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In migraine, the trigeminal nerve is intimately involved in the pathophysiology of the disease. We hypothesized that alterations in the sensory trigeminal activation in migraine would be reflected by EEG-derived event-related potentials (ERP). We aimed to investigate differences in the temporal and spatial processing of trigeminal stimuli between interictal migraine patients and healthy subjects. ERP to trigeminal stimuli were recorded at 128-channels to allow localization of their cortical sources with high temporal resolution. Seventeen patients with episodic migraine without aura, with episodic migraine with aura, and 17 healthy subjects participated in the study. The first branch of the trigeminal nerve was stimulated using intranasal chemical (CO2), cutaneous electrical, and cutaneous mechanical (air puff) stimuli. Analyses were performed with regard to micro-state segmentation, ERP source localization, and correlation with the patients’ clinical characteristics.Topographical assessments of EEG configurations were associated with the pathological condition. The source analysis revealed altered trigeminal-sensory response patterns in the precuneus, temporal pole, and cerebellum for both migraine groups during the interictal phase. The estimated current source density was positively correlated with migraine disease duration, indicating brain functional and structural changes as a consequence of the disease. Hyperactivity of the cerebellar posterior lobe was observed as a specific trigeminal response of migraine patients with aura. In conclusion, our results suggest the presence of brain changes accompanying the advancement of migraine as an expression of dysfunctional central pain processing. Hence, we identified EEG patterns in response to mechano-/chemosensory stimuli that can serve as biomarkers of migraine.

ZusammenfassungPädagogisch tätige Lai*innen haben an Schulen in den letzten zwei Dekaden an quantitativer Bedeutung gewonnen, weil mit ihnen schulische Ganztagsangebote facettenreich vorgehalten werden können und sich die Fachdiskussion in den letzten Jahren auf die Bedeutung von Schule als zunehmend multiprofessioneller Organisation ausrichtet. Eine differenziertere Betrachtung der Lai*innen erfolgt bislang aber eher zögerlich. Obwohl die Präsenz der Lai*innen in Ganztagsschulen spätestens seit der Erhebungswelle 2009 im Rahmen der Studie zur Entwicklung von Ganztagsschulen (StEG) empirisch belegt ist, werden sie diskursiv weiterhin nur am Rande unter der Globalkategorie weiteres pädagogisch tätiges Personal mitgeführt und als eher unwesentliche Akteur*innengruppe in der Ganztagforschung behandelt. Das hier skizzierte Forschungsvorhaben nimmt das aufgeworfene Forschungsdesiderat zum Ausgangspunkt und hat zum Ziel, die Bedeutung von Lai*innen in der Ganztagsschule wie auch ihre organisationale Einbindung in Schule und ihre pädagogischen Orientierungen in einem Mixed-Methods-Design sowohl quantitativ als auch qualitativ auf den drei Ebenen System, Organisation und Akteur*in zu analysieren und die Ergebnisse in einer explorativen Theorie zu Lai*innen und Laisierung in Schule zu verdichten. Damit wird der Versuch unternommen, das Phänomen der institutionellen Laisierung der Ganztagsschulen über drei Teilstudien multiperspektivisch zu betrachten.

This paper examines four simple stereotypical electricity-sector investments and estimates selected direct and indirect job impacts. To do so, the analysis focuses on the development of a simple Input-Output model and generic financial descriptions of energy efficiency and renewable energy interventions. These are applied to the Tunisian electricity sector. Sensitivities are developed around the assumptions required to calibrate the resulting financial flows. All aspects of this analysis are open source and drawing from ubiquitously available social accounting matrices, with the aim of increasing their scalability and lowering the threshold of energy-economy modelling. This analysis is used to develop intermediate data for a dynamic systems model as well as to produce selected policy insights. They relate to: the payback period associated with energy efficiency investments; local content; capital intensity; and implications on gas (for power generation) imports. Associated with this are policy recommendations that relate to the choice of new power generation, the scheduling of energy efficiency programs and defining future data needs to better calibrate the analysis of those interventions.

This work extends a simple open source energy systems model of the Tunisian electricity sector, used for research purposes. The extension includes addition of job creation multipliers from an Input-Output analysis. Test scenarios are then developed, to assess future emissions and job creation trajectories associated with the introduction of energy efficiency and renewable energy programs. The results indicate that increased economic efficiency associated with significant (but limited) injections of energy efficiency and renewable energy reduce gas imports, reduce emissions and increase local jobs. The analysis is cursory and initial. Its objective is to enhance open modelling that can be developed and co-created for deeper policy analysis.

