Parameter Optimisation of a Virtual Synchronous Machine in a Microgrid

Parameters of a virtual synchronous machine in a small microgrid are optimised. The dynamical behaviour of the system is simulated after a perturbation, where the system needs to return to its steady state. The cost functional evaluates the system behaviour for different parameters. This functional is minimised by Parallel Tempering. Two perturbation scenarios are investigated and the resulting optimal parameters agree with analytical predictions. Dependent on the focus of the optimisation different optima are obtained for each perturbation scenario. During the transient the system leaves the allowed voltage and frequency bands only for a short time if the perturbation is within a certain range.Comment: 17 pages, 5 figure

Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment

Despite of multitude investigations no reliable prognostic immunohistochemical biomarkers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy. 320 primary tumor samples with available tumor tissue were immunohistochemically analyzed prior to treatment for the expression of cell cycle regulators and apoptosis modulators cyclin D1, p21, p16, CDK4, E2F1, MDM2, p53 and p-RB1. TP53 mutational analysis was possible in 245 cases. A high expression of CDK4 was observed in 32.8% of all cases and was associated with a favorable recurrence free survival (RFS), whereas high expression of MDM2 (12.2%) or p53 (35.3%) was associated with a shorter RFS. These results were independent from the primary KIT or PDGFRA mutation. In GISTs with higher mitotic counts was a significantly increased expression of cyclin D1, p53 and E2F1. The expression of p16 and E2F1 significantly correlated to a non-gastric localization. Furthermore, we observed a significant higher expression of p21 and E2F1 in KIT mutant GISTs compared to PDGFRA mutant and wt GISTs. The overall frequency of TP53 mutations was low (n = 8; 3.5%) and could not be predicted by the immunohistochemical expression of p53. In summary, mutation analysis in TP53 plays a minor role in the subgroup of high-risk GIST before adjuvant treatment with imatinib. Strong expression of MDM2 and p53 correlated with a shorter recurrence free survival, whereas a strong expression of CDK4 correlated to a better recurrence free survival.Peer reviewe

Elucidating different pattern of immunoregulation in BALB/c and C57BL/6 mice and their F1 progeny

© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .Helminths are large multicellular parasites that infect one quarter of the human population. To prolong their survival, helminths suppress the immune responses of their hosts. Strongyloides ratti delays its expulsion from the gut by induction of regulatory circuits in a mouse strain-specific manner: depletion of Foxp3+ regulatory T cells (Treg) improves the anti-S. ratti immunity in BALB/c but not in C57BL/6 mice. In the current study we compare the hierarchy of immunoregulatory pathways in BALB/c, C57BL/6 mice and their F1 progeny (BALB/c × C57BL/6). Using multicolor flow cytometry, we show that S. ratti induces a distinct pattern of inhibitory checkpoint receptors by Foxp3+ Treg and Foxp3- T cells. Intensity of expression was highest in C57BL/6 and lowest in BALB/c mice, while the F1 cross had an intermediate phenotype or resembled BALB/c mice. Treg subsets expanded during infection in all three mouse strains. Similar to BALB/c mice, depletion of Treg reduced intestinal parasite burden and increased mucosal mast cell activation in S. ratti-infected F1 mice. Our data indicate that Treg dominate the regulation of immune responses in BALB/c and F1 mice, while multiple regulatory layers exist in C57BL/6 mice that may compensate for the absence of Treg.Open Access funding enabled and organized by Projekt DEAL.info:eu-repo/semantics/publishedVersio

IL-33 facilitates rapid expulsion of the parasitic nematode <i>Strongyloides ratti</i> from the intestine via ILC2- and IL-9-driven mast cell activation

