A Systematic Approach to Model Objectives in Predevelopment Projects

This contribution presents a systematic for the elicitation of objectives and the utilization of objectives to identify reference products. The systematic is based on existing meta models. The model of objectives as proposed in this research eases decision-making and outlines the next validation activities. A key success factor is the project transferability between teams, which is often necessary in predevelopment. This is ensured through comprehensibility of objectives which benefits from the linkage between the model of objectives and the knowledge base. The proposed systematic is applied to a predevelopment project which is used as case study. In the case study it has been shown that objectives can be used to identify reference products. The approach is validated in a live-lab setting with seven engineering teams with six graduate students, two engineers of an industrial partner and a research associate. Several workshops were used to train all members of the teams in the systematic. The effects of the systematic are assessed in dedicated interviews, a survey as well as with observation of the engineering teams during milestones and engineering activities between milestones

DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells

Within 2–3 months of in vitro culture-expansion, mesenchymal stromal cells (MSC) undergo replicative senescence characterized by cell enlargement, loss of differentiation potential and ultimate growth arrest. In this study, we have analyzed DNA methylation changes upon long-term culture of MSC by using the HumanMethylation27 BeadChip microarray assessing 27 578 unique CpG sites. Furthermore, we have compared MSC from young and elderly donors. Overall, methylation patterns were maintained throughout both long-term culture and aging but highly significant differences were observed at specific CpG sites. Many of these differences were observed in homeobox genes and genes involved in cell differentiation. Methylation changes were verified by pyrosequencing after bisulfite conversion and compared to gene expression data. Notably, methylation changes in MSC were overlapping in long-term culture and aging in vivo. This supports the notion that replicative senescence and aging represent developmental processes that are regulated by specific epigenetic modifications

Inhibitory framing in hypersexual patients with Parkinson's disease. An fMRI pilot study

Hypersexuality in medicated patients with PD is caused by an increased influence of motivational drive areas and a decreased influence of inhibitory control areas due to dopaminergic medication. In this pilot study, we test a newly developed paradigm investigating the influence of dopaminergic medication on brain activation elicited by sexual pictures with and without inhibitory contextual framing. Twenty PD patients with and without hypersexuality were examined with fMRI either OFF or ON standardized dopaminergic medication. The paradigm consisted of a priming phase where either a neutral context or an inhibitory context was presented. This priming phase was either followed by a sexual or a neutral target. Sexual, compared to neutral pictures resulted in a BOLD activation of various brain regions implicated in sexual processing. Hypersexual PD patients showed increased activity compared to PD controls in these regions. There was no relevant effect of medication between the two groups. The inhibitory context elicited less activation in inhibition-related areas in hypersexual PD, but had no influence on the perception of sexual cues. The paradigm partially worked: reactivity of motivational brain areas to sexual cues was increased in hypersexual PD and inhibitory contextual framing lead to decreased activation of inhibitory control areas in PD. We could not find a medication effect and the length of the inhibitory stimulus was not optimal to suppress reactivity to sexual cues. Our data provide new insights into the mechanisms of hypersexuality and warrant a replication with a greater cohort and an optimized stimulus length in the future

Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis

Objectives: MicroRNAs (miRNAs) have been implicated in the pathogenesis of autoimmune diseases, not least for their critical role in the regulation of regulatory T cell (Treg) function. Deregulated expression of miR-146a and miR-155 has been associated with rheumatoid arthritis (RA). We therefore investigated miR-146a and miR-155 expression in Tregs of patients with RA and their possible impact on Treg function and disease activity. Methods: Expression of miR-146a and miR-155 was assessed in RA patients and controls. MiRNA expression was correlated with disease activity and expression of target genes. Interference with biological activity of miRNAs was evaluated in functional Treg assays. Results: Diminished upregulation of miR-146a and miR-155 in response to T cell stimulation was found in Tregs of RA patients. Diminution of miR-146a expression was observed in particular in patients with active disease, and correlated with joint inflammation. In patients with active RA, Tregs demonstrated a pro-inflammatory phenotype characterised by inflammatory cytokine expression. This was due to an augmented expression and activation of signal transducer and activator transcription 1 (STAT1), a direct target of miR-146a. Conclusions: Our results suggest that in RA miR-146a facilitates a pro-inflammatory phenotype of Tregs via increased STAT1 activation, and contributes thereby to RA pathogenesis

DNA methylation-based classification of ependymomas in adulthood: implications for diagnosis and treatment

Background Ependymal tumors are glial tumors that commonly manifest in children and young adults. Their classification has remained entirely morphological until recently, and surgery and radiotherapy are the main treatment options, especially in adults. Here we sought to correlate DNA methylation profiles with clinical and pathological characteristics in the prospective cohort of the German Glioma Network. Methods Tumors from 122 adult patients with myxopapillary ependymoma, ependymoma, anaplastic ependymoma, subependymoma or RELA fusion-positive ependymoma classified according to the World Heath Organization classification (WHO) 2016 were subjected to DNA methylation profiling using the Illumina HumanMethylation450 BeadChip platform. Molecular data were correlated with histologic features and clinical characteristics. Results At a median follow-up of 86.7 months, only 22 patients experienced progression (18.0%) and 13 patients (10.7%) died. Each tumor could be assigned to one of the previously defined molecular ependymoma subgroups. All histologic subependymomas corresponded to subependymoma (SE) DNA methylation subgroups, but the reverse was not true: 19 histologic ependymomas (WHO grade II) were allocated to molecular SE groups. Similarly, all histological myxopapillary ependymomas were assigned to the molecularly defined SP-MPE class, but this molecular subgroup additionally included 15 WHO grade II ependymomas by histology. Overall, WHO grade II ependymomas distributed into seven molecular subgroups. Conclusions Most adult patients with ependymoma show a favorable prognosis. Molecular classification may provide diagnostic and prognostic information beyond histology and facilitate patient stratification in future clinical trials. The prognostic significance of a subependymoma or myxopapillary ependymoma DNA methylation phenotype without according histology requires further study