The COVID-19 pandemic has affected the economy of Tunisia, like that of many other countries. With electricity consumption dropping, consumption patterns changing, international fuel prices oscillating and uncertainty raging, the pandemic has affected not least the planning of investments in electricity supply. Although the government seems unlikely to revise the decarbonisation targets downwards, questions arise on whether the investments planned before the pandemic are still relevant in the changed global landscape and what effects they may have on the country's economy. In this study, we analyse post-pandemic scenarios for the electricity supply system of Tunisia with an energy-economy modelling framework, soft-linking the energy modelling tool OSeMOSYS and an open source Input-Output model. We extract insights on the cost-competitiveness of different – previously planned and new – electricity supply solutions and their impacts on job creation and loss in the entire economy. We find that renewable solutions based on solar photovoltaic remain highly competitive with gas-fired generation under different projections of gas prices and that several low-carbon and energy efficiency solutions have high potential for job creation. We also find that more ambitious investments in renewables and energy efficiency are needed to take Tunisia towards the path of deep decarbonisation.

Energy modelling is the process of using mathematical models to develop abstractions and then seek insights into future energy systems. It can be an abstract academic activity. Or, it can insert threads that influence our development. We argue therefore, that energy modelling that provides policy support (EMoPS) should not only be grounded in rigorous analytics, but also in good governance principles. As, together with other policy actions, it should be accountable. Almost all aspects of society and much of its impact on the environment are influenced by our use of energy. In this context, EMoPS can inspire, motivate, calibrate, and ‘post assess’ energy policy. But, such modeling is often undertaken by too few analysts under time and resource pressure. Building on the advances of ‘class leaders’, we propose that EMoPS should reach for practical goals — including engagement and accountability with the communities it involves, and those it will later affect. (We use the term Ubuntu, meaning ‘I am because you are’ to capture this interdependency). We argue that Ubuntu, together with retrievability, repeatability, reconstructability, interoperability and auditability (U4RIA) of EMoPS should be used to signal the beginnings of a new default practice. We demonstrate how the U4RIA principles can contribute in practice using recent modelling of aspirational energy futures by Costa Rica as a case study. This modelling effort includes community involvement and interfaces and integrates stakeholder involvement. It leaves a trail that allows for its auditing and accountability, while building capacity and sustainable institutional memory.

Hematopoietic stem cells (HSCs) are a rare population of somatic stem cells that have the ability to regenerate the entire mature blood system in a hierarchical way for the duration of an adult life. Adult HSCs reside in the bone marrow niche. Different niche cell types and molecules regulate the balance of HSC dormancy and activation as well as HSC behavior in both normal and malignant hematopoiesis. Here, we describe the interplay of HSCs and their niche, in particular the involvement of the Wnt signaling pathway. Although the prevailing notion has been that malignant transformation of HSCs is the main cause of leukemia, evidence is mounting that disruption of niche regulation by transformed hematopoietic cells, which may overexpress Wnt signaling or intrinsic stromal defects in gene expression, is at least a collaborative factor in leukemogenesis. Thus, insights into the normal and altered functions of niche components will help to obtain a better understanding of normal and malignant hematopoiesis and how environmental factors affect these processes.

Taste and odour (T&O) causing compounds, in particular, 2-methylisoborneol (MIB) and geosmin, are a problem for water authorities as they are recalcitrant to conventional water treatment. In this study, biological sand filtration was shown to be an effective process for the complete removal of MIB and geosmin, with removal shown to be predominantly through biodegradation. In addition, MIB and geosmin were also effectively degraded in batch bioreactor experiments using biofilm sourced from one of the sand filters as the microbial inoculum. The biodegradation of MIB and geosmin was determined to be a pseudo-first-order reaction with rate constants ranging between 0.10 and 0.58 d(-1) in the bioreactor experiments. Rate constants were shown to be dependent upon the initial concentration of the microbial inoculum but not the initial concentration of MIB and geosmin when target concentrations of 200 and 50 ng l(-1) were used. Furthermore, rate constants were shown to increase upon re-exposure of the biofilm to both T&O compounds. Enrichment cultures with subsequent community profile analysis using 16S rRNA-directed PCR-DGGE identified four bacteria most likely involved in the biodegradation of geosmin within the sand filters and bioreactors. These included a Pseudomonas sp., Alphaproteobacterium, Sphingomonas sp. and an Acidobacteriaceae member.

The objective of this study was to describe the cephalometric characteristics of the open bite, and to classify the open bite according to individualized norms. The lateral cephalograms of 134 patients with an anterior open bite (min —0.5 mm) were analyzed. Patients were classified according to the inclination of the jaws, applying the principles of individualized cephalometry. The harmony box described by Hasund [11] was used to define individualized norms for the inclination of the upper and lower jaws in each patient. The open bite was classified into four sub-types: (1) dental, (2) skeletal with enlarged ML-NSL angle, (3) skeletal with reduced ML-NSL angle, and (4) skeletal with deviations in upper and lower jaws. A skeletal open bite was found in 89 patients (66.4%). A dental open bite was found in 45 patients (33.6%). A number of significant differences were found between these four groups using single-factor variance analysis and the Bonferroni a posteriori test, (p ≤ 0.05, p ≤ 0.01, p ≤ 0.001). The most prominent variables were index value of anterior facial hight, total facial height ratio, gonial angle, and Y-axis. No significant differences were found for overbite, however. It was possible to use individualized norms to classify the open bite into four sub-types. The demarcation between the four groups was supported statistically. The extent of the anterior open bite does not allow any conclusions as to the craniofacial pattern.

Hematopoietic stem cells (HSCs) are a rare population of somatic stem cells that have the ability to regenerate the entire mature blood system in a hierarchical way for the duration of an adult life. Adult HSCs reside in the bone marrow niche. Different niche cell types and molecules regulate the balance of HSC dormancy and activation as well as HSC behavior in both normal and malignant hematopoiesis. Here, we describe the interplay of HSCs and their niche, in particular the involvement of the Wnt signaling pathway. Although the prevailing notion has been that malignant transformation of HSCs is the main cause of leukemia, evidence is mounting that disruption of niche regulation by transformed hematopoietic cells, which may overexpress Wnt signaling or intrinsic stromal defects in gene expression, is at least a collaborative factor in leukemogenesis. Thus, insights into the normal and altered functions of niche components will help to obtain a better understanding of normal and malignant hematopoiesis and how environmental factors affect these processes.

Pleiotrophin (Ptn) is strongly expressed by stromal cells which maintain HSCs. However, in vivo, Ptn deficiency does not alter steady-state hematopoiesis. However, knockdown of Ptn (PtnKD) in stromal cells increases production of hematopoietic progenitors as well as HSC activity in cocultures, suggesting that Ptn may have a role in HSC activation. Indeed, transplantations of wild-type (Ptn+/+) HSCs into Ptn−/− mice show increased donor cell production in serial transplantations and dominant myeloid regeneration caused by Ptn-dependent regulation of HSC repopulation behavior. This regulation of Lin−Kit+Sca1+ function is associated with increased proliferation and, on a molecular level, with up-regulated expression of cyclin D1 (Ccnd1) and C/EBPα (Cepba), but reduced of PPARγ. The known HSC regulator β-catenin is, however, not altered in the absence of Ptn. In conclusion, our results point to different Ptn-mediated regulatory mechanisms in normal hemostasis and in hematopoietic regeneration and in maintaining the balance of myeloid and lymphoid regeneration. Moreover, our results support the idea that microenvironmental Ptn regulates hematopoietic regeneration through β-catenin–independent regulation of Ccnd1 and Cebpa.

Recently, mutations of additional sex comb-like 1 (ASXL1) have been identified as an independent poor prognostic factor in MDS patients. We previously demonstrated that C-terminal–truncating ASXL1 mutations (ASXL1-MT) inhibited myeloid differentiation and induced MDS-like disease in mice by inhibiting polycomb repressive complex 2–mediated methylation of histone H3K27. Intriguingly, the patients with ASXL1 mutation have significantly higher incidences of concurrent SET binding protein 1 (SETBP1) mutation than those with wild-type ASXL1, which prompted us to investigate whether SETBP1 mutation plays a critical role in leukemic transformation of MDS. Most SETBP1 mutations, such as D868N, have been shown to occur in the PEST domain of ski homology region, resulting in the prevention from proteasomal degradation. In in vitro experiment, the expression of both SETBP1-D868N and ASXL1-MT enhanced myeloid colony output, reinforced ASXL1-MT-induced differentiation block and inhibited apoptosis. Of note, SETBP1-D868N collaborated with ASXL1-MT in inducing MDS/AML in mice BMT model compared to control mice (0.0001). Using GSEA, we demonstrated that SETBP1-MT enriched hematopoietic stem cells-related genes and deregulated p53 and Myc pathway. In addition, SETBP1-MT inhibited PP2a leading to the activation of the Akt pathway and exhibited characteristic histone modification pattern. In conclusion, our data provide evidence for the role of SETBP1-MT in leukemic transformation and suggest the deregulated pathways as a potential therapeutic target in MDS to prevent disease progression.

Hematopoietic stem cells (HSC) are regulated by an interplay of intrinsic and extrinsic signals, the latter of which are mostly transmitted by the niche. The processes involved and their interactions are largely unknown. We studied the dynamic interaction of HSC and niche stromal cells, using co-cultures of HSC (lineage-negative Sca-1+ c-Kit+: LSK) cells and HSC-maintaining UG26-1B6 stromal cells. Microarray analyses from cells prior to co-culture and cells sorted separately from the cultures revealed that most changes in gene expression take place in the first 24 hours of co-culture. Analyses using STEM clustering, LIMMA, and ToppGene databases showed early activation of cell cycle progression In LSK cells and extensive remodeling of chomatin structure and transcriptional activation in both LSK and stromal cells. Interestingly, connective tissue growth factor (Ctgf/Ccn2), which is involved in TGFb, BMP and Wnt signaling, was strongly upregulated in both stromal and LSK cells. To study the role of Ctgf as a stromal mediator, LSK cells were co-cultured with siCTGF knockdown stromal cells. We showed that although short-term HSC activity was unchanged, siCtgf-stromal cells were unable to sustain long-term repopulating ability. To study underlying mechanisms, a Boolean model simulating possible signaling mechanisms leading to cell cycle activation was extracted from the data. We validated this model by co-cultures of LSK cells with control and Ctgf-knockdown stroma, separating LSK and stromal cells and assessing protein levels and phosphorylation using immunocytofluorescence in LSK cells. We found that in the absence of extrinsic Ctgf, expression of Pten was increased in LSK cells. However, phosphorylation of Akt (both p308, and p473) and Erk was unchanged. In contrast, both canonical Wnt (LRP6, Gsk3b, b-catenin) and Tgfb (Smad2/3) signaling were significantly affected in that Wnt signaling was turned off, whereas Tgf signaling was turned on, by the lack of extrinsic Ctgf. This resulted in a downregulation of G1 transition, as was exemplified by downregulation of Cyclin D1, upregulation of p27Kip1 and modulations in the phosphoryalation of both Rb and p53. Equally interestingly, we could show that extrinsic Ctgf deficiency also downregulates induction of Ctgf in HSC, suggesting the existence of intrinsic-extrinsic feedback signaling. In summary, co-culture of LSK cells with stromal cells results in cellular activation of both stromal cells and LSK cells, involving Tgf and canonical Wnt signaling pathways. Furthermore, reduced expression of extrinsic Ctgf, regulates mediators of G1 cell cycle progression in LSK cells an a biochemical level and functionally results in an increased production of myeloid progenitors and decreased long-term repopulating ability. Our studies show the dynamics of reciprocal signaling between HSC and niche stromal cells and give insights how the niche regulates early regenerative responses in hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

Abstract 2353 Hematopoiesis is maintained throughout life by the constant production of mature blood cells from hematopoietic stem cells (HSC). One mechanism by which the number of HSC is maintained is self-renewal, a cell division in which at least one of the daughter cells is a cell with the same functional potential as the mother cell. The mechanisms of this process are largely unknown. We have described cell lines that maintain self-renewal in culture. To study possible mechanisms and mediators involved in self-renewal, we performed co-cultures of HSC model cells: Lineage-negative Sca-1+ c-Kit+ (LSK) cells and HSC maintaining UG26–1B6 stromal cells. Microarray analyses were performed on cells prior to co-culture and cells sorted from the cultures. STEM clustering analysis of the data revealed that most changes in gene expression were due to early cell activation. Functional enrichment analysis revealed dynamic changes in focal adhesion and mTOR signaling, as well as changes in epigenetic regulators, such as HDAC in stromal cells. In LSK cells, genes whose products are involved in inflammation, Oxygen homeostasis and metabolism were differentially expressed after the co-culture. In addition, genes involved in the regulaton of H3K27 methylation were also affected. Interestingly, connective tissue growth factor (CTGF), which is involved in TGF-b, BMP and Wnt signaling, was upregulated in both stromal and LSK cells in the first day of co-culture. To study a possible extrinsic role of CTGF as a stromal mediator, we co-cultured siCTGF knockdown stromal cells with wild-type LSK cells. Since self-renewal requires cell division, we focused on cell cycle regulation of LSK cells. We found that knockdown of CTGF in stromal cells downregulates CTGF in LSK cells. In addition, knockdown of stromal CTGF downregulated Ccnd1, Cdk2, Cdkn1a (p21), Ep300 and Fos. On the other hand, decreased CTGF in stromal cells upregulates Cdkn1b (p27) and phosphorylation of Smad2/3. These results show that stromal CTGF regulates the cell cycle of LSK cells. On a functional level, we found that decreased stromal CTGF results in an increased production of MPP and myeloid colony-forming cells in 1-week co-cultures. We will present data showing whether and how a decrease in CTGF in stromal cells affects the maintenance of transplantable HSC. In summary, our current results indicate that reduced expression of CTGF in stromal cells regulates mediators of cell cycle and Smad2/3-mediated signaling in LSK cells, resulting in an increased production of myeloid progenitors. Disclosures: No relevant conflicts of interest to declare.