Parasitic helminths are sensed by the immune system via tissue-derived alarmins that promote the initiation of the appropriate type 2 immune responses. Here we establish the nuclear alarmin cytokine IL-33 as a non-redundant trigger of specifically IL-9-driven and mast cell-mediated immunity to the intestinal parasite Strongyloides ratti. Blockade of endogenous IL-33 using a helminth-derived IL-33 inhibitor elevated intestinal parasite burdens in the context of reduced mast cell activation while stabilization of endogenous IL-33 or application of recombinant IL-33 reciprocally reduced intestinal parasite burdens and increased mast cell activation. Using gene-deficient mice, we show that application of IL-33 triggered rapid mast cell-mediated expulsion of parasites directly in the intestine, independent of the adaptive immune system, basophils, eosinophils or Gr-1+ cells but dependent on functional IL-9 receptor and innate lymphoid cells (ILC). Thereby we connect the described axis of IL-33-mediated ILC2 expansion to the rapid initiation of IL-9-mediated and mast cell-driven intestinal anti-helminth immunity

Schlussbericht zum Vorhaben

Reaktiver Stickstoff (Nr) umfasst alle im Stickstoffkreislauf vorkommenden stickstoffhaltigen Verbindungen mit Ausnahme von molekularem Stickstoff (N2). Besonders umweltrelevant sind das starke Treibhausgas (THG) Lachgas (N2O), der Vorläufer des gesundheitsschädlichen Ozons (Stickstoffmonoxid, NO), sowie verflüchtigtes Ammoniak (NH3) und gelöstes Nitrat (NO3). Diese Verbindungen tragen zur Erderwärmung, Eutrophierung und Beeinträchtigung der Biodiversität bei. Die Freisetzung von Nr wurde durch den Einsatz von Düngern in der landwirtschaftlichen Produktion immens verstärkt, insbesondere dadurch, dass ca. 77 kg mehr Stickstoff (N) in landwirtschaftliche Systeme eingebracht wird, als durch die Ernte wieder entnommen wird (Eurostat, 2017). Diese Situation im landwirtschaftlichen Betrieb ist unter anderem eine Konsequenz der Applikation großer Düngermengen zu wenigen Ausbringungsterminen, da während eines temporären NÜberschusses N ausgewaschen oder in Form von N2O, N2 oder NH3 aus dem landwirtschaftlichen System ausgetragen werden kann. Während in der Vergangenheit die genannten Verluste durch verbesserte Wahl der Ausbringungsmenge und des Ausbringungstermins erzielt wurden, können auch andere Faktoren eine Rolle spielen. Ein wichtiger Aspekt wie ausgebrachter Nr im Boden gehalten werden kann, ist die Immobilisierung durch Mikroorganismen, da diese ausgebrachten Nr zwar in organische Bodensubstanz überfuhren, aber über die Mineralisierung wieder für Pflanzen verfügbar wird. Die mikrobiellen Prozesse Mineralisierung und Immobilisierung hängen unter anderem von der mikrobiellen Biomasse im Boden und dem Bodenkohlenstoffgehalt ab, sodass Anbausysteme, die den Humusaufbau fördern, potentiell Nr-Verluste aus landwirtschaftlichen Flächen reduzieren können. In diesem Zusammenhang sind Anbausysteme mit organischer Düngung oder Leguminosen in der Fruchtfolge vielversprechende Kandidaten, da diese das Potential haben, Humus aufzubauen. Datei-Upload durch TI

Impairment of LTD and cerebellar learning by Purkinje cell–specific ablation of cGMP-dependent protein kinase I

The molecular basis for cerebellar plasticity and motor learning remains controversial. Cerebellar Purkinje cells (PCs) contain a high concentration of cGMP-dependent protein kinase type I (cGKI). To investigate the function of cGKI in long-term depression (LTD) and cerebellar learning, we have generated conditional knockout mice lacking cGKI selectively in PCs. These cGKI mutants had a normal cerebellar morphology and intact synaptic calcium signaling, but strongly reduced LTD. Interestingly, no defects in general behavior and motor performance could be detected in the LTD-deficient mice, but the mutants exhibited an impaired adaptation of the vestibulo-ocular reflex (VOR). These results indicate that cGKI in PCs is dispensable for general motor coordination, but that it is required for cerebellar LTD and specific forms of motor learning, namely the adaptation of the VOR

