenicity that has been extensively investigated for formulating carrier and delivery systems for therapeutic macromolecules (Janes et al., 2001 and Richardson et al., 1999).

Functional equality in RTs is present in luteal women, when proge

Functional equality in RTs is present in luteal women, when progesterone is elevated. A decline in progesterone in early follicular women correlates

with functional inequality visualized by larger latency in RTs in right compared to left hemifield presentation. Thus, at the behavioral level right hemisphere is dominant in attention tasks. Dominance of right hemisphere has been Selleck Z-VAD-FMK identified in several attention tasks (Petersen and Posner, 2012 and Somers and Sheremata, 2013). Mutual inter-hemispheric inhibition at the physiological level is visualized in differences in ERP or alpha-amplitude. Ipsilateral alpha amplitude is larger in right than left visual field presentation. This asymmetry in amplitude is statistically significant in luteal women. Thus, suppression of the dominant right hemisphere requires

synchronization of a larger inhibitory neuronal network than suppression of the subdominant left hemisphere. One interpretation of larger right hemisphere synchronization is that subdominant areas in the left hemisphere may trigger synchronization of a larger inhibitory network in the dominant, right hemisphere when progesterone is elevated. An alternative interpretation is that the dominant right hemisphere suppresses the subdominant left hemisphere more efficiently and, thus, decreases interferences in information processing. In both cases, progesterone find more enhances synchronization in alpha frequency band and therefore leads to suppression of irrelevant information in the ipsilateral hemisphere and minimizes interferences between cerebral hemispheres. Thus, our findings may contribute to elucidate an interesting paradox regarding the impact of sex hormones on functional cerebral asymmetry and physiological hemisphere laterality. On the one hand, the progesterone-mediated interhemispheric decoupling model by Hausmann and Güntürkün predicts that an increase in progesterone decrease hemisphere asymmetry (Hausmann

and Güntürkün, 2000). This model PRKD3 states that hemispheres are coupled when the dominant hemisphere suppresses homotopic areas of the subdominant hemisphere. Glutamatergic neurons, projecting form the dominant to the subdominant hemisphere, synapse on pyramidal neurons, which activate GABAergic neurons. An increase in progesterone decouples cerebral hemispheres and, thus, decreases functional cerebral asymmetry. Accordingly, functional cerebral asymmetry is only detectable in menstrual cycle phases with low progesterone level (Hausmann and Güntürkün, 2000). On the other hand, the Hampson model predicts that an elevation of ovarian sex hormones facilitates left hemisphere processing. Accordingly, hemispheric lateralization is associated with an increase in sex hormones (Hampson, 1990). In conclusion, we suggest that functional cerebral asymmetry at the behavioral level in early follicular women is related to dominance of the task specific hemisphere.

, 1988) In vivo, EC grow on a basement membrane in close juxtapo

, 1988). In vivo, EC grow on a basement membrane in close juxtaposition with pericytes or smooth muscle cells depending on the vessel, but may not usually have direct contact with fibroblasts. Here, behaviour (morphology, recruitment of leukocytes and response to cytokines) of EC was not impaired when cultured on collagen matrix alone or as part of the double gel model (where EC are seeded above a gel, above a fibroblast containing gel). Such behaviour is similar to that observed when endothelial cells are cultured on a range of surfaces, including plastic tissue culture wells and Transwell filters (McGettrick et al., 2009a). This indicates that collagen itself is unlikely to impair EC function

or behaviour, rather the loss of integrity was a fibroblast-specific effect. The integrity of the endothelium may be differentially modulated by different stromal cells in vitro, and so the best model for co-culture might be different check details also. These findings do, however,

raise the question as to whether fibroblasts potentiated lymphocyte transmigration at the level of the filter rather than the endothelium in that model. This was investigated further in the layered-gel model (see below). In either model, fibroblasts reduced the proportion of transmigrated PBL that penetrated into the gel and those that did enter migrated only half as deep when fibroblasts were present. Of note, responses to cytokine-treatment were similar for fibroblasts cultured on plastic as those within the gel. In fact, higher levels of the adhesion molecules, ICAM-1, were observed in co-culture gel constructs, AZD2281 cell line indicating that the fibroblasts had sufficient

receptors to support and encourage lymphocyte migration through the gel. Density, spatial arrangement and source of collagen fibres have all been suggested to alter the ability of leukocytes Interleukin-3 receptor to move within gel constructs (Wolf et al., 2009). Here it became evident that fibroblasts caused significant contraction and reduction in depth of the gels. When we purposely made gels with increasing collagen concentrations, the inhibition of initial penetration was reproduced. Thus the main effect of the fibroblasts in the later stages of migration appeared to be through matrix modification, while effects through direct contact with the PBL or release of attractants were not obvious. The fibroblasts probably also deposited matrix proteins such as fibronectin over the duration of the culture and assay, and it would be interesting to investigate whether this might affect migration in the future. Preliminary studies where we have purposely added fibronectin into the collagen gels did not, however, cause increased penetration at least (G. Jevons; unpublished observations). Others have reduced fibroblast contraction of collagen gels through the chelation of divalent cations (e.g. Ca2 +) (Ilagan et al., 2010) or the antagonism of endogenous TGFβ signalling or heparin sulfate-containing proteoglycan synthesis (Chen et al., 2005).

A terapêutica com infliximab, anticorpo monoclonal quimérico com

A terapêutica com infliximab, anticorpo monoclonal quimérico com ação antifator de necrose tumoral alfa, mostrou-se eficaz na indução e manutenção da remissão nos doentes resistentes às terapêuticas de primeira linha, corticodependentes ou com doença fistulizante grave2 and 3. O esquema atualmente recomendado

preconiza a realização de 3 doses de indução (5 mg/kg às 0, 2 e 6 semanas) e depois a manutenção de 5 mg/kg cada 8 semanas. Embora a resposta clínica inicial possa ser muito favorável4, aproximadamente 30-55% dos doentes sob este esquema apresentam falência terapêutica5 and 6. this website Nestes doentes, usualmente procura-se manter o tratamento com infliximab, aumentando a dose para 10 mg/kg e/ou buy BYL719 reduzindo os intervalos entre as administrações, por norma até 4 semanas7. Contudo, estudos recentes demonstraram que o encurtamento do intervalo para 6/7 semanas é tão eficaz quanto a duplicação da dose e a redução até 4 semanas2 and 8. Os autores procederam à análise retrospetiva

dos doentes pediátricos que realizaram tratamento com infliximab nos últimos 5 anos, avaliando as situações de falência e as opções terapêuticas adotadas. Estudo descritivo, retrospetivo dos doentes seguidos no nosso centro com diagnóstico de doença de Crohn, que iniciaram tratamento com infliximab nos últimos 5 anos (em esquema de manutenção), em idade inferior a 19 anos. Os dados foram obtidos através da consulta direta do processo clínico do doente e a avaliação estatística foi realizada com o apoio do programa informático SPSS 17.0©. Desde a introdução do infliximab Ceramide glucosyltransferase como recurso terapêutico no tratamento da doença de Crohn, no nosso centro, foram analisados 16

doentes com idade inferior a 19 anos. Destes, 10 (62,5%) eram do género masculino e a idade média de diagnóstico da doença de Crohn foi de 12 ± 2 anos (5-15 anos). Na apresentação inicial, a extensão da doença era variável: um (6,2%) intestino delgado; 2 (12,5%) cólon; 7 (43,8%) íleo-cólon e 6 (37,5%) atingimento global. Um quarto dos doentes manifestava ainda atingimento perianal. Nestes 16 doentes não foi conseguida remissão duradoura da doença com imunomodulador (azatioprina) e, por dependência da corticoterapia, foi iniciada terapêutica com infliximab em média ao fim de 2 anos de tratamento (0,9-3,0), embora a maioria o tenho feito 10 meses após o diagnóstico. Em todos os casos foi realizado o rastreio de tuberculose no momento do diagnóstico e antes do início da terapêutica biológica. A monitorização da resposta ao tratamento foi feita tendo por base critérios clínicos e analíticos. Todos mantiveram o esquema com corticoide em curso e iniciaram perfusão de infliximab numa dose de 5 mg/kg, mas num doente ainda durante o esquema de indução foi aumentada a dose para 10 mg/kg, mantendo o intervalo de 8 semanas.

mellifera, rp49 (GenBank accession number AF441189) ( Lourenço et

mellifera, rp49 (GenBank accession number AF441189) ( Lourenço et al., 2008). The primers used for amplification of this internal control were: forward 5′-CGT CAT ATG TTG

CCA ACT GGT-3′ and reverse 5′-TTG AGC ACG TTC AAC AAT GG-3′. Each run was followed by a melting curve analysis to confirm the specificity of amplification and absence of primer dimers. The relative quantification of transcript levels was calculated using the Ct method as described in Lourenço et al. (2009). To check reproducibility, each SYBR green assay was done in triplicate and repeated GDC-0068 manufacturer with three independent samples. Expression of vasa (GenBank accession number GB14804) was analyzed by semi-quantitative RT-PCR. Amplifications were carried out using 1 μl (10 pmol) of specific primers (forward 5′-GAG GAA AGT TGT CTG CTG G-3′ and reverse 5′-CTC GGA TAA GAA AAC GGC-3′), 1 μl of cDNA, 10 μl of Master Mix PCR (2.5×) (Eppendorf) and 12 μl of water. PCR conditions were 94 °C for 2 min followed by 35 cycles of 94 °C for 30 s, 55 °C for 30 s, 72 °C for 30 s and a final Natural Product Library clinical trial extension step at 72 °C for 7 min. As an endogenous control we used the A. mellifera rp49 gene. Amplification conditions were 94 °C for 2 min followed by 27 cycles of 94 °C for 30 s, 60 °C for 30 s, 72 °C for 30 s with a final extension step at 72 °C for 7 min. The number of cycles was carefully tested to avoid saturation. The amplification products were analyzed

by electrophoresis in 1% agarose gels containing ethidium bromide, and quantified using Kodak 1D Image Analysis program, version 3.6.2 (Eastman Kodak Co.). Hemolymph was rapidly collected using glass microcapillaries and kept at −20 °C until the use. Aliquots of 1 μl hemolymph were analyzed by SDS–PAGE. Electrophoresis was carried out at 15 mA, according to Laemmli (1970), using 7.5% polyacrylamide gels (100 × 120 × 0.9 mm). Acyl CoA dehydrogenase Gels were stained with 1% Coomassie Brillant Blue dissolved in a solution of glacial acetic acid, ethanol and water (1:5:5 v/v) that was also used for gel destaining. Data on transcript quantification and the mean volumes of diet

consumed per bee were analyzed using one-way ANOVA and the Holm–Sidak test for post hoc comparisons. When the assumptions of normality for ANOVA were not fulfilled, the analyses were done using the Kruskal–Wallis and Student–Neuman–Keuls test for post hoc comparison. The Chi-square test was used for the proportions of workers with activated and non-activated ovaries. Survival analysis was done by a Kaplan–Meier log-rank test with Holm–Sidak post hoc testing for multiple comparisons. Analyses were performed with Jandel SigmaStat 3.1 software (Jandel Corporation, USA). We analyzed the expression of genes encoding storage proteins (vg, hex 70a, apoLp-III and apoLp-II/I) and encoding the Vg (vgR) and ApoLp (apoLpR) receptors in A. mellifera workers fed different diets (beebread, royal jelly or syrup) and infected with S. marcescens.


The Selleckchem ONO-4538 genes of cluster 6 were first downregulated after 3 h and upregulated after 6 h. Metacore analysis of the genes from the individual clusters revealed a clear difference in functionality between the genes of cluster 2, 4, and 6. Genes from cluster 2 were involved in immune pathways, including the IL-17 and IL-1 signalling pathway (p value: 10−13 and 10−12, respectively) and the Toll-like receptor pathway (p value: 10−9). The genes that were downregulated at the latest time point (cluster 4) were part of several

cell cycle pathways, such as those involved in metaphase checkpoint control and APC-mediated cell cycle regulation (p value: 10−25 and 10−20, respectively). Genes from cluster 6 were involved in the cell cycle as well. The two most significant pathways were “start of DNA replication in early S phase” (p value: 10−6) and “the metaphase checkpoint” (p value: 10−6). Metacore analysis of genes from clusters 1, 3, and 5 did not result in significantly regulated pathways. Gene set enrichment analysis was used for the identification of gene sets affected by DON in order to unravel mechanisms of DON toxicity. This enables the comparison of our results with results already published in literature or derived from microarray studies. A three-step approach was followed. Torin 1 mw Firstly, GSEA was

performed on each of the nine treatment groups in relation to the control samples at the same time point. Up- and downregulation of significant gene sets were visualized in heat maps enabling comparison between the treatment groups. This resulted in 264 gene sets, obtained Inositol monophosphatase 1 from five gene set collections, that were significantly affected by at least one treatment. Secondly,

molecular concepts mapping was performed to further facilitate the biological interpretation. This provided a visualization of the overlap in genes among the significant gene sets from the combined gene set collections. Based on clusters of highly similar gene sets, the main biological events were elucidated. Molecular concepts mapping was performed for one treatment: 6-h exposure to 10 mg/kg. This treatment was selected since nearly all gene sets affected by any treatment were also affected by this dose at this time point. Thirdly, gene sets showing high overlap according to molecular concepts mapping were merged. The rationale for this step was that a high overlap is indicative for comparable biological effects. Heat maps were made to investigate the expression of the individual genes of merged gene sets for all treatment groups. The results of the molecular concepts mapping for all gene sets are shown in Supplementary Fig. 1. The gene sets upregulated by 6-h exposure to 10 mg/kg DON clustered into five themes: lymphocyte activation, inflammatory response, blood cell infiltration, late precursor T cells, and a combination of cell adhesion and cytoskeleton (Supplementary Fig. 1A).