Evolution of sex-specific pace-of-life syndromes: genetic architecture and physiological mechanisms

Sex differences in life history, physiology, and behavior are nearly ubiquitous across taxa, owing to sex-specific selection that arises from different reproductive strategies of the sexes. The pace-of-life syndrome (POLS) hypothesis predicts that most variation in such traits among individuals, populations, and species falls along a slow-fast pace-of-life continuum. As a result of their different reproductive roles and environment, the sexes also commonly differ in pace-of-life, with important consequences for the evolution of POLS. Here, we outline mechanisms for how males and females can evolve differences in POLS traits and in how such traits can covary differently despite constraints resulting from a shared genome. We review the current knowledge of the genetic basis of POLS traits and suggest candidate genes and pathways for future studies. Pleiotropic effects may govern many of the genetic correlations, but little is still known about the mechanisms involved in trade-offs between current and future reproduction and their integration with behavioral variation. We highlight the importance of metabolic and hormonal pathways in mediating sex differences in POLS traits; however, there is still a shortage of studies that test for sex specificity in molecular effects and their evolutionary causes. Considering whether and how sexual dimorphism evolves in POLS traits provides a more holistic framework to understand how behavioral variation is integrated with life histories and physiology, and we call for studies that focus on examining the sex-specific genetic architecture of this integration

Sunitinib Inhibits Cell Proliferation and Alters Steroidogenesis by Down-Regulation of HSD3B2 in Adrenocortical Carcinoma Cells

The multi-tyrosine kinase inhibitor sunitinib is used in the treatment of several solid tumors. Animal experiments pointed to an adrenotoxic effect of sunitinib. Therefore, we evaluated the expression of key targets of sunitinib in human adrenocortical carcinoma (ACC) tumor samples and investigated its in vitro effects in ACC cell lines. We carried out immunohistochemistry for vascular endothelial growth factor (VEGF) and its receptor (VEGF-R2) in 157 ACC samples and nine normal adrenal glands. VEGF and VEGF-R2 protein were expressed in 72 and 99% of ACC samples, respectively. Using NCI-H295 and SW13 ACC cell lines, we investigated the effects of sunitinib on cell proliferation. Sunitinib reduced dose-dependently cell viability of both NCI-H295 and SW13 cells (SW13: 0.1 μM 96 ± 7%, 1 μM 90 ± 9%*, 5 μM 62 ± 6%*, controls 100 ± 9%; *p < 0.05). To determine sunitinib effects on steroidogenesis, we measured steroid hormones in cell culture supernatant by gas chromatography–mass spectrometry. We observed a pronounced decrease of cortisol secretion (1 μM 90.1 ± 1.5%*, 5 μM 57.2 ± 0.3%*, controls 100 ± 2.4%) and a concomitant increase in the DHEA/4-androstenedione and 17-hydroxypregnenolone/17-hydroxyprogesterone ratios, indicating specific inhibition of 3β-hydroxysteroid dehydrogenase (HSD3B2). In yeast microsomes transformed with HSD3B2, no direct inhibition of HSD3B2 by sunitinib was detected. Sunitinib induced down-regulation of HSD3B2 mRNA and protein in ACC cell lines (mRNA: 1 μM 44 ± 16%*; 5 μM 22 ± 2%*; 10 μM 19 ± 4%*; protein: 1 μM 82 ± 8%; 5 μM 63 ± 8%*; 10 μM 55 ± 9%*). CYP11B1 was down-regulated at mRNA but not at protein level and CYP11A1 remained unchanged. In conclusion, target molecules of sunitinib are expressed in the vast majority of ACC samples. Sunitinib exhibits anti-proliferative effects in vitro, and appears to specifically block adrenal steroidogenesis by down-regulation of HSD3B2, rendering it a promising option for treatment of ACC

Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites.

Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s toward